Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer's disease. de Flores Robin,Wisse Laura E M,Das Sandhitsu R,Xie Long,McMillan Corey T,Trojanowski John Q,Robinson John L,Grossman Murray,Lee Edward,Irwin David J,Yushkevich Paul A,Wolk David A Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). METHODS:We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aβ, and α-synuclein measured in post-mortem tissue from 92 individuals with intermediate to high AD neuropathology. Receiver-operating characteristic (ROC) curves were analyzed for each subregion in order to discriminate TDP-43-negative and TDP-43-positive patients. RESULTS:TDP-43 was strongly associated with anterior MTL regions, whereas tau was relatively more associated with the posterior hippocampus. Among the MTL regions, the anterior hippocampus showed the highest area under the ROC curve (AUC). DISCUSSION:We found specific contributions of different pathologies on MTL substructure in this population with AD neuropathology. The anterior hippocampus may be a relevant region to detect concomitant TDP-43 pathology in the MTL of patients with AD. 10.1002/alz.12079
    Copper and Zinc Dysregulation in Alzheimer's Disease. Sensi Stefano L,Granzotto Alberto,Siotto Mariacristina,Squitti Rosanna Trends in pharmacological sciences Alzheimer's disease (AD) is one of the most common forms of dementia. Despite a wealth of knowledge on the molecular mechanisms involved in AD, current treatments have mainly focused on targeting amyloid β (Aβ) production, but have failed to show significant effects and efficacy. Therefore, a critical reconsideration of the multifactorial nature of the disease is needed. AD is a complex multifactorial disorder in which, along with Aβ and tau, the convergence of polygenic, epigenetic, environmental, vascular, and metabolic factors increases the global susceptibility to the disease and shapes its course. One of the cofactors converging on AD is the dysregulation of brain metals. In this review, we focus on the role of AD-related neurodegeneration and cognitive decline triggered by the imbalance of two endogenous metals: copper and zinc. 10.1016/j.tips.2018.10.001
    Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing. Chhatwal Jasmeer P,Schultz Aaron P,Johnson Keith A,Hedden Trey,Jaimes Sehily,Benzinger Tammie L S,Jack Clifford,Ances Beau M,Ringman John M,Marcus Daniel S,Ghetti Bernardino,Farlow Martin R,Danek Adrian,Levin Johannes,Yakushev Igor,Laske Christoph,Koeppe Robert A,Galasko Douglas R,Xiong Chengjie,Masters Colin L,Schofield Peter R,Kinnunen Kirsi M,Salloway Stephen,Martins Ralph N,McDade Eric,Cairns Nigel J,Buckles Virginia D,Morris John C,Bateman Randall,Sperling Reisa A, Brain : a journal of neurology Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks. 10.1093/brain/awy053
    Genetic data and cognitively defined late-onset Alzheimer's disease subgroups. Mukherjee Shubhabrata,Mez Jesse,Trittschuh Emily H,Saykin Andrew J,Gibbons Laura E,Fardo David W,Wessels Madeline,Bauman Julianna,Moore Mackenzie,Choi Seo-Eun,Gross Alden L,Rich Joanne,Louden Diana K N,Sanders R Elizabeth,Grabowski Thomas J,Bird Thomas D,McCurry Susan M,Snitz Beth E,Kamboh M Ilyas,Lopez Oscar L,De Jager Philip L,Bennett David A,Keene C Dirk,Larson Eric B, , , , , , ,Crane Paul K Molecular psychiatry Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10 and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci. 10.1038/s41380-018-0298-8
    Retinal changes in Alzheimer's disease- integrated prospects of imaging, functional and molecular advances. Gupta Veer B,Chitranshi Nitin,den Haan Jurre,Mirzaei Mehdi,You Yuyi,Lim Jeremiah Kh,Basavarajappa Devaraj,Godinez Angela,Di Angelantonio Silvia,Sachdev Perminder,Salekdeh Ghasem H,Bouwman Femke,Graham Stuart,Gupta Vivek Progress in retinal and eye research Alzheimer's Disease (AD) is a devastating neurodegenerative disorder of the brain, clinically characterised by cognitive deficits that gradually worsen over time. There is, at present, no established cure, or disease-modifying treatments for AD. As life expectancy increases globally, the number of individuals suffering from the disease is projected to increase substantially. Cumulative evidence indicates that AD neuropathological process is initiated several years, if not decades, before clinical signs are evident in patients, and diagnosis made. While several imaging, cognitive, CSF and blood-based biomarkers have been proposed for the early detection of AD; their sensitivity and specificity in the symptomatic stages is highly variable and it is difficult to justify their use in even earlier, pre-clinical stages of the disease. Research has identified potentially measurable functional, structural, metabolic and vascular changes in the retina during early stages of AD. Retina offers a distinctively accessible insight into brain pathology and current and developing ophthalmic technologies have provided us with the possibility of detecting and characterising subtle, disease-related changes. Recent human and animal model studies have further provided mechanistic insights into the biochemical pathways that are altered in the retina in disease, including amyloid and tau deposition. This information coupled with advances in molecular imaging has allowed attempts to monitor biochemical changes and protein aggregation pathology in the retina in AD. This review summarises the existing knowledge that informs our understanding of the impact of AD on the retina and highlights some of the gaps that need to be addressed. Future research will integrate molecular imaging innovation with functional and structural changes to enhance our knowledge of the AD pathophysiological mechanisms and establish the utility of monitoring retinal changes as a potential biomarker for AD. 10.1016/j.preteyeres.2020.100899
    Chiral gold nanoparticles enantioselectively rescue memory deficits in a mouse model of Alzheimer's disease. Hou Ke,Zhao Jing,Wang Hui,Li Bin,Li Kexin,Shi Xinghua,Wan Kaiwei,Ai Jing,Lv Jiawei,Wang Dawei,Huang Qunxing,Wang Huayi,Cao Qin,Liu Shaoqin,Tang Zhiyong Nature communications Preventing aggregation of amyloid beta (Aβ) peptides is a promising strategy for the treatment of Alzheimer's disease (AD), and gold nanoparticles have previously been explored as a potential anti-Aβ therapeutics. Here we design and prepare 3.3 nm L- and D-glutathione stabilized gold nanoparticles (denoted as L3.3 and D3.3, respectively). Both chiral nanoparticles are able to inhibit aggregation of Aβ42 and cross the blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses a larger binding affinity to Aβ42 and higher brain biodistribution compared with its enantiomer L3.3, giving rise to stronger inhibition of Aβ42 fibrillation and better rescue of behavioral impairments in AD model mice. This conjugation of a small nanoparticle with chiral recognition moiety provides a potential therapeutic approach for AD. 10.1038/s41467-020-18525-2
    Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a "gray zone"? McRae-McKee Kevin,Udeh-Momoh Chinedu T,Price Geraint,Bajaj Sumali,de Jager Celeste A,Scott David,Hadjichrysanthou Christoforos,McNaughton Emily,Bracoud Luc,Ahmadi-Abhari Sara,de Wolf Frank,Anderson Roy M,Middleton Lefkos T, Alzheimer's & dementia : the journal of the Alzheimer's Association The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be. 10.1016/j.jalz.2019.07.010
    Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease. Vöglein Jonathan,Paumier Katrina,Jucker Mathias,Preische Oliver,McDade Eric,Hassenstab Jason,Benzinger Tammie L,Noble James M,Berman Sarah B,Graff-Radford Neill R,Ghetti Bernardino,Farlow Martin R,Chhatwal Jasmeer,Salloway Stephen,Xiong Chengjie,Karch Celeste M,Cairns Nigel,Mori Hiroshi,Schofield Peter R,Masters Colin L,Goate Alison,Buckles Virginia,Fox Nick,Rossor Martin,Chrem Patricio,Allegri Ricardo,Ringman John M,Höglinger Günter,Steiner Harald,Dieterich Marianne,Haass Christian,Laske Christoph,Morris John C,Bateman Randall J,Danek Adrian,Levin Johannes, Brain : a journal of neurology Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier. 10.1093/brain/awz050
    Regional differences in Alzheimer's disease pathology confound behavioural rescue after amyloid-β attenuation. Morrone Christopher D,Bazzigaluppi Paolo,Beckett Tina L,Hill Mary E,Koletar Margaret M,Stefanovic Bojana,McLaurin JoAnne Brain : a journal of neurology Failure of Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression. 10.1093/brain/awz371
    Extracellular vesicle biomarkers of Alzheimer's disease associated with sub-clinical cognitive decline in late middle age. Eren Erden,Hunt Jack F V,Shardell Michelle,Chawla Sahil,Tran Joyce,Gu Jeffrey,Vogt Nick M,Johnson Sterling C,Bendlin Barbara B,Kapogiannis Dimitrios Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age-associated cognitive decline. METHODS:This case-control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change. RESULTS:Declining compared to stable individuals showed higher baseline total, p231-, and p181-tau with older age and higher annualized change for p-IR and p-IGF-1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively. DISCUSSION:Combining nEV biomarkers can identify individuals with age-associated cognitive decline. 10.1002/alz.12130
