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Background: Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aβ)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel., Methods: The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aβ pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [ 11 C] PiB PET, [ 18 F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers., Results: NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype., Conclusions: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD., (© 2024. The Author(s).)

Objectives: Neurocritically ill patients are at high risk for developing delirium, which can worsen the long-term outcomes of this vulnerable population. However, existing delirium assessment tools do not account for neurologic deficits that often interfere with conventional testing and are therefore unreliable in neurocritically ill patients. We aimed to determine the accuracy and predictive validity of the Fluctuating Mental Status Evaluation (FMSE), a novel delirium screening tool developed specifically for neurocritically ill patients., Design: Prospective validation study., Setting: Neurocritical care unit at an academic medical center., Patients: One hundred thirty-nine neurocritically ill stroke patients (mean age, 63.9 [sd, 15.9], median National Institutes of Health Stroke Scale score 11 [interquartile range, 2-17])., Interventions: None., Measurements and Main Results: Expert raters performed daily Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based delirium assessments, while paired FMSE assessments were performed by trained clinicians. We analyzed 717 total noncomatose days of paired assessments, of which 52% (n = 373) were rated by experts as days with delirium; 53% of subjects were delirious during one or more days. Compared with expert ratings, the overall accuracy of the FMSE was high (area under the curve [AUC], 0.85; 95% CI, 0.82-0.87). FMSE scores greater than or equal to 1 had 86% sensitivity and 74% specificity on a per-assessment basis, while scores greater than or equal to 2 had 70% sensitivity and 88% specificity. Accuracy remained high in patients with aphasia (FMSE ≥ 1: 82% sensitivity, 64% specificity; FMSE ≥ 2: 64% sensitivity, 84% specificity) and those with decreased arousal (FMSE ≥ 1: 87% sensitivity, 77% specificity; FMSE ≥ 2: 71% sensitivity, 90% specificity). Positive FMSE assessments also had excellent accuracy when predicting functional outcomes at discharge (AUC, 0.86 [95% CI, 0.79-0.93]) and 3 months (AUC, 0.85 [95% CI, 0.78-0.92])., Conclusions: In this validation study, we found that the FMSE was an accurate delirium screening tool in neurocritically ill stroke patients. FMSE scores greater than or equal to 1 indicate "possible" delirium and should be used when prioritizing sensitivity, whereas scores greater than or equal to 2 indicate "probable" delirium and should be used when prioritizing specificity., Competing Interests: Dr. Reznik’s institution received funding from the National Institute on Aging (NIA) and the Rhode Island Foundation; he is supported by the Network for Investigation of Delirium: Unifying Scientists (NIDUS) Junior Investigator Award (NIA R24AG054259 subaward). Drs. Reznik and Snitz received support for article research from the National Institutes of Health (NIH). Dr. Margolis’ institution received funding from the NIDUS; he received support for article research from NIDUS. Dr. Girard’s institution received funding from the NIH, the Department of Defense, Ceribell, and Lungpacer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Importance: Poststroke cognitive impairment is common, but the cognitive trajectory following a first stroke, relative to prestroke cognitive function, remains unclear., Objective: To map the trajectory of cognitive function before any stroke and after stroke in global cognition and in 4 cognitive domains, as well as to compare the cognitive trajectory prestroke in stroke survivors with the trajectory of individuals without incident stroke over follow-up., Design, Setting, and Participants: The study used harmonized and pooled data from 14 population-based cohort studies included in the Cohort Studies of Memory in an International Consortium collaboration. These studies were conducted from 1993 to 2019 across 11 countries among community-dwelling older adults without a history of stroke or dementia. For this study, linear mixed-effects models were used to estimate trajectories of cognitive function poststroke relative to a stroke-free cognitive trajectory. The full model adjusted for demographic and vascular risk factors. Data were analyzed from July 2022 to March 2024., Exposure: Incident stroke., Main Outcomes and Measures: The primary outcome was global cognition, defined as the standardized average of 4 cognitive domains (language, memory, processing speed, and executive function). Cognitive domain scores were formed by selecting the most commonly administered test within each domain and standardizing the scores., Results: The study included 20 860 participants (12 261 [58.8%] female) with a mean (SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD; 95% CI, -0.33 to -0.17 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year; 95% CI, -0.057 to -0.019 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures. The mean rate of decline without a previous stroke was -0.049 SD per year (95% CI, -0.051 to -0.047 SD) in global cognition., Conclusions and Relevance: In this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aβ PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aβ in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aβ (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aβ differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Blood-based biomarkers are gaining grounds for Alzheimer's disease (AD) detection. However, two key obstacles need to be addressed: the lack of methods for multi-analyte assessments and the need for markers of neuroinflammation, vascular, and synaptic dysfunction. Here, we evaluated a novel multi-analyte biomarker platform, NULISAseq CNS disease panel, a multiplex NUcleic acid-linked Immuno-Sandwich Assay (NULISA) targeting ~120 analytes, including classical AD biomarkers and key proteins defining various disease hallmarks., Methods: The NULISAseq panel was applied to 176 plasma samples from the MYHAT-NI cohort of cognitively normal participants from an economically underserved region in Western Pennsylvania. Classical AD biomarkers, including p-tau181 p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were also measured using Single Molecule Array (Simoa). Amyloid pathology, tau pathology, and neurodegeneration were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and MRI, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA biomarkers and AD pathologies. Spearman correlations were used to compare NULISA and Simoa., Results: NULISA concurrently measured 116 plasma biomarkers with good technical performance, and good correlation with Simoa measures. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET+ participants, including TIMP3, which regulates brain Aβ production, the neurotrophic factor BDNF, the energy metabolism marker MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET+ participants. Markers with tau PET-dependent longitudinal changes included the microglial activation marker CHIT1, the reactive astrogliosis marker CHI3L1, the synaptic protein NPTX1, and the cerebrovascular markers PGF, PDGFRB, and VEFGA; all previously linked to AD but only reliably measured in cerebrospinal fluid. SQSTM1, the autophagosome cargo protein, exhibited a significant association with neurodegeneration status after adjusting age, sex, and APOE ε4 genotype., Conclusions: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

