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BackgroundPerivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. However, it is unknown whether PVS can predict dementia risk and brain atrophy trajectories in participants without dementia, as longitudinal studies on PVS are scarce and current methods for PVS assessment lack robustness and inter-scanner reproducibility.MethodsWe developed a robust algorithm to automatically assess PVS count and size on clinical MRI, and investigated 1) their relationship with dementia risk and brain atrophy in participants without dementia, 2) their longitudinal evolution, and 3) their potential use as a screening tool in simulated clinical trials. We analysed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1 ± 9.7 years-old, 56.6% women) from three publicly available observational studies on ageing and dementia (the Alzheimer's Disease Neuroimaging Initiative, the National Alzheimer's Coordinating Centre database, and the Open Access Series of Imaging Studies). Clinical and MRI data collected between 2004 and 2022 were analysed with consistent methods, controlling for confounding factors, and combined using mixed-effects models.FindingsOur fully-automated method for PVS assessment showed excellent inter-scanner reproducibility (intraclass correlation coefficients >0.8). Fewer PVS and larger PVS diameter at baseline predicted higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers differed significantly in participants without dementia who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants at low risk of dementia based on our PVS markers enhanced the power of the trial independently of Alzheimer's disease biomarkers.InterpretationThese robust cerebrovascular markers predict dementia risk and brain atrophy and may improve risk-stratification of patients, potentially reducing cost and increasing throughput of clinical trials to combat dementia.FundingUS National Institutes of Health.

IntroductionBlood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear.MethodsOlder adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE ?4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4.ResultsBBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers.DiscussionAPOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade.HighlightsGray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

IntroductionThere is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD).MethodsUsing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS.ResultsThe MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau.DiscussionThe MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment.HighlightsA multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer's disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

BackgroundDeep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics.MethodsThe c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification.FindingsThe application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6).InterpretationOur results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation.FundingThe specific funding of this article is provided in the acknowledgements section.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R 2). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.HighlightsWe found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

Studies have shown that women on the Alzheimer's disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-β (Aβ) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aβ and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aβ positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

The interaction between APOE ɛ4 and vascular risk factors on cognitive function is stronger in women than in men. These effects may be mediated by the amount of tau pathology in the brain. Therefore, we examined whether APOE ɛ4 and sex modify cross-sectional associations between cardiovascular risk and tau deposition in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative. We calculated the Framingham Heart Study cardiovascular disease risk score for 141 participants (74 women, 47 APOE ɛ4 carriers) with complete medical history data, processed tau-PET data and a Clinical Dementia Rating global score of 0.0 at the time of the tau-PET scan, implying no significant cognitive or functional impairment. We used linear regression models to examine the effects of sex, APOE ɛ4, cardiovascular risk and their interactions on tau deposition in the entorhinal cortex, inferior temporal cortex and a composite meta-region of interest of temporal lobe areas. We found a significant three-way interaction among sex, APOE ɛ4 status and cardiovascular disease risk on tau deposition in the entorhinal cortex (β = 0.04; 95% CI, 0.01-0.07; P = 0.008), inferior temporal cortex (β = 0.02; 95% CI, 0.0-0.05; P = 0.029) and meta-region (β = 0.02; 95% CI, 0.0-0.04; P = 0.042). After stratifying by APOE ɛ4 status to examine interactions between sex and cardiovascular disease risk on tau in APOE ɛ4 carriers and non-carriers, we found a significant two-way interaction between sex and cardiovascular disease risk on tau in the entorhinal cortex (β = 0.05; 95% CI, 0.02-0.08; P = 0.001), inferior temporal cortex (β = 0.03; 95% CI, 0.01-0.05; P =0.009) and meta-region (β = 0.02; 95% CI, 0.01-0.04; P = 0.008) only among APOE ɛ4 carriers. In analyses stratified by sex, higher cardiovascular risk scores were associated with higher levels of tau in the entorhinal cortex (β = 0.05; 95% CI, 0.02-0.08; P = 0.002), inferior temporal cortex (β = 0.02; 95% CI, 0.0-0.05; P = 0.023) and meta-region (β = 0.02; 95% CI, 0.01-0.04; P = 0.013) in female APOE ɛ4 carriers but not in male carriers. Our findings suggest that cognitively normal older women carrying at least one APOE ɛ4 allele, may be particularly vulnerable to the effects of cardiovascular disease risk on early tau deposition.