    The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: Application to clinical trials. Cummings Jeffrey Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:The National Institute on Aging-Alzheimer's Association Research Framework on Alzheimer's disease (AD) represents an important advance in the biological characterization of the AD spectrum. METHODS:The National Institute on Aging-Alzheimer's Association Framework is considered as it applies to clinical trials. RESULTS:Using the combination of amyloid (A), tau (T), and neurodegeneration (N) biomarkers, the Framework provides a means of defining the state of patients with regard to Alzheimer pathologic change. The Framework is relevant to clinical trials of disease-modifying agents, allowing participants to be characterized biologically at baseline. The ATN Framework can also inform trial outcomes. The preclinical phase of the disease after amyloid deposition is defined by A+T-N-, and the transition to prodromal disease and dementia is characterized by the addition of T and N. Most symptomatic patients in clinical trials are in the class of A+T+N- and A+T+N+. DISCUSSION:The National Institute on Aging-Alzheimer's Association Framework on AD represents progress in providing biomarker profiles of participants in the AD spectrum that can be used to help design clinical trials. 10.1016/j.jalz.2018.05.006
    A nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis. Latimer Caitlin S,Shively Carol A,Keene C Dirk,Jorgensen Matthew J,Andrews Rachel N,Register Thomas C,Montine Thomas J,Wilson Angela M,Neth Bryan J,Mintz Akiva,Maldjian Joseph A,Whitlow Christopher T,Kaplan Jay R,Craft Suzanne Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Nonhuman primates may serve as excellent models of sporadic age-associated brain β-amyloid deposition and Alzheimer's disease pathologic changes. We examined whether a vervet nonhuman primate model recapitulated pathologic, physiologic, and behavioral features of early Alzheimer's disease. METHODS:Nine middle-aged (mean = 11.2 years) and nine aged (mean = 21.7 years) female vervet/African green monkeys underwent cerebrospinal fluid collection, gait speed measurement, and neuroimaging before neuropathologic assessment. RESULTS:β-amyloid plaques were identified in all aged vervets and paired helical filament tau immunoreactivity was observed in all animals. Cerebrospinal fluid β-amyloid and gait speed correlated negatively with age and plaque density. Greater plaque and paired helical filament tau burden predicted reduced volumes and CMRg in several brain regions. DISCUSSION:We observed a coordinated set of relationships among neuropathologic, cerebrospinal fluid, imaging, and behavioral modalities consistent with early Alzheimer's disease. Our results support future use of the vervet model to explore disease mechanisms, biomarkers, and novel therapeutic strategies. 10.1016/j.jalz.2018.06.3057
    Clinical and cortical decline in the aphasic variant of Alzheimer's disease. Rogalski Emily Joy,Sridhar Jaiashre,Martersteck Adam,Rader Benjamin,Cobia Derin,Arora Anupa K,Fought Angela J,Bigio Eileen H,Weintraub Sandra,Mesulam Marek-Marsel,Rademaker Alfred Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Primary progressive aphasia (PPA) displays variable progression trajectories that require further elucidation. METHODS:Longitudinal quantitation of atrophy and language over 12 months was completed for PPA patients with and without positive amyloid PET (PPA and PPA), an imaging biomarker of underlying Alzheimer's disease. RESULTS:Over 12 months, both PPA groups showed significantly greater cortical atrophy rates in the left versus right hemisphere, with a more widespread pattern in PPA. The PPA group also showed greater decline in performance on most language tasks. There was no obligatory relationship between the logopenic PPA variant and amyloid status. Effect sizes from quantitative MRI data were more robust than neuropsychological metrics. DISCUSSION:Preferential language network neurodegeneration is present in PPA irrespective of amyloid status. Clinical and anatomical progression appears to differ for PPA due to Alzheimer's disease versus non-Alzheimer's disease neuropathology, a distinction that may help to inform prognosis and the design of intervention trials. 10.1016/j.jalz.2018.12.003
    Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus. Reeves Benjamin C,Karimy Jason K,Kundishora Adam J,Mestre Humberto,Cerci H Mert,Matouk Charles,Alper Seth L,Lundgaard Iben,Nedergaard Maiken,Kahle Kristopher T Trends in molecular medicine Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-β (Aβ) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia-lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics. 10.1016/j.molmed.2019.11.008
    Memory trace interference impairs recall in a mouse model of Alzheimer's disease. Poll Stefanie,Mittag Manuel,Musacchio Fabrizio,Justus Lena C,Giovannetti Eleonora Ambrad,Steffen Julia,Wagner Jens,Zohren Lioba,Schoch Susanne,Schmidt Boris,Jackson Walker S,Ehninger Dan,Fuhrmann Martin Nature neuroscience In Alzheimer's disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD. 10.1038/s41593-020-0652-4
    Retinal imaging in Alzheimer's and neurodegenerative diseases. Snyder Peter J,Alber Jessica,Alt Clemens,Bain Lisa J,Bouma Brett E,Bouwman Femke H,DeBuc Delia Cabrera,Campbell Melanie C W,Carrillo Maria C,Chew Emily Y,Cordeiro M Francesca,Dueñas Michael R,Fernández Brian M,Koronyo-Hamaoui Maya,La Morgia Chiara,Carare Roxana O',Sadda Srinivas R,van Wijngaarden Peter,Snyder Heather M Alzheimer's & dementia : the journal of the Alzheimer's Association In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study. 10.1002/alz.12179
    Differential expression of microRNAs in Alzheimer's disease brain, blood, and cerebrospinal fluid. Takousis Petros,Sadlon Angélique,Schulz Jessica,Wohlers Inken,Dobricic Valerija,Middleton Lefkos,Lill Christina M,Perneczky Robert,Bertram Lars Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive. METHODS:A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty. RESULTS:Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles. DISCUSSION:Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance. 10.1016/j.jalz.2019.06.4952
    Profound degeneration of wake-promoting neurons in Alzheimer's disease. Oh Jun,Eser Rana A,Ehrenberg Alexander J,Morales Dulce,Petersen Cathrine,Kudlacek Jessica,Dunlop Sara R,Theofilas Panos,Resende Elisa D P F,Cosme Celica,Alho Eduardo J L,Spina Salvatore,Walsh Christine M,Miller Bruce L,Seeley William W,Bittencourt Jackson C,Neylan Thomas C,Heinsen Helmut,Grinberg Lea T Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Sleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. METHODS:We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. RESULTS:The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. DISCUSSION:WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP. 10.1016/j.jalz.2019.06.3916
    Mitochondria and Calcium in Alzheimer's Disease: From Cell Signaling to Neuronal Cell Death. Calvo-Rodriguez Maria,Bacskai Brian J Trends in neurosciences Mitochondrial dysfunction has been implicated in the pathogenesis of almost all neurological diseases, including Alzheimer's disease (AD). Historically, a primary focus in this context has been the link between mitochondrial dynamics and amyloid β toxicity. Recent evidence suggests that dysregulation of mitochondrial calcium homeostasis is also related to tau and other risk factors in AD, although an ongoing challenge in the field is that data collected from different models or experimental settings have not always been consistent. We examine recent literature on mitochondrial dysregulation in AD, with special emphasis on mitochondrial calcium. We include data from in vitro systems, genetic animal models, and AD-derived human tissue, and discuss whether mitochondrial calcium transporters should be proposed as therapeutic candidates for the development of neuroprotective drugs against AD. 10.1016/j.tins.2020.10.004
    Shared genetic etiology underlying late-onset Alzheimer's disease and posttraumatic stress syndrome. Lutz Michael W,Luo Sheng,Williamson Douglas E,Chiba-Falek Ornit Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies. METHODS:We performed genetic pleiotropy analysis using LOAD and PTSD genome-wide association study (GWAS) datasets from white and African-American populations, followed by functional-genomic analyses. RESULTS:We found an enrichment for LOAD across increasingly stringent levels of significance with the PTSD GWAS association (LOAD|PTSD) in the discovery and replication cohorts and a modest enrichment for the reverse conditional association (PTSD|LOAD). LOAD|PTSD association analysis identified and replicated the MS4A genes region. These genes showed similar expression pattern in brain regions affected in LOAD, and across-brain-tissue analysis identified a significant association for MS4A6A. The African-American samples showed moderate enrichment; however, no false discovery rate-significant associations. DISCUSSION:We demonstrated common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases. 10.1002/alz.12128