Introduction: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains., Methods: In a prospective study with repeated assessments of a randomly selected population-based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)., Results: Cross-sectionally, memory showed the strongest associations with p-tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data-driven cutoffs, most efficiently with Aβ42/40. GFAP and Aβ42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively., Discussion: These relatively non-invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis., Highlights: We performed a prospective study with up to 8 years of repeated domain-specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population-based cohort. We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique. Cross-sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain. Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein. These relatively non-invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies., (© 2024. The Author(s).)

Introduction: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition., Methods: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aβ) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction., Results: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aβ- and tau-affected regions, respectively. Racialization did not modify these relationships., Discussion: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups., Highlights: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years., Methods: We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments., Results: By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster ( p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years)., Discussion: There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

In this study, we examined associations of social isolation and loneliness with cognitive impairment among older adults from a Rust Belt region in Southwest Pennsylvania. We used data from the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study. We found that (a) 11 items combined into two reliable composites of social isolation and loneliness; (b) unique to this study, providing unpaid help to others was an indicator of reduced social isolation; (c) social isolation and loneliness were positively associated with cognitive impairment; and (d) these associations were appreciably attenuated by general health and physical functional status and depressive symptoms, respectively. We concluded that social isolation and loneliness are differentially associated with older adults' cognitive health, and that their effects might operate through separate pathways. Approaches to address social isolation and loneliness should consider the community context and its implications for older adults' cognitive health., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Cognitive abilities have substantial heritability throughout life, as shown by twin- and population-based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains., Methods: We conducted a meta-analysis on 3045 individuals aged ≥65, derived from three population-based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene-based and functional bioinformatics analyses., Results: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E-09) and global cognitive function (p = 1.84E-08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E-08), near RASEF. Gene-based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS-CoV-2, to be associated with the decline in global cognitive function (p = 4.28E-07)., Discussion: Domain-specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains., Highlights: rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS-CoV-2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk., (© 2023. The Author(s).)