BackgroundStudies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.MethodsOur sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.ResultsTotal and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = -2.10 [-3.97 to -0.27], p = 0.027 and β = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).ConclusionsMMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.

Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit.

IntroductionSuperAgers are individuals over age 80 with superior episodic memory, at a level consistent with individuals 20 to 30 years their junior and who seem to show resistance to age-related neurofibrillary degeneration. Here we examine whether low genetic risk for Alzheimer's disease (AD) contributes to SuperAgers' unusually high episodic memory performance in advanced age.MethodsThe AD polygenic hazard score (PHS) was calculated for each SuperAger and cognitively normal participant and compared between groups.ResultsA total of 37 SuperAgers (73% female, mean [standard deviation] 82.7 [2.8] years old) and 35 controls (54% female, 83.7 [4.3] years old) were included. There was no significant difference in the AD PHS between SuperAgers and cognitively normal controls.DiscussionUnusually successful cognitive aging cannot be simply explained by low polygenic risk for AD as assessed by common genetic variants. However, rare variants and common protective genetic factors may contribute to resistance or resilience.HighlightsSuperAging cannot be simply explained by low polygenic risk for Alzheimer's disease.Rare variants and common protective genetic factors may contribute to SuperAging.A protective factors polygenic score may uncover mechanisms for SuperAging.

BackgroundThe increasing prevalence of Alzheimer's disease (AD) and lack of effective medications has led to a need to identify modifiable risk factors as targets for interventions.ObjectiveIn this cross-sectional study, we sought to determine whether worse sleep quality is associated with increased pathological tau, and whether this relationship is affected by amyloid pathology.Methods66 male participants underwent Florbetapir (AV45) positron emission tomography (PET) and Flortaucipir (FTP) PET and completed the Pittsburgh Sleep Quality Index questionnaire (PSQI) as part of the Department of Defense Alzheimer's Disease Neuroimaging Initiative, a multicenter study collecting data from Vietnam War veterans, some of whom have a history of post-traumatic stress disorder, or non-penetrating traumatic brain injury. AV45 PET was used to determine the presence of significant amyloid pathology. We used regression models to determine the effects of amyloid pathology and PSQI on tau deposition in brain regions associated with Braak stages.ResultsAmong the 66 participants, 14 individuals were amyloid positive (21%) and 52 were amyloid negative (79%). In regions associated with Braak stages III-IV, there was a significant interaction of amyloid status on PSQI (β= 0.04, p = 0.003) with higher PSQI correlating with higher FTP SUVr in amyloid-positive individuals only (β= 0.031, p = 0.005).ConclusionOur study found that an AD profile of tau deposition was associated with an interaction between self-reported sleep quality and amyloid pathology such that worse self-reported sleep was related to higher tau in regions usually associated with AD progression, but only in individuals with high cerebral amyloid deposition.

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.

IntroductionElevated β-amyloid is used to enroll individuals into preclinical Alzheimer's disease trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment.MethodsAlzheimer's disease incidence rates and a polygenic hazard score were used to create a gene- and age-defined ADAge. An ADAge cutpoint was chosen to optimally predict β-amyloid positivity among clinically normal Alzheimer's Disease Neuroimaging Initiative participants and applied to an independent Alzheimer's Disease Research Center validation cohort. The impact of ADAge enrichment on screening costs was evaluated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial data.ResultsIn the validation cohort, the ADAge-enriched sample had a higher proportion of individuals with elevated β-amyloid (difference [95% CI] 0.19[0.07 to 0.33]) than the unenriched sample. ADAge enrichment lowered screening costs by $4.41 million (31.00%) in the real-world clinical trial scenario.DiscussionADAge enrichment provides for a more efficient and cost-effective means to enroll clinically normal individuals with elevated β-amyloid in clinical trials.