    Subjective cognitive decline and rates of incident Alzheimer's disease and non-Alzheimer's disease dementia. Slot Rosalinde E R,Sikkes Sietske A M,Berkhof Johannes,Brodaty Henry,Buckley Rachel,Cavedo Enrica,Dardiotis Efthimios,Guillo-Benarous Francoise,Hampel Harald,Kochan Nicole A,Lista Simone,Luck Tobias,Maruff Paul,Molinuevo José Luis,Kornhuber Johannes,Reisberg Barry,Riedel-Heller Steffi G,Risacher Shannon L,Roehr Susanne,Sachdev Perminder S,Scarmeas Nikolaos,Scheltens Philip,Shulman Melanie B,Saykin Andrew J,Verfaillie Sander C J,Visser Pieter Jelle,Vos Stephanie J B,Wagner Michael,Wolfsgruber Steffen,Jessen Frank, , , , ,van der Flier Wiesje M Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS:Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS:In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION:SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts. 10.1016/j.jalz.2018.10.003
    A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study. Boada Mercè,López Oscar L,Olazarán Javier,Núñez Laura,Pfeffer Michael,Paricio María,Lorites Jesús,Piñol-Ripoll Gerard,Gámez José E,Anaya Fernando,Kiprov Dobri,Lima José,Grifols Carlota,Torres Mireia,Costa Montserrat,Bozzo Jordi,Szczepiorkowski Zbigniew M,Hendrix Suzanne,Páez Antonio Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD). METHODS:Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). RESULTS:PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales. DISCUSSION:This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted. 10.1002/alz.12137
    Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease. Berron David,van Westen Danielle,Ossenkoppele Rik,Strandberg Olof,Hansson Oskar Brain : a journal of neurology Human episodic memory critically depends on subregions of the medial temporal lobe, which are part of functional brain systems such as the anterior-temporal and the posterior-medial system. Here we analysed how Alzheimer's pathology affects functional connectivity within these systems. Data from 256 amyloid-β-negative cognitively unimpaired, 103 amyloid-β-positive cognitively unimpaired, and 83 amyloid-β-positive individuals with mild cognitive impairment were analysed. Amyloid-β and tau pathology were measured using the CSF amyloid-β42/40 ratio and phosphorylated tau, respectively. We found that amyloid-β-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the medial temporal lobe and regions in the anterior-temporal system, most prominently between left perirhinal/entorhinal cortices and medial prefrontal cortex. Furthermore, correlation analysis in this group revealed decreasing functional connectivity between bilateral perirhinal/entorhinal cortices, anterior hippocampus and posterior-medial regions with increasing levels of phosphorylated tau. The amyloid-β-positive individuals with mild cognitive impairment mostly exhibited reduced connectivity between the medial temporal lobe and posterior-medial regions, predominantly between the anterior hippocampus and posterior cingulate cortex. In addition, they showed hyperconnectivity within the medial temporal lobe and its immediate proximity. Lower medial temporal-cortical functional connectivity networks resulting from the group comparisons of cognitively unimpaired individuals were associated with reduced memory performance and more rapid longitudinal memory decline as shown by linear mixed-effects regression analysis. Finally, we found that reduced medial temporal-cortical connectivity in mildly cognitively impaired individuals was related to reduced entorhinal thickness and white matter integrity of the parahippocampal cingulum and the fornix. No such relationships were found in cognitively unimpaired individuals. In conclusion, our findings show that the earliest changes in preclinical Alzheimer's disease might involve decreased connectivity within the anterior-temporal system, and early changes in connectivity might be related to memory impairment, but not to structural changes. With disease progression and increased tau pathology, medial temporal functional connectivity with posterior-medial regions seems to be increasingly impaired. In individuals with mild cognitive impairment, reduced functional connectivity is associated with structural brain changes as well as the emergence of locally increased connectivity patterns. Thus, functional connectivity between the medial temporal lobe and the anterior-temporal and posterior-medial system could serve as stage-specific functional markers in early Alzheimer's disease. 10.1093/brain/awaa068
    Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Janelidze Shorena,Mattsson Niklas,Palmqvist Sebastian,Smith Ruben,Beach Thomas G,Serrano Geidy E,Chai Xiyun,Proctor Nicholas K,Eichenlaub Udo,Zetterberg Henrik,Blennow Kaj,Reiman Eric M,Stomrud Erik,Dage Jeffrey L,Hansson Oskar Nature medicine Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials. 10.1038/s41591-020-0755-1
    in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Dominy Stephen S,Lynch Casey,Ermini Florian,Benedyk Malgorzata,Marczyk Agata,Konradi Andrei,Nguyen Mai,Haditsch Ursula,Raha Debasish,Griffin Christina,Holsinger Leslie J,Arastu-Kapur Shirin,Kaba Samer,Lee Alexander,Ryder Mark I,Potempa Barbara,Mydel Piotr,Hellvard Annelie,Adamowicz Karina,Hasturk Hatice,Walker Glenn D,Reynolds Eric C,Faull Richard L M,Curtis Maurice A,Dragunow Mike,Potempa Jan Science advances , the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral infection in mice resulted in brain colonization and increased production of Aβ, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established brain infection, blocked Aβ production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating brain colonization and neurodegeneration in Alzheimer's disease. 10.1126/sciadv.aau3333
    Deficits in Spontaneous Cognition as an Early Marker of Alzheimer's Disease. Kvavilashvili Lia,Niedźwieńska Agnieszka,Gilbert Sam J,Markostamou Ioanna Trends in cognitive sciences In the absence of a pharmacological cure, finding the most sensitive early cognitive markers of Alzheimer's disease (AD) is becoming increasingly important. In this article we review evidence showing that brain mechanisms of spontaneous, but stimulus-dependent, cognition overlap with key hubs of the default mode network (DMN) that become compromised by amyloid pathology years before the clinical symptoms of AD. This leads to the formulation of a novel hypothesis which predicts that spontaneous, but stimulus-dependent, conscious retrieval processes, that are generally intact in healthy aging, will be particularly compromised in people at the earliest stages of AD. Initial evidence for this hypothesis is presented across diverse experimental paradigms (e.g., prospective memory, mind-wandering), and new avenues for research in this area are outlined. 10.1016/j.tics.2020.01.005
    Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease. Korte Nils,Nortley Ross,Attwell David Acta neuropathologica Therapies targeting late events in Alzheimer's disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aβ. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration by upregulating the BACE1 enzyme that makes Aβ and by promoting tau hyperphosphorylation. Surprisingly, therefore, CBF reduction may play a crucial role in driving cognitive decline by initiating the amyloid cascade itself, or being caused by and amplifying Aβ production. Here, we review developments in this area that are neglected in current approaches to AD, with the aim of promoting novel mechanism-based therapeutic approaches. 10.1007/s00401-020-02215-w