Introduction: Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task. We also explored associations of DSST task performance with brain activation, SCD severity, and amyloid-ß (Aß) load., Methods: We analyzed data from 63 cognitively normal older individuals (mean age 73.6 ± 7.2) with varying degree of SCD symptoms. Participants completed a computerized version of DSST in the MR scanner and a Pittsburgh Compound-B (PiB)-PET scan to measure global cerebral Aß load., Results: A voxel-wise analysis revealed that greater SCD severity was associated with lower dorsomedial thalamus activation. While task performance was not associated with brain activation nor Aß load, slower reaction time was associated with greater SCD severity., Discussion: The observed lower dorsomedial thalamus activation may reflect declining familiarity-based working memory and the trans-thalamic executive function pathway in SCD. SCD symptoms may reflect altered neural function and subtle decline of executive function, while Aß load may have an indirect impact on neural function and performance. Self-perceived cognitive decline may serve as a psychological/subjective marker reflecting subtle brain changes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mizuno, Karim, Ly, Lopresti, Cohen, Ali, Mathis, Klunk, Aizenstein and Snitz.)

An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast + ). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast + individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials., (© 2023. The Author(s).)

Objective: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies., Method: We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies., Results: We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change., Conclusions: This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: To investigate the relationship between anxiety and mild cognitive impairment (MCI), and whether it is mediated by perceived stress, at the population level., Method and Design: In a longitudinal study of 368 adults aged 65+ from a population-based cohort, we annually assessed anxiety symptoms (GAD-7), perceived stress (PSS-4), and ratings on the Clinical Dementia Rating (CDR®), where CDR = 0.5 was operationalized as MCI. Examining data from three consecutive assessment waves, we first determined the associations between anxiety at the first wave with MCI at the third wave, and vice versa. We then used mediation analyses to determine whether the pathways in both directions were mediated by perceived stress at the second wave, adjusting for demographics and other relevant covariates., Results: We confirmed significant bidirectional longitudinal associations between anxiety and MCI. Perceived stress was detected as a significant mediator for both pathways between anxiety and MCI, explaining 37.1% of the total effect (TE) of anxiety on incident MCI while conversely explaining 27.1% of the TE of MCI on anxiety., Conclusions: A bidirectional relationship with a 2-year lag between anxiety and MCI was mediated through perceived stress. Clinicians should be sensitive both to potential consequent anxiety when patients present with cognitive impairment, and to potential incipient MCI when the presenting complaint is anxiety. Managing stress may help mitigate adverse outcomes., (© 2023 John Wiley & Sons Ltd.)

Objective: Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aβ) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume., Methods: This study included 61 cognitively normal older adults (age range: 65-93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aβ, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity., Results: We found that, in WMH (+) older adults greater Aβ burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aβ burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy., Conclusion: These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD., Competing Interests: DISCLOSUREs The authors declare no competing interests in relation to the work described., (Copyright © 2022. Published by Elsevier Inc.)