In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P

The lack of accessible noninvasive tools to examine the molecular alterations occurring in the brain limits our understanding of the causes and progression of Alzheimer's disease (AD), as well as the identification of effective therapeutic strategies. Here, we conducted a comprehensive profiling of circulating, cell-free messenger RNA (cf-mRNA) in plasma of 126 patients with AD and 116 healthy controls of similar age. We identified 2591 dysregulated genes in the cf-mRNA of patients with AD, which are enriched in biological processes well known to be associated with AD. Dysregulated genes included brain-specific genes and resembled those identified to be dysregulated in postmortem AD brain tissue. Furthermore, we identified disease-relevant circulating gene transcripts that correlated with the severity of cognitive impairment. These data highlight the potential of high-throughput cf-mRNA sequencing to evaluate AD-related pathophysiological alterations in the brain, leading to precision healthcare solutions that could improve AD patient management.

BackgroundGrowing awareness of Alzheimer's disease (AD) has prompted a demand for quick and effective ways to screen for memory loss and cognitive decline in large numbers of individuals in the community. Periodic Memory Screening Day events provide free, brief cognitive screening aimed at those 65 years and older, and can serve as an opportunity to gauge participants' attitudes towards AD research and recruit them into ongoing research projects.MethodsOver 6 single-day events in 2 years, more than 574 individuals were individually screened using the MoCA and a story recall task (immediate and delayed), given feedback about their performance, and introduced to AD research and opportunities to participate.ResultsScreening classified 297 individuals (52.0%) as having "No Decline," 192 (33.6%) as "Possible decline," and 82 (14.4%) as "Likely decline." Those with "Likely decline" were older and less educated, had more memory concerns, were more likely to be men, and were less likely to have a positive family history of dementia than those with "No Decline." Subsequent validation of screening procedures against a full clinical evaluation showed 72% classification accuracy with a skew towards over-calling Possible and Likely decline and thereby guiding questionable individuals to a more thorough evaluation. Of those screened, 378 (66%) agreed to additional research and consented to being listed in a research registry, and a majority (70-85%) of those consenting reported they were amenable to various AD research procedures including lumbar puncture, MRI, and autopsy. Overall, 19.1% of those screened met inclusion criteria for ongoing studies and were successfully recruited into AD research.ConclusionsConducting a few concentrated community memory screening events each year may help meet the public's demand for brief assessment of memory concerns and can be a relatively effective and efficient recruitment strategy for AD research.

In the clinical diagnosis of dementia with Lewy bodies, distinction from Alzheimer's disease is suboptimal and complicated by shared genetic risk factors and frequent co-pathology. In the present study we tested the ability of polygenic scores for Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease to differentiate individuals in a 2713-participant, pathologically defined sample. A dementia with Lewy bodies polygenic score that excluded apolipoprotein E due to its overlap with Alzheimer's disease risk was specifically associated with at least limbic (transitional) Lewy-related pathology and a pathological diagnosis of dementia with Lewy bodies. An Alzheimer's disease polygenic score was associated with neuritic plaques and neurofibrillary tangles but not Lewy-related pathology, and was most strongly associated with an Alzheimer's pathological diagnosis. Our results indicate that an assessment of genetic risk may be useful to clinically distinguish between Alzheimer's disease and dementia with Lewy bodies. Notably, we found no association with a Parkinson's disease polygenic score, which aligns with evidence that dementia with Lewy bodies has a distinct genetic signature that can be exploited to improve clinical diagnoses.