    The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications. Arranz Amaia M,De Strooper Bart The Lancet. Neurology BACKGROUND:Astrocytes, also called astroglia, maintain homoeostasis of the brain by providing trophic and metabolic support to neurons. They recycle neurotransmitters, stimulate synaptogenesis and synaptic neurotransmission, form part of the blood-brain barrier, and regulate regional blood flow. Although astrocytes have been known to display morphological alterations in Alzheimer's disease for more than a century, research has remained neurocentric. Emerging evidence suggests that these morphological changes reflect functional alterations that affect disease. RECENT DEVELOPMENTS:Genetic studies indicate that most of the risk of developing late onset Alzheimer's disease, the most common form of the disease, affecting patients aged 65 years and older, is associated with genes (ie, APOE, APOJ, and SORL) that are mainly expressed by glial cells (ie, astrocytes, microglia, and oligodendrocytes). This insight has moved the focus of research away from neurons and towards glial cells and neuroinflammation. Molecular studies in rodent models suggest a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease; however, these models might insufficiently mimic the human disease, because rodent astrocytes differ considerably in morphology, functionality, and gene expression. In-vivo studies using stem-cell derived human astrocytes are allowing exploration of the human disease and providing insights into the neurotoxic or protective contributions of these cells to the pathogenesis of disease. The first attempts to develop astrocytic biomarkers and targeted therapies are emerging. WHERE NEXT?: Single-cell transcriptomics allows the fate of individual astrocytes to be followed in situ and provides the granularity needed to describe healthy and pathological cellular states at different stages of Alzheimer's disease. Given the differences between human and rodent astroglia, study of human cells in this way will be crucial. Although refined single-cell transcriptomic analyses of human post-mortem brains are important for documentation of pathology, they only provide snapshots of a dynamic reality. Thus, functional work studying human astrocytes generated from stem cells and exposed to pathological conditions in rodent brain or cell culture are needed to understand the role of these cells in the pathogenesis of Alzheimer's disease. These studies will lead to novel biomarkers and hopefully a series of new drug targets to tackle this disease. 10.1016/S1474-4422(18)30490-3
    Complex interactions underlie racial disparity in the risk of developing Alzheimer's disease dementia. Xiong Chengjie,Luo Jingqin,Coble Dean,Agboola Folasade,Kukull Walter,Morris John C Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:We aim to determine racial disparities and their modifying factors in risk for Alzheimer's disease (AD) dementia among cognitively normal individuals 65 years or older. METHODS:Longitudinal data from the National Alzheimer's Coordinating Center Uniform Data Set on 1229 African Americans (AAs) and 6679 whites were analyzed for the risk of AD using competing risk models with death as a competing event. RESULTS:Major AD risk factors modified racial differences which, when statistically significant, occurred only with older age among APOE ε4 negative individuals, but also with younger age among APOE ε4 positive individuals. The racial differences favored AAs among individuals with body mass index (BMI) < 30, but whites among individuals with a high BMI (≥ 30), and were additionally modified by sex, education, hypertension, and smoking status. CONCLUSIONS:The presence, direction, and relative magnitude of racial disparity for AD represent an interactive function of major AD and cerebrovascular risk factors. 10.1002/alz.12060
    Atrophy subtypes in prodromal Alzheimer's disease are associated with cognitive decline. Ten Kate Mara,Dicks Ellen,Visser Pieter Jelle,van der Flier Wiesje M,Teunissen Charlotte E,Barkhof Frederik,Scheltens Philip,Tijms Betty M, Brain : a journal of neurology Alzheimer's disease is a heterogeneous disorder. Understanding the biological basis for this heterogeneity is key for developing personalized medicine. We identified atrophy subtypes in Alzheimer's disease dementia and tested whether these subtypes are already present in prodromal Alzheimer's disease and could explain interindividual differences in cognitive decline. First we retrospectively identified atrophy subtypes from structural MRI with a data-driven cluster analysis in three datasets of patients with Alzheimer's disease dementia: discovery data (dataset 1: n = 299, age = 67 ± 8, 50% female), and two independent external validation datasets (dataset 2: n = 181, age = 66 ± 7, 52% female; dataset 3: n = 227, age = 74 ± 8, 44% female). Subtypes were compared on clinical, cognitive and biological characteristics. Next, we classified prodromal Alzheimer's disease participants (n = 603, age = 72 ± 8, 43% female) according to the best matching subtype to their atrophy pattern, and we tested whether subtypes showed cognitive decline in specific domains. In all Alzheimer's disease dementia datasets we consistently identified four atrophy subtypes: (i) medial-temporal predominant atrophy with worst memory and language function, older age, lowest CSF tau levels and highest amount of vascular lesions; (ii) parieto-occipital atrophy with poor executive/attention and visuospatial functioning and high CSF tau; (iii) mild atrophy with best cognitive performance, young age, but highest CSF tau levels; and (iv) diffuse cortical atrophy with intermediate clinical, cognitive and biological features. Prodromal Alzheimer's disease participants classified into one of these subtypes showed similar subtype characteristics at baseline as Alzheimer's disease dementia subtypes. Compared across subtypes in prodromal Alzheimer's disease, the medial-temporal subtype showed fastest decline in memory and language over time; the parieto-occipital subtype declined fastest on executive/attention domain; the diffuse subtype in visuospatial functioning; and the mild subtype showed intermediate decline in all domains. Robust atrophy subtypes exist in Alzheimer's disease with distinct clinical and biological disease expression. Here we observe that these subtypes can already be detected in prodromal Alzheimer's disease, and that these may inform on expected trajectories of cognitive decline. 10.1093/brain/awy264
    Vascular dysfunction-The disregarded partner of Alzheimer's disease. Sweeney Melanie D,Montagne Axel,Sagare Abhay P,Nation Daniel A,Schneider Lon S,Chui Helena C,Harrington Michael G,Pa Judy,Law Meng,Wang Danny J J,Jacobs Russell E,Doubal Fergus N,Ramirez Joel,Black Sandra E,Nedergaard Maiken,Benveniste Helene,Dichgans Martin,Iadecola Costantino,Love Seth,Bath Philip M,Markus Hugh S,Salman Rustam A,Allan Stuart M,Quinn Terence J,Kalaria Rajesh N,Werring David J,Carare Roxana O,Touyz Rhian M,Williams Steve C R,Moskowitz Michael A,Katusic Zvonimir S,Lutz Sarah E,Lazarov Orly,Minshall Richard D,Rehman Jalees,Davis Thomas P,Wellington Cheryl L,González Hector M,Yuan Chun,Lockhart Samuel N,Hughes Timothy M,Chen Christopher L H,Sachdev Perminder,O'Brien John T,Skoog Ingmar,Pantoni Leonardo,Gustafson Deborah R,Biessels Geert Jan,Wallin Anders,Smith Eric E,Mok Vincent,Wong Adrian,Passmore Peter,Barkof Frederick,Muller Majon,Breteler Monique M B,Román Gustavo C,Hamel Edith,Seshadri Sudha,Gottesman Rebecca F,van Buchem Mark A,Arvanitakis Zoe,Schneider Julie A,Drewes Lester R,Hachinski Vladimir,Finch Caleb E,Toga Arthur W,Wardlaw Joanna M,Zlokovic Berislav V Alzheimer's & dementia : the journal of the Alzheimer's Association Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. 10.1016/j.jalz.2018.07.222
    Diet, psychosocial stress, and Alzheimer's disease-related neuroanatomy in female nonhuman primates. Frye Brett M,Craft Suzanne,Register Thomas C,Andrews Rachel N,Appt Susan E,Vitolins Mara Z,Uberseder Beth,Silverstein-Metzler Marnie G,Chen Haiying,Whitlow Christopher T,Kim Jeongchul,Barcus Richard A,Lockhart Samuel N,Hoscheidt Siobhan,Say Brandon M,Corbitt Sarah E,Shively Carol A Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Associations between diet, psychosocial stress, and neurodegenerative disease, including Alzheimer's disease (AD), have been reported, but causal relationships are difficult to determine in human studies. METHODS:We used structural magnetic resonance imaging in a well-validated non-human primate model of AD-like neuropathology to examine the longitudinal effects of diet (Mediterranean vs Western) and social subordination stress on brain anatomy, including global volumes, cortical thicknesses and volumes, and 20 individual regions of interest (ROIs). RESULTS:Western diet resulted in greater cortical thicknesses, total brain volumes, and gray matter, and diminished cerebrospinal fluid and white matter volumes. Socially stressed subordinates had smaller whole brain volumes but larger ROIs relevant to AD than dominants. DISCUSSION:The observation of increased size of AD-related brain areas is consistent with similar reports of mid-life volume increases predicting increased AD risk later in life. While the biological mechanisms underlying the findings require future investigation, these observations suggest that Western diet and psychosocial stress instigate pathologic changes that increase risk of AD-associated neuropathology, whereas the Mediterranean diet may protect the brain. 10.1002/alz.12232