A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 - 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 - 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD., Competing Interests: Disclosure Statement The authors have no actual or potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Amyloid-β (Aβ) deposits asymmetrically early in Alzheimer's disease (AD). This process is variable and has been associated with asymmetric hypometabolism., Objective: We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults., Methods: We analyzed data from 77 cognitively healthy, older adults who completed functional magnetic resonance imaging, positron emission tomography, and cognitive testing. We identified regions of significant activation and asymmetry during the Digital Symbol Substitution Task (DSST). We examined associations between regions with significant hemispheric asymmetry (directional and absolute) and global cerebral Aβ, cerebral glucose metabolism, white matter hyperintensities, APOE ɛ4 allele status, DSST reaction time, age, sex, education, and cognitive function., Results: Asymmetry was not associated with several factors including cognitive function, Aβ, and white matter hyperintensities. The presence of at least one ɛ4 APOE allele in participants was associated with less asymmetric activation in the angular gyrus (right dominant activation). Greater education was associated with less asymmetric activation in mediodorsal thalamus (left dominant activation)., Conclusions: Genetic risk of AD was associated with lower asymmetry in angular gyrus activation, while greater education was associated with lower asymmetry in mediodorsal thalamus activation. Changes in asymmetry may reflect components of compensation or cognitive reserve. Asymmetric neural recruitment during working memory may be related to maintenance of cognitive function in cognitively normal older adults.

Objective: Emerging evidence suggests low vision may be a modifiable risk factor for cognitive decline. We examined effects of baseline visual acuity (VA) on level of, and change in, cognitive test performance over 9 years., Method: A population-based sample of 1,621 participants (average age 77 years) completed a comprehensive neuropsychological evaluation and VA testing at baseline and reassessed at nine subsequent annual visits. Linear regression modeled the association between baseline VA and concurrent cognitive test performance. Joint modeling of a longitudinal sub-model and a survival sub-model to adjust for attrition were used to examine associations between baseline VA and repeated cognitive test performance over time., Results: Better baseline VA was associated cross-sectionally with younger age, male sex, greater than high school education, and higher baseline neuropsychological test scores on both vision-dependent (B coefficient range -0.163 to -0.375, p = .006 to <.001) and vision-independent tests (-0.187 to -0.215, p = .003 to .002). In longitudinal modeling, better baseline VA was associated with slower decline in vision-dependent tests (B coefficient range -0.092 to 0.111, p = .005 to <.001) and vision-independent tests (-0.107 to 0.067, p = .007 to <.001)., Conclusions: Higher VA is associated with higher concurrent cognitive abilities and slower rates of decline over 9 years in both vision-dependent and vision-independent tests of memory, language, and executive functioning. Findings are consistent with emerging literature supporting vision impairment in aging as a potentially modifiable risk factor for cognitive decline. Clinicians should encourage patient utilization of vision assessment and correction with the added aim of protecting cognition.