ObjectiveTo determine the cognitive consequences of anticholinergic medications (aCH) in cognitively normal older adults as well as interactive effects of genetic and CSF Alzheimer disease (AD) risk factors.MethodsA total of 688 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative were evaluated (mean age 73.5 years, 49.6% female). Cox regression examined risk of progression to mild cognitive impairment (MCI) over a 10-year period and linear mixed effects models examined 3-year rates of decline in memory, executive function, and language as a function of aCH. Interactions with APOE ε4 genotype and CSF biomarker evidence of AD pathology were also assessed.ResultsaCH+ participants had increased risk of progression to MCI (hazard ratio [HR] 1.47, p = 0.02), and there was a significant aCH × AD risk interaction such that aCH+/ε4+ individuals showed greater than 2-fold increased risk (HR 2.69, p < 0.001) for incident MCI relative to aCH-/ε4-), while aCH+/CSF+) individuals demonstrated greater than 4-fold (HR 4.89, p < 0.001) increased risk relative to aCH-/CSF-. Linear mixed effects models revealed that aCH predicted a steeper slope of decline in memory (t = -2.35, p = 0.02) and language (t = -2.35, p = 0.02), with effects exacerbated in individuals with AD risk factors.ConclusionsaCH increased risk of incident MCI and cognitive decline, and effects were significantly enhanced among individuals with genetic risk factors and CSF-based AD pathophysiologic markers. Findings underscore the adverse impact of aCH medications on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD.

BACKGROUND: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimers disease, their independent or synergistic effects on cognitive decline are unclear. OBJECTIVE: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. METHODS: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimers disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. RESULTS: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. CONCLUSION: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.

BackgroundAlthough amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer's disease, their independent or synergistic effects on cognitive decline are unclear.ObjectiveTo examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia.MethodsRestriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline.ResultsLower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF.ConclusionAβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.

BackgroundLate-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness.MethodsWe analyzed data from 131 amyloid-β positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores.ResultsFTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition.ConclusionsOur findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness.

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

ImportanceEdonerpic maleate (T-817MA) protects against Aβ40-induced neurotoxic effects and memory deficits, promotes neurite outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice. These effects may be mediated via sigma-1 receptor activation, delivery of synaptic AMPA receptors, or modulation of microglial function and may benefit patients with Alzheimer disease.ObjectiveTo assess the efficacy, safety, and tolerability of edonerpic for patients with mild to moderate Alzheimer disease.Design, setting, and participantsRandomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial conducted over 52 weeks from June 2, 2014, to December 14, 2016, at 52 US clinical and academic centers. Of 822 outpatients screened, 484 met the following criteria and were randomly assigned to treatment: 55 to 85 years of age, probable Alzheimer disease, Mini-Mental State Examination scores from 12 to 22, and taking stable doses of donepezil or rivastigmine with or without memantine.InterventionsRandom assignment (1:1:1 allocation) to placebo or 224 mg or 448 mg of edonerpic maleate, once per day.Main outcomes and measuresCoprimary outcomes were scores on the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinical Impression of Change (ADCS-CGIC) at week 52. Biomarkers were brain, lateral ventricular, and hippocampal volumes, as determined on magnetic resonance imaging, and cerebrospinal fluid Aβ40, Aβ42, total tau, and phospho-tau181. The primary efficacy analysis was performed on the coprimary end points for the modified intention-to-treat population.ResultsOf 482 participants in the safety population, 140 of 158 participants (88.6%) assigned to placebo, 117 of 166 participants (70.5%) to 224 mg of edonerpic maleate, and 120 of 158 participants (76.0%) to 448 mg of edonerpic maleate completed the trial. The mean ADAS-cog score change at week 52 was 7.91 for the placebo group, 7.45 for the 224-mg group, and 7.08 for the 448-mg group. Mean differences from placebo were -0.47 (95% CI, -2.36 to 1.43; P = .63) for the 224-mg group and -0.84 (95% CI, -2.75 to 1.08; P = .39) for the 448-mg group. Mean ADCS-CGIC scores were 5.22 for the placebo group, 5.24 for the 224-mg group, and 5.25 for the 448-mg group, with mean differences from placebo of 0.03 (95% CI, -0.20 to 0.25; P = .81) for the 224-mg group and 0.04 (95% CI, -0.19 to 0.26; P = .76) for the 448-mg group. In the safety population, a total of 7 of 158 participants (4.4%) in the placebo group, 23 of 166 participants (13.9%) in the 224-mg group, and 23 of 158 participants (14.6%) in the 448-mg group discontinued because of adverse events. The most frequent adverse events were diarrhea and vomiting.Conclusions and relevanceEdonerpic maleate appeared to be safe and tolerable, with expected gastrointestinal symptoms occurring early but without evidence for a clinical effect among patients with mild to moderate Alzheimer disease.Trial registrationClinicalTrials.gov identifier: NCT02079909.