    A 3D human brain-like tissue model of herpes-induced Alzheimer's disease. Cairns Dana M,Rouleau Nicolas,Parker Rachael N,Walsh Katherine G,Gehrke Lee,Kaplan David L Science advances Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive decline, memory loss, and inability to perform everyday functions. Hallmark features of AD-including generation of amyloid plaques, neurofibrillary tangles, gliosis, and inflammation in the brain-are well defined; however, the cause of the disease remains elusive. Growing evidence implicates pathogens in AD development, with herpes simplex virus type I (HSV-1) gaining increasing attention as a potential causative agent. Here, we describe a multidisciplinary approach to produce physiologically relevant human tissues to study AD using human-induced neural stem cells (hiNSCs) and HSV-1 infection in a 3D bioengineered brain model. We report a herpes-induced tissue model of AD that mimics human disease with multicellular amyloid plaque-like formations, gliosis, neuroinflammation, and decreased functionality, completely in the absence of any exogenous mediators of AD. This model will allow for future studies to identify potential downstream drug targets for treating this devastating disease. 10.1126/sciadv.aay8828
    Shared proteomic effects of cerebral atherosclerosis and Alzheimer's disease on the human brain. Wingo Aliza P,Fan Wen,Duong Duc M,Gerasimov Ekaterina S,Dammer Eric B,Liu Yue,Harerimana Nadia V,White Bartholomew,Thambisetty Madhav,Troncoso Juan C,Kim Namhee,Schneider Julie A,Hajjar Ihab M,Lah James J,Bennett David A,Seyfried Nicholas T,Levey Allan I,Wingo Thomas S Nature neuroscience Cerebral atherosclerosis contributes to dementia via unclear processes. We performed proteomic sequencing of dorsolateral prefrontal cortex in 438 older individuals and found associations between cerebral atherosclerosis and reduced synaptic signaling and between RNA splicing and increased oligodendrocyte development and myelination. Consistently, single-cell RNA sequencing showed cerebral atherosclerosis associated with higher oligodendrocyte abundance. A subset of proteins and modules associated with cerebral atherosclerosis was also associated with Alzheimer's disease, suggesting shared mechanisms. 10.1038/s41593-020-0635-5
    Recognizing African-American contributions to neurology: The role of Solomon Carter Fuller (1872-1953) in Alzheimer's disease research. Mohammed Hamzah Alzheimer's & dementia : the journal of the Alzheimer's Association Solomon Carter Fuller (1872-1953) is widely acknowledged as the first African-American psychiatrist but underappreciated as a pioneer of Alzheimer's disease. He immigrated to the United States from Liberia at age 17 and excelled in his medical career to become associate professor of both pathology and neurology at Boston University by 1921. He was one of five research assistants selected by Alois Alzheimer to work in his laboratory at the Royal Psychiatric Hospital in Munich, an experience that arguably paved the way for trailblazing research in Alzheimer's disease. Dr Fuller was the first to translate much of Alzheimer's pivotal work into English, including that of Auguste Deter, the first reported case of the disease. He published what is now recognized to be the first comprehensive review of Alzheimer's disease, in it reporting the ninth case ever described. His achievements, in a period when African-American physicians were under-represented, merit greater recognition. 10.1002/alz.12183
    Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. Egan Michael F,Kost James,Voss Tiffini,Mukai Yuki,Aisen Paul S,Cummings Jeffrey L,Tariot Pierre N,Vellas Bruno,van Dyck Christopher H,Boada Merce,Zhang Ying,Li Wen,Furtek Christine,Mahoney Erin,Harper Mozley Lyn,Mo Yi,Sur Cyrille,Michelson David The New England journal of medicine BACKGROUND:Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS:We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS:The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS:Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.). 10.1056/NEJMoa1812840
    Initiation of symptomatic medication in Alzheimer's disease clinical trials: Hypothetical versus treatment policy approach. Donohue Michael C,Model Fabian,Delmar Paul,Volye Nicola,Liu-Seifert Hong,Rafii Michael S,Aisen Paul S, Alzheimer's & dementia : the journal of the Alzheimer's Association In clinical trials in populations with mild cognitive impairment, it is common for participants to initiate concurrent symptomatic medications for Alzheimer's disease after randomization to the experimental therapy. One strategy for addressing this occurrence is to exclude any observations that occur after the concurrent medication is initiated. The rationale for this approach is that these observations might reflect a symptomatic benefit of the concurrent medication that would adversely bias efficacy estimates for an effective experimental therapy. We interrogate the assumptions underlying such an approach by estimating the effect of newly prescribed concurrent medications in an observational study, the Alzheimer's Disease Neuroimaging Initiative. 10.1002/alz.12058
    Evaluation of CD33 as a genetic risk factor for Alzheimer's disease. Estus Steven,Shaw Benjamin C,Devanney Nicholas,Katsumata Yuriko,Press Eileen E,Fardo David W Acta neuropathologica In 2011, genome-wide association studies implicated a polymorphism near CD33 as a genetic risk factor for Alzheimer's disease. This finding sparked interest in this member of the sialic acid-binding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found that CD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying the CD33 genetic association with Alzheimer's disease. The allele that protects from Alzheimer's disease acts predominately to increase a CD33 isoform lacking exon 2 at the expense of the prototypic, full-length CD33 that contains exon 2. Since this exon encodes the sialic acid ligand-binding domain, the finding that the loss of exon 2 was associated with decreased Alzheimer's disease risk was interpreted as meaning that a decrease in functional CD33 and its associated immune suppression was protective from Alzheimer's disease. However, this interpretation may need to be reconsidered given current findings that a genetic deletion which abrogates CD33 is not associated with Alzheimer's disease risk. Therefore, integrating currently available findings leads us to propose a model wherein the CD33 isoform lacking the ligand-binding domain represents a gain of function variant that reduces Alzheimer's disease risk. 10.1007/s00401-019-02000-4
    Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients. Finsterwalder Sofia,Vlegels Naomi,Gesierich Benno,Araque Caballero Miguel Á,Weaver Nick A,Franzmeier Nicolai,Georgakis Marios K,Konieczny Marek J,Koek Huiberdina L, ,Karch Celeste M,Graff-Radford Neill R,Salloway Stephen,Oh Hwamee,Allegri Ricardo F,Chhatwal Jasmeer P, ,Jessen Frank,Düzel Emrah,Dobisch Laura,Metzger Coraline,Peters Oliver,Incesoy Enise I,Priller Josef,Spruth Eike J,Schneider Anja,Fließbach Klaus,Buerger Katharina,Janowitz Daniel,Teipel Stefan J,Kilimann Ingo,Laske Christoph,Buchmann Martina,Heneka Michael T,Brosseron Frederic,Spottke Annika,Roy Nina,Ertl-Wagner Birgit,Scheffler Klaus, , ,Seo Sang Won,Kim Yeshin,Na Duk L,Kim Hee Jin,Jang Hyemin,Ewers Michael,Levin Johannes,Schmidt Reinhold,Pasternak Ofer,Dichgans Martin,Biessels Geert Jan,Duering Marco Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations. METHODS:We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures. RESULTS:SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant. DISCUSSION:In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD. 10.1002/alz.12150
    Using Medicare claims in identifying Alzheimer's disease and related dementias. Jain Siddharth,Rosenbaum Paul R,Reiter Joseph G,Hoffman Geoffrey,Small Dylan S,Ha Jinkyung,Hill Alexander S,Wolk David A,Gaulton Timothy,Neuman Mark D,Eckenhoff Roderic G,Fleisher Lee A,Silber Jeffrey H Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:This study develops a measure of Alzheimer's disease and related dementias (ADRD) using Medicare claims. METHODS:Validation resembles the approach of the American Psychological Association, including (1) content validity, (2) construct validity, and (3) predictive validity. RESULTS:We found that four items-a Medicare claim recording ADRD 1 year ago, 2 years ago, 3 years ago, and a total stay of 6 months in a nursing home-exhibit a pattern of association consistent with a single underlying ADRD construct, and presence of any two of these four items predict a direct measure of cognitive function and also future claims for ADRD. DISCUSSION:Our four items are internally consistent with the measurement of a single quantity. The presence of any two items do a better job than a single claim when predicting both a direct measure of cognitive function and future ADRD claims. 10.1002/alz.12199
    Unmasking selective path integration deficits in Alzheimer's disease risk carriers. Bierbrauer Anne,Kunz Lukas,Gomes Carlos A,Luhmann Maike,Deuker Lorena,Getzmann Stephan,Wascher Edmund,Gajewski Patrick D,Hengstler Jan G,Fernandez-Alvarez Marina,Atienza Mercedes,Cammisuli Davide M,Bonatti Francesco,Pruneti Carlo,Percesepe Antonio,Bellaali Youssef,Hanseeuw Bernard,Strange Bryan A,Cantero Jose L,Axmacher Nikolai Science advances Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD ( ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in ε4-carriers during a virtual navigation task. We report a selective impairment in ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset. 10.1126/sciadv.aba1394