Background: Changes in physical health and cognition during aging can result in some older adults to stop driving. In this population-based longitudinal study, we describe potential predictors of driving cessation in older adults., Methods: Age-stratified random population cohort of 1982 adults aged 65 years and older drawn from voter registration lists. Participant characteristics were measured using demographics, physical and self-rated health, sleeping habits, driving status, cognitive screening, modified Center for Epidemiologic Studies-Depression scale, clinical dementia rating, and mini-mental state examination., Results: Over 12 years of follow-up, 390 participants stopped driving. These individuals were older, more likely to be women and to have a clinical dementia rating score ≥1, had worse self-reported health, and more symptoms of depression, compared with those who were still driving. In addition, individuals with lower test performance in all cognitive domains, loss of visual acuity and fields, and bilateral hearing loss were more likely to stop driving., Conclusions: Age, sex, cognitive impairments, physical health, and depressive symptoms were associated with driving cessation in this cohort. By identifying potential driving cessation predictors, health care providers and families may better recognize these risk factors and begin the driving cessation discussion early., Competing Interests: M.G., B.E.S., and E.J. report grants from National Institute on Aging during the conduct of the study. C.-C.H.C. reports grants from NIH during the conduct of the study. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cancer-related cognitive impairment (CRCI) has long-term effects on survivor quality of life, but CRCI research on patients with gastrointestinal stromal tumor (GIST) is lacking. The aims of this study were to investigate CRCI and concomitant quality of life among patients with GIST., Methods: An online survey was used to assess CRCI in adult patients with GIST using the validated Functional Assessment of Cancer Therapy-Cognitive-v.3. Age, education, demographically indexed IQ, general health, and quality of life factors (e.g., fatigue, emotional distress) were also assessed. The online survey was administered through five international GIST and sarcoma support organizations., Results: Over the 3-month recruitment period, the survey was completed by 485 participants: mean age, 57.80 (SD, 11.51), median 5 years after diagnosis. A majority (63.91%) reported experiencing cognitive symptoms with a significant negative quality of life impact. Controlling for age, patients with GIST ≥5 years after diagnosis reported worse cognitive function than those <5 years after diagnosis (p < .05) but did not differ in educational level or IQ. Whereas longer term survivors were more likely to have been treated with tyrosine kinase inhibitor (TKI) therapies, there was no observed association of TKI therapy with self-reported cognitive impairments., Conclusions: A majority of GIST patients report cognitive symptoms that have a negative impact on quality of life, with longer term survivors (≥5 years) tending to report more cognitive impairments. Given the success of TKI therapy to substantially increase overall survival of patients with GIST, addressing CRCI in clinical practice may improve long-term GIST survivor function and quality of life., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objectives: The restrictions put in place in 2020 to mitigate the spread of the coronavirus disease 2019 limited or eliminated social connections that are vital for psychosocial well-being. The objectives of this research were to examine the impact of early pandemic-related restrictions on feelings of loneliness, depression, and anxiety as well as social activity disruption and their concomitant associations in a sample of community-dwelling older adults residing in a small-town region in the USA., Design and Setting: Cross-sectional data collected from an ongoing population-based cohort study in Southwestern, Pennsylvania., Participants: Analyses included 360 adults aged 65 years and older whose annual study assessment occurred during the first 120 days of pandemic-related restrictions., Measurements: Self-reported feelings of loneliness, depression, and anxiety due to the pandemic-related restrictions were each measured using a single question. Depressive symptoms and anxiety were also assessed with the modified Center for Epidemiologic Studies-Depression and Generalized Anxiety Disorder-7 item tools. Disruption in a variety of common social activities was also assessed., Results: Feeling lonely affected 36% of participants who were more likely to be female, not currently married, and living alone. Giving up in-person visits with family was associated with significantly higher odds of feeling lonely, and feeling lonely was associated with significantly higher odds of feelings of anxiety and depression., Conclusions: Loneliness is a serious outcome of pandemic-related restrictions among older adults, potentially linked to loss of connection with family, and may be associated with increased feelings of depression and anxiety.

Introduction: We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95., Methods: SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009-2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aβ) and repeat clinical-cognitive evaluations every 6 months., Results: By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P = .03). The amount of Aβ was directly related to SBP levels. In multivariate analysis, Aβ+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aβ, SBP became a significant predictor of dementia., Discussion: Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aβ., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The human brain shows modest traits of sexual dimorphism, with the female brain, on average, 10% smaller than the male brain. These differences do not imply a lowered cognitive performance, but suggest a more optimal brain organization in women. Here we evaluate the patterns of functional connectivity (FC) in women and men from the Connectomics of Brain Aging and Dementia sample. Methods: We used phase locking values to calculate FC from the magnetoencephalography time series in a sample of 138 old adults (87 females and 51 males). We compared the FC patterns between sexes, with the intention of detecting regions with different levels of connectivity. Results: We found a frontal cluster, involving anterior cingulate and the medial frontal lobe, where women showed higher FC values than men. Involved connections included the following: (1) medial parietal areas, such as posterior cingulate cortices and precunei; (2) right insula; and (3) medium cingulate and paracingulate cortices. Moreover, these differences persisted when considering only cognitively intact individuals, but not when considering only cognitively impaired individuals. Discussion: Increased anteroposterior FC has been identified as a biomarker for increased risk of developing cognitive impairment or dementia. In our study, cognitively intact women showed higher levels of FC than their male counterparts. This result suggests that neurodegenerative processes could be taking place in these women, but the changes are undetected by current diagnosis tools. FC, as measured here, might be valuable for early identification of this neurodegeneration.