Structural adaptations in brain regions involved in domain-general cognitive control are associated with life-long bilingualism and may contribute to the executive function advantage of bilinguals over monolinguals. To the degree that these adaptations support bilingualism, their disruption by Alzheimer's disease (AD) may compromise the ability to maintain proficiency in two languages, particularly in the less proficient, or nondominant, language that has greater control demands. The present study assessed this possibility in Spanish-English bilinguals with AD (n = 21) and cognitively normal controls (n = 30) by examining the brain correlates of dominant versus nondominant language performance on the Multilingual Naming Test (MINT), adjusting for age and education. There were no significant structural correlates of naming performance for either language in controls. In patients with AD, dominant language MINT performance was associated with cortical thickness of the entorhinal cortex and middle temporal gyrus, consistent with previous findings of temporal atrophy and related decline of naming abilities in AD. Nondominant language MINT performance, in contrast, was correlated with thickness of the left caudal anterior cingulate cortex (ACC), a central cognitive control region involved in error monitoring and task switching. The relationship between naming in the nondominant language and ACC in patients with AD but not in controls may reflect increased reliance on the ACC for nondominant language use in the face of atrophy of other control network components. The results are consistent with the possibility that the increased burden nondominant language use places on cognitive control systems compromised in AD may account for faster nondominant than dominant language decline in AD.

Hippocampal sclerosis (HS) is a prevalent cause of dementia in the oldest old but is generally misdiagnosed as Alzheimer's disease (AD) due to similarities in clinical presentation. To determine if clinical and cognitive features diverge over time, we compared results from longitudinal evaluations of participants in the University of California, San Diego, Alzheimer's Disease Research Center with autopsy-confirmed AD (n = 195), HS (n = 21), or both HS + AD (n = 18). Each group exhibited decline in all cognitive measures, with HS declining at a slower rate than AD on the Mini-Mental State Examination, immediate recall condition of a word-list learning test, and Dementia Rating Scale total and subtest scores (except memory). Five years before the final evaluation, more prominent semantic and visuospatial deficits were apparent in AD participants than in HS participants despite comparable global cognitive impairment. Groups did not differ on any measure of executive function. HS + AD differed from AD only on the Boston Naming Test. Overall, results suggest that HS dementia is associated with cognitive deficits that progress more slowly than, but generally mimic, those observed in AD.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR

BackgroundBiomarkers may soon be used to predict decline in older individuals. Extended follow-up studies are needed to determine the stability of such biomarker-based predictions.ObjectiveTo examine the long-term performance of baseline cognitive, neuroimaging, and cerebrospinal fluid (CSF) biomarker-assisted prognosis in patients with mild cognitive impairment.MethodsEstablished, biomarker-defined, cohorts of subjects with mild cognitive impairment were examined for progression to dementia. Subjects with a baseline volumetric MRI, lumbar puncture, and Rey Auditory Verbal Learning Test were included. Dementia-free survival time in each biomarker-defined risk group was determined with Kaplan-Meier survival curves. The influence of each risk factor or combination of factors on dementia-free survival was examined with Cox proportional hazard analyses.Results185 subjects were followed longitudinally for a mean (SD) 4.3 (2.8) years. 59% of participants converted within the follow-up period and the median dementia-free survival time was 2.8 years. Each individual risk factor predicted conversion to dementia (HR 1.9-3.7). The joint presence of any two risk factors increased risk for conversion (HR 7.1-11.0), with the presence of medial temporal atrophy and memory impairment showing the greatest risk for decline. Concordant atrophy, memory impairment, and abnormal CSF amyloid and tau was associated with the highest risk for conversion (HR 15.1). The presence of medial temporal atrophy was associated with the shortest dementia-free survival time, both alone and in combination with memory impairment, abnormal CSF amyloid and tau, or both.ConclusionThese results suggest that baseline biomarker-assisted predictions of decline to dementia are stable over the long term, and that combinations of complementary biomarkers can improve the accuracy of these predictions.

Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.

There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4-91.4, 98.83% white) individuals from the Alzheimer's Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3-108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.

Improved characterization of the microstructural brain changes occurring in the early stages of Alzheimer's disease may permit more timely disease detection. This study examined how longitudinal change in brain microstructure relates to cognitive decline in aging and prodromal Alzheimer's disease. At baseline and two-year follow-up, 29 healthy controls and 21 individuals with mild cognitive impairment or mild Alzheimer's disease underwent neuropsychological evaluation and restriction spectrum imaging (RSI). Microstructural change in the hippocampus, entorhinal cortex, and white matter tracts previously shown to be vulnerable to Alzheimer's disease, was compared between healthy controls and impaired participants. Partial correlations and stepwise linear regressions examined whether baseline RSI metrics predicted subsequent cognitive decline, or change in RSI metrics correlated with cognitive change. In medial temporal gray and white matter, restricted isotropic diffusion and crossing fibers were lower, and free water diffusion was higher, in impaired participants. Restricted isotropic diffusion in the hippocampus declined more rapidly for cognitively impaired participants. Baseline hippocampal restricted isotropic diffusion predicted cognitive decline, and change in hippocampal and entorhinal restricted isotropic diffusion correlated with cognitive decline. Within controls, changes in white matter restricted oriented diffusion and crossing fibers correlated with memory decline. In contrast, there were no correlations between rates of cortical atrophy and cognitive decline in the full sample or within controls. Changes in medial temporal lobe microarchitecture were associated with cognitive decline in prodromal Alzheimer's disease, and these changes were distinct from microstructural changes in normal cognitive aging. RSI metrics of brain microstructure may hold value for predicting cognitive decline in aging and for monitoring the course of Alzheimer's disease.

BackgroundDiffusion imaging has demonstrated sensitivity to structural brain changes in Alzheimer's disease (AD). However, there remains a need for a more complete characterization of microstructural alterations occurring at the earliest disease stages, and how these changes relate to underlying neuropathology. This study evaluated the sensitivity of restriction spectrum imaging (RSI), an advanced diffusion magnetic resonance imaging (MRI) technique, to microstructural brain changes in mild cognitive impairment (MCI) and AD.MethodsMRI and neuropsychological test data were acquired from 31 healthy controls, 12 individuals with MCI, and 13 individuals with mild AD, aged 63-93 years. Cerebrospinal fluid amyloid-β levels were measured in a subset (n = 38) of participants. RSI measures of neurite density (ND) and isotropic free water (IF) were computed in fiber tracts and in hippocampal and entorhinal cortex gray matter, respectively. Analyses evaluated whether these measures predicted memory performance, correlated with amyloid-β levels, and distinguished impaired individuals from controls. For comparison, analyses were repeated with standard diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity.ResultsBoth RSI and DTI measures correlated with episodic memory and disease severity. RSI, but not DTI, measures correlated with amyloid-β42 levels. ND and FA in the arcuate fasciculus and entorhinal cortex IF most strongly predicted recall performance. RSI measures of arcuate fasciculus ND and entorhinal cortex IF best discriminated memory impaired participants from healthy participants.ConclusionsRSI is highly sensitive to microstructural changes in the early stages of AD, and is associated with biochemical markers of AD pathology. Reduced ND in cortical association fibers and increased medial temporal lobe free-water diffusion predicted episodic memory, distinguished cognitively impaired from healthy individuals, and correlated with amyloid-β. Although further research is needed to assess the sensitivity of RSI to preclinical AD and disease progression, these results suggest that RSI may be a promising tool to better understand neuroanatomical changes in AD and their association with neuropathology.