    Implications of sleep disturbance and inflammation for Alzheimer's disease dementia. Irwin Michael R,Vitiello Michael V The Lancet. Neurology Nearly half of all adults older than 60 years of age report sleep disturbance, as characterised either by reports of insomnia complaints with daytime consequences, dissatisfaction with sleep quality or quantity, or the diagnosis of insomnia disorder. Accumulating evidence shows that sleep disturbance contributes to cognitive decline and might also increase the risk of Alzheimer's disease dementia by increasing β-amyloid burden. That sleep disturbance would be a candidate risk factor for Alzheimer's disease might seem surprising, given that disturbed sleep is usually considered a consequence of Alzheimer's disease. However, a bidirectional relationship between sleep and Alzheimer's disease is supported by advances in our understanding of sleep disturbance-induced increases in systemic inflammation, which can be viewed as an early event in the course of Alzheimer's disease. Inflammation increases β-amyloid burden and is thought to drive Alzheimer's disease pathogenesis. Improved understanding of the mechanisms linking sleep disturbance and Alzheimer's disease risk could facilitate the identification of targets for prevention, given that both sleep disturbance and inflammatory activation might be modifiable risk factors for Alzheimer's disease. 10.1016/S1474-4422(18)30450-2
    Nrf2: a dark horse in Alzheimer's disease treatment. Osama Alsiddig,Zhang Junmin,Yao Juan,Yao Xiaojun,Fang Jianguo Ageing research reviews Alzheimer's disease (AD), an age-dependent neurodegenerative disorder, is the main cause of dementia. Common hallmarks of AD include the amyloid β-peptide (Aβ) aggregation, high levels of hyperphosphorylated tau protein (p-tau) and failure in redox homeostasis. To date, all proposed drugs affecting Aβ and/or p-tau have been failed in clinical trials. A decline in the expression of the transcription factor Nrf2 (nuclear factor-erythroid 2-p45 derived factor 2) and its driven genes (NQO1, HO-1, and GCLC), and alteration of the Nrf2-related pathways have been observed in AD brains. Nrf2 plays a critical role in maintaining cellular redox homeostasis and regulating inflammation response. Nrf2 activation also provides cytoprotection against increasing pathologies including neurodegenerative diseases. These lines of evidence imply that Nrf2 activation may be a novel AD treatment option. Interestingly, recent studies have also demonstrated that Nrf2 interferes with several key pathogenic processes in AD including Aβ and p-tau pathways. The current review aims to provide insights into the role of Nrf2 in AD. Also, we discuss the progress and challenges regarding the Nrf2 activators for AD treatment. 10.1016/j.arr.2020.101206
    Circadian and sleep dysfunction in Alzheimer's disease. Uddin Md Sahab,Tewari Devesh,Mamun Abdullah Al,Kabir Md Tanvir,Niaz Kamal,Wahed Mir Imam Ibne,Barreto George E,Ashraf Ghulam Md Ageing research reviews Alzheimer's disease (AD) is a devastating and irreversible cognitive impairment and the most common type of dementia. Along with progressive cognitive impairment, dysfunction of the circadian rhythms also plays a pivotal role in the progression of AD. A mutual relationship among circadian rhythms, sleep, and AD has been well-recommended. The etiopathogenesis of the disturbances of the circadian system and AD share some general features that also unlock the outlook of observing them as a mutually dependent pathway. Indeed, the burden of amyloid β (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, and dysfunction of circadian rhythms may lead to AD. Aging can alter both sleep timings and quality that can be strongly disrupted in AD. Increased production of Aβ and reduced Aβ clearance are caused by a close interplay of Aβ, sleep disturbance and raised wakefulness. Besides Aβ, the impact of tau pathology is possibly noteworthy to the sleep deprivation found in AD. Hence, this review is focused on the primary mechanistic complexities linked to disruption of circadian rhythms, sleep deprivation, and AD. Furthermore, this review also highlights the potential therapeutic strategies to abate AD pathogenesis. 10.1016/j.arr.2020.101046
    The role of innate immunity in Alzheimer's disease. Ennerfelt Hannah E,Lukens John R Immunological reviews The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain-resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses. 10.1111/imr.12896
    Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. Heckmann Bradlee L,Teubner Brett J W,Boada-Romero Emilio,Tummers Bart,Guy Clifford,Fitzgerald Patrick,Mayer Ulrike,Carding Simon,Zakharenko Stanislav S,Wileman Thomas,Green Douglas R Science advances Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer's disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease. 10.1126/sciadv.abb9036
    Effects of bilingualism on age at onset in two clinical Alzheimer's disease variants. de Leon Jessica,Grasso Stephanie M,Welch Ariane,Miller Zachary,Shwe Wendy,Rabinovici Gil D,Miller Bruce L,Henry Maya L,Gorno-Tempini Maria Luisa Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:The effect of bilingualism on age at onset has yet to be examined within different clinical variants of Alzheimer's disease. METHODS:We reviewed the research charts of 287 well-characterized participants with either amnestic Alzheimer's dementia or logopenic variant primary progressive aphasia (lvPPA) and identified bilingual speakers based on regular use of two or more languages and/or ability to communicate with native speakers in two or more languages. We evaluated whether bilingual speakers demonstrated a delay in age of symptom onset relative to monolingual speakers while controlling for other variables known to influence cognitive reserve. RESULTS:A 5-year delay in age at symptom onset was observed for bilingual relative to monolingual speakers with lvPPA. This delay in onset was not observed in the amnestic Alzheimer's dementia cohort. DISCUSSION:Bilingualism may serve as a unique cognitive reserve variable in lvPPA, but not in amnestic Alzheimer's dementia. 10.1002/alz.12170
    Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease. Liu Kathy Y,Reeves Suzanne,McAleese Kirsty E,Attems Johannes,Francis Paul,Thomas Alan,Howard Robert Brain : a journal of neurology There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden. Nearly all donors had dementia; three (two pure LATE-NC and one pure ADNC) donors had mild cognitive impairment and another two donors with LATE-NC did not have dementia. The mixed ADNC/LATE-NC group was older than the pure ADNC group, had a higher proportion of females compared to the pure ADNC and LATE-NC groups, and had more severe dementia versus the pure LATE-NC group. After adjustment for length of follow-up, cognitive and demographic factors, mixed ADNC/LATE-NC was associated with lower total Neuropsychiatric Inventory and agitation factor scores than pure ADNC, and lower frontal factor scores than pure LATE-NC. Our findings indicate that concomitant LATE pathology in Alzheimer's disease is not associated with greater neuropsychiatric symptom burden. Future longitudinal studies are needed to further investigate whether mixed ADNC/LATE-NC may be protective against agitation and frontal symptoms in dementia caused by Alzheimer's disease or LATE pathology. 10.1093/brain/awaa315
    Association between alcohol consumption and Alzheimer's disease: A Mendelian randomization study. Andrews Shea J,Goate Alison,Anstey Kaarin J Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Observational studies have suggested that light-to-moderate alcohol consumption decreases the risk of Alzheimer's disease, but it is unclear if this association is causal. METHODS:Two-sample Mendelian randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence, or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late-Onset Alzheimer's disease (LOAD) or Alzheimer's disease age of onset survival (AAOS). Additionally, γ-glutamyltransferase levels were included as a positive control. RESULTS:There was no evidence of a causal association between alcohol consumption, alcohol dependence, or AUDIT, and LOAD. Alcohol consumption was associated with an earlier AAOS and increased γ-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS. DISCUSSION:MR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias. 10.1016/j.jalz.2019.09.086
    Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study. Jia Longfei,Li Fangyu,Wei Cuibai,Zhu Min,Qu Qiumin,Qin Wei,Tang Yi,Shen Luxi,Wang Yanjiang,Shen Lu,Li Honglei,Peng Dantao,Tan Lan,Luo Benyan,Guo Qihao,Tang Muni,Du Yifeng,Zhang Jiewen,Zhang Junjian,Lyu Jihui,Li Ying,Zhou Aihong,Wang Fen,Chu Changbiao,Song Haiqing,Wu Liyong,Zuo Xiumei,Han Yue,Liang Junhua,Wang Qi,Jin Hongmei,Wang Wei,Lü Yang,Li Fang,Zhou Yuying,Zhang Wei,Liao Zhengluan,Qiu Qiongqiong,Li Yan,Kong Chaojun,Li Yan,Jiao Haishan,Lu Jie,Jia Jianping Brain : a journal of neurology Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation. 10.1093/brain/awaa364
    Disease-associated astrocytes in Alzheimer's disease and aging. Habib Naomi,McCabe Cristin,Medina Sedi,Varshavsky Miriam,Kitsberg Daniel,Dvir-Szternfeld Raz,Green Gilad,Dionne Danielle,Nguyen Lan,Marshall Jamie L,Chen Fei,Zhang Feng,Kaplan Tommy,Regev Aviv,Schwartz Michal Nature neuroscience The role of non-neuronal cells in Alzheimer's disease progression has not been fully elucidated. Using single-nucleus RNA sequencing, we identified a population of disease-associated astrocytes in an Alzheimer's disease mouse model. These disease-associated astrocytes appeared at early disease stages and increased in abundance with disease progression. We discovered that similar astrocytes appeared in aged wild-type mice and in aging human brains, suggesting their linkage to genetic and age-related factors. 10.1038/s41593-020-0624-8
    The subjective experience of recollection and familiarity in Alzheimer's disease. Kapogiannis Dimitrios,El Haj Mohamad The Behavioral and brain sciences Although the integrative memory model proposed by Bastin et al. is interesting, particularly for Alzheimer's disease, it may benefit from incorporating the subjective experience of recollection. We therefore offer complementary lines of interpretation to explain how recollection and familiarity in Alzheimer's disease can be dissociated based not only on accounts of their neural correlates but, critically, on the subjective experience of memory in patients. 10.1017/S0140525X19001766
    Development and validation of an interpretable deep learning framework for Alzheimer's disease classification. Qiu Shangran,Joshi Prajakta S,Miller Matthew I,Xue Chonghua,Zhou Xiao,Karjadi Cody,Chang Gary H,Joshi Anant S,Dwyer Brigid,Zhu Shuhan,Kaku Michelle,Zhou Yan,Alderazi Yazan J,Swaminathan Arun,Kedar Sachin,Saint-Hilaire Marie-Helene,Auerbach Sanford H,Yuan Jing,Sartor E Alton,Au Rhoda,Kolachalama Vijaya B Brain : a journal of neurology Alzheimer's disease is the primary cause of dementia worldwide, with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and MRI to identify likely cases, yet effective practices remain variably applied and lacking in sensitivity and specificity. Here we report an interpretable deep learning strategy that delineates unique Alzheimer's disease signatures from multimodal inputs of MRI, age, gender, and Mini-Mental State Examination score. Our framework linked a fully convolutional network, which constructs high resolution maps of disease probability from local brain structure to a multilayer perceptron and generates precise, intuitive visualization of individual Alzheimer's disease risk en route to accurate diagnosis. The model was trained using clinically diagnosed Alzheimer's disease and cognitively normal subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 417) and validated on three independent cohorts: the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) (n = 382), the Framingham Heart Study (n = 102), and the National Alzheimer's Coordinating Center (NACC) (n = 582). Performance of the model that used the multimodal inputs was consistent across datasets, with mean area under curve values of 0.996, 0.974, 0.876 and 0.954 for the ADNI study, AIBL, Framingham Heart Study and NACC datasets, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n = 11), and high-risk cerebral regions predicted by the model closely tracked post-mortem histopathological findings. This framework provides a clinically adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for Alzheimer's disease diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease. 10.1093/brain/awaa137
    Risk factors for earlier dementia onset in autopsy-confirmed Alzheimer's disease, mixed Alzheimer's with Lewy bodies, and pure Lewy body disease. Schaffert Jeff,LoBue Christian,White Charles L,Wilmoth Kristin,Didehbani Nyaz,Lacritz Laura,Nguyen Trung,Peters Matthew E,Fields Lindy,Li Chengxi,Cullum C Munro Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Clinical Alzheimer's disease (AD) and dementia with Lewy bodies often have mixed AD and Lewy pathology, making it difficult to delineate risk factors. METHODS:Six risk factors for earlier dementia onset due to autopsy-confirmed AD (n = 647), mixed AD and Lewy body disease (AD + LBD; n = 221), and LBD (n = 63) were entered into multiple linear regressions using data from the National Alzheimer's Coordinating Center. RESULTS:In AD and AD + LBD, male sex and apolipoprotein E (APOE) ɛ4 alleles each predicted a 2- to 3-year-earlier onset and depression predicted a 3-year-earlier onset. In LBD, higher education predicted earlier onset and depression predicted a 5.5-year-earlier onset. DISCUSSION:Male sex and APOE ɛ4 alleles increase risk for earlier dementia onset in AD but not LBD. Depression increases risk for earlier dementia onset in AD, LBD, and AD + LBD, but evaluating the course, treatment, and severity is needed in future studies. 10.1002/alz.12049
    Microglial activation and tau burden predict cognitive decline in Alzheimer's disease. Malpetti Maura,Kievit Rogier A,Passamonti Luca,Jones P Simon,Tsvetanov Kamen A,Rittman Timothy,Mak Elijah,Nicastro Nicolas,Bevan-Jones W Richard,Su Li,Hong Young T,Fryer Tim D,Aigbirhio Franklin I,O'Brien John T,Rowe James B Brain : a journal of neurology Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer's disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer's disease pathology. Twenty-six patients (n = 12 with clinically probable Alzheimer's dementia and n = 14 with amyloid-positive mild cognitive impairment) and 29 healthy control subjects underwent baseline assessment with 18F-AV-1451 PET, 11C-PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke's Cognitive Examination. Regional grey matter volumes, and regional binding of 18F-AV-1451 and 11C-PK11195 were derived from 15 temporo-parietal regions characteristically affected by Alzheimer's disease pathology. A principal component analysis was used on each imaging modality separately, to identify the main spatial distributions of pathology. A latent growth curve model was applied across the whole sample on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the individuals' estimated rate of cognitive decline on the neuroimaging components and examined univariable predictive models with single-modality predictors, and a multi-modality predictive model, to identify the independent and combined prognostic value of the different neuroimaging markers. Principal component analysis identified a single component for the grey matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-sample, the single-modality models indicated significant correlations between the rate of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer's disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer's disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer's disease. 10.1093/brain/awaa088
    The Alzheimer's Disease Exposome. Finch Caleb E,Kulminski Alexander M Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Environmental factors are poorly understood in the etiology of Alzheimer's disease (AD) and related dementias. The importance of environmental factors in gene environment interactions (GxE) is suggested by wide individual differences in cognitive loss, even for carriers of AD-risk genetic variants. RESULTS AND DISCUSSION:We propose the "AD exposome" to comprehensively assess the modifiable environmental factors relevant to genetic underpinnings of cognitive aging and AD. Analysis of endogenous and exogenous environmental factors requires multi-generational consideration of these interactions over age and time (GxExT). New computational approaches to the multi-level complexities may identify accessible interventions for individual brain aging. International collaborations on diverse populations are needed to identify the most relevant exposures over the life course for GxE interactions. 10.1016/j.jalz.2019.06.3914
    An 80,000-Piece Puzzle of Alzheimer's Disease. Iram Tal,Keller Andreas,Wyss-Coray Tony Immunity To gain unfettered insight into one of the scourges of our aging societies, Mathys and colleagues in Nature (Mathys et al., 2019) illuminate the brain transcriptome of Alzheimer's disease at single-cell resolution. Their findings implicate oligodendrocytes, a cell type largely neglected in Alzheimer's disease research, and sex in the disease in intriguing ways. 10.1016/j.immuni.2019.05.016
    Cognitive tests aid in clinical differentiation of Alzheimer's disease versus Alzheimer's disease with Lewy body disease: Evidence from a pathological study. Azar Martina,Chapman Silvia,Gu Yian,Leverenz James B,Stern Yaakov,Cosentino Stephanie Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Clinical differentiation between Alzheimer's disease (AD) and AD with Lewy body disease (LBD) is relatively imprecise. The current study examined pathologically confirmed group differences in neuropsychological functioning, and the classification ability of specific tests. METHODS:Fifty-one participants with postmortem diagnoses of AD (n = 34) and AD plus LBD (n = 17) were drawn from the Predictors Study. One-way analyses of variance (ANOVAs) and χ analyses examined group differences in neuropsychological performance. Binary logistic regressions examined predictive utility of specific tests for pathological diagnosis. RESULTS:Individuals with AD had better visuoconstruction (P = .006), phonemic fluency (P = .08), and processing speed than AD plus LBD (P = .013). No differences were found in memory, naming, semantic fluency, or set-switching. Processing speed and visuoconstruction predicted pathologic group (P = .03). DISCUSSION:Processing speed and visuoconstruction predicted postmortem diagnosis of AD versus AD plus LBD. Current results offer guidance in the selection and interpretation of neuropsychological tests to be used in the differential diagnosis of early dementia. 10.1002/alz.12120
    ATN status in amnestic and non-amnestic Alzheimer's disease and frontotemporal lobar degeneration. Cousins Katheryn A Q,Irwin David J,Wolk David A,Lee Edward B,Shaw Leslie M J,Trojanowski John Q,Da Re Fulvio,Gibbons Garrett S,Grossman Murray,Phillips Jeffrey S Brain : a journal of neurology Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer's disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer's disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-β1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-β1-42. Results show that non-amnestic Alzheimer's disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-β1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-β1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-β1-42 were significantly lower in non-amnestic compared to amnestic Alzheimer's disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer's disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer's disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer's disease pathology. We conclude that amyloid-β1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer's disease than either the ATN framework or the phosphorylated-tau/amyloid-β1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer's disease. 10.1093/brain/awaa165
    Morphometric network differences in ageing versus Alzheimer's disease dementia. Pichet Binette Alexa,Gonneaud Julie,Vogel Jacob W,La Joie Renaud,Rosa-Neto Pedro,Collins D Louis,Poirier Judes,Breitner John C S,Villeneuve Sylvia,Vachon-Presseau Etienne, , Brain : a journal of neurology Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ranging from young adults (n = 468; age range 18-35 years), to older adults with intact cognition (n = 431; age range 55-90 years) and with Alzheimer's disease (n = 50 with late mild cognitive impairment and 71 with Alzheimer's dementia, age range 56-88 years), we investigated grey matter organization and volume differences in ageing and Alzheimer's disease. Using independent component analysis on all participants' structural MRI, we first derived morphometric networks and extracted grey matter volume in each network. We also derived a measure of whole-brain grey matter pattern organization by correlating grey matter volume in all networks across all participants from the same cohort. We used logistic regressions and receiver operating characteristic analyses to evaluate how well grey matter volume in each network and whole-brain pattern could discriminate between ageing and Alzheimer's disease. Because increased heterogeneity is often reported as one of the main features characterizing brain ageing, we also evaluated interindividual heterogeneity within morphometric networks and across the whole-brain organization in ageing and Alzheimer's disease. Finally, to investigate the clinical validity of the different grey matter features, we evaluated whether grey matter volume or whole-brain pattern was related to clinical progression in cognitively normal older adults. Ageing and Alzheimer's disease contributed additive effects on grey matter volume in nearly all networks, except frontal lobe networks, where differences in grey matter were more specific to ageing. While no networks specifically discriminated Alzheimer's disease from ageing, heterogeneity in grey matter volumes across morphometric networks and in the whole-brain grey matter pattern characterized individuals with cognitive impairments. Preservation of the whole-brain grey matter pattern was also related to lower risk of developing cognitive impairment, more so than grey matter volume. These results suggest both ageing and Alzheimer's disease involve widespread atrophy, but that the clinical expression of Alzheimer's disease is uniquely associated with disruption of morphometric organization. 10.1093/brain/awz414
    Exercise benefits on Alzheimer's disease: State-of-the-science. Valenzuela Pedro L,Castillo-García Adrián,Morales Javier S,de la Villa Pedro,Hampel Harald,Emanuele Enzo,Lista Simone,Lucia Alejandro Ageing research reviews Although there is no unanimity, growing evidence supports the value of regular physical exercise to prevent Alzheimer's disease as well as cognitive decline in affected patients. Together with an introductory summary on epidemiological evidence, the aim of this review is to summarize the current knowledge on the potential biological mechanisms underlying exercise benefits in this condition. Regular physical exercise has proven to be beneficial for traditional cardiovascular risk factors (e.g., reduced vascular flow, diabetes) involved in the pathogenesis of Alzheimer's disease. Exercise also promotes neurogenesis via increases in exercise-induced metabolic factors (e.g., ketone bodies, lactate) and muscle-derived myokines (cathepsin-B, irisin), which in turn stimulate the production of neurotrophins such as brain-derived neurotrophic factor. Finally, regular exercise exerts anti-inflammatory effects and improves the brain redox status, thereby ameliorating the pathophysiological hallmarks of Alzheimer's disease (e.g., amyloid-β deposition). In summary, physical exercise might provide numerous benefits through different pathways that might, in turn, help prevent risk and progression of Alzheimer's disease. More evidence is needed, however, based on human studies. 10.1016/j.arr.2020.101108
    Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument. Amariglio Rebecca E,Donohue Michael C,Marshall Gad A,Rentz Dorene M,Salmon David P,Ferris Steven H,Karantzoulis Stella,Aisen Paul S,Sperling Reisa A, JAMA neurology IMPORTANCE:Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. OBJECTIVE:To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. DESIGN, SETTING, AND PARTICIPANTS:Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. MAIN OUTCOMES AND MEASURES:The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. RESULTS:At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P<.001), partner (5.08, SE=0.59, P<.001), and self plus partner (7.04, SE=0.83, P<.001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P<.012) and self plus partner (1.56, SE=0.63, P<.014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. CONCLUSIONS AND RELEVANCE:Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease. 10.1001/jamaneurol.2014.3375
    Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease. Younan Diana,Petkus Andrew J,Widaman Keith F,Wang Xinhui,Casanova Ramon,Espeland Mark A,Gatz Margaret,Henderson Victor W,Manson JoAnn E,Rapp Stephen R,Sachs Bonnie C,Serre Marc L,Gaussoin Sarah A,Barnard Ryan,Saldana Santiago,Vizuete William,Beavers Daniel P,Salinas Joel A,Chui Helena C,Resnick Susan M,Shumaker Sally A,Chen Jiu-Chiuan Brain : a journal of neurology Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 μg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage. 10.1093/brain/awz348
    Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease. Müller Stephan,Preische Oliver,Sohrabi Hamid R,Gräber Susanne,Jucker Mathias,Ringman John M,Martins Ralph N,McDade Eric,Schofield Peter R,Ghetti Bernardino,Rossor Martin,Fox Nick N,Graff-Radford Neill R,Levin Johannes,Danek Adrian,Vöglein Jonathan,Salloway Stephen,Xiong Chengjie,Benzinger Tammie,Buckles Virginia,Masters Colin L,Sperling Reisa,Bateman Randall J,Morris John C,Laske Christoph, Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Little is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer's disease (AD). METHODS:A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross-sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations. RESULTS:Mutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD-like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers. DISCUSSION:These results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD. 10.1016/j.jalz.2018.06.3059