Background: Mobility is important for independence in older age. While brain health correlates of objectively measured mobility-related features like gait and balance have been reported, we aimed to test neuroimaging and cognitive correlates of subjective measures of mobility-related confidence., Methods: We carried out a cross-sectional observational study comprised of N = 29 cognitively unimpaired older adult participants, mean age 75.8 ± 5.8, 52% female, 24% non-white. We measured cognition, hippocampal volume, white matter hyperintensities, cerebral amyloid-β (Aβ), and gait and balance confidence. We tested associations using unadjusted Spearman correlations and correlations partialling out covariates of interest one at a time., Results: Greater gait confidence was associated with better attention (unadjusted ρ = 0.37, p = 0.05; partially attenuated by adjustment for age, APOE4, anxiety, motivation, gait speed, or Aβ); executive performance (unadjusted ρ = 0.35, p = 0.06; partially attenuated by adjustment for age, APOE4, gait speed, or Aβ); and lower Aβ levels (unadjusted ρ = -0.40, p = 0.04; partially attenuated by adjustment for age, depressive symptoms, motivation, or gait speed). Greater balance confidence was associated with better global cognition (unadjusted ρ = 0.41, p = 0.03; partially attenuated by adjustment for APOE4, gait speed, or Aβ); attention (unadjusted ρ = 0.46, p = 0.01; robust to adjustment); and lower Aβ levels (unadjusted ρ = -0.35, p = 0.07; partially attenuated by adjustment for age, education, APOE4, depressive symptoms, anxiety, motivation, or gait speed)., Conclusions: Self-reported mobility-related confidence is associated with neuroimaging and cognitive measures and would be easy for providers to use in clinical evaluations. These associations should be further evaluated in larger samples, and longitudinal studies can help determine temporality of declines., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Better understanding of the lifestyle activities shared among older adult subgroups may inform further health behavioral interventions that can be deployed at the group or community level. We applied latent class analysis to characterize qualitatively distinct lifestyle engagement groups, examined their differential risk of incident dementia, and compared their predictive utility to traditional activity frequency and variety scores., Method: Participants were from the Ginkgo Evaluation of Memory Study (N = 3,068, mean age = 78.5). Lifestyle activities were measured at baseline using the Lifestyle Activity Questionnaire. All-cause dementia was screened every 6 months and cases were clinically adjudicated. Median follow-up was 6 years. Time to dementia was assessed using discrete-time proportional hazards models, adjusted for demographic and health covariates., Results: Latent classes provided slightly poorer case discrimination than the frequency scores but identified distinct qualitative subgroups. In the 4-class model, the Variety (22%) and Intellectual (18%) lifestyle groups had high engagement in intellectual activities, whereas the Variety and Social groups (32%) had high engagement in formal social activities. Compared to the Least Active group (28%), the Variety (hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.48, 0.93) and Intellectual (HR = 0.65, 95% CI: 0.45, 0.93) groups had significantly lower risk of incident dementia, but only among those without prevalent mild cognitive impairment., Discussion: Older adults highly engaged in intellectual activities, but not necessarily social activities, had the lowest risk of incident dementia. Activity frequency scores provided only slightly better case discrimination than activity variety scores and latent classes. Latent classes of older adults differed by their amount and types of activities, which may inform intervention design., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: In a population-based study of mild cognitive impairment (MCI), to validate the assessment of social cognition in older adults., Methods: Cross-sectional study of 902 adults aged 65+ with mean age 76.6 years (SD 8.06). We created a social cognition composite comprising standardized z scores on the Social Norms Questionnaire and the 10-item Reading the Mind in the Eyes Test. We identified associated factors and compared sensitivity, specificity, and the area under the curve of social cognition, for MCI defined as Clinical Dementia Rating (CDR)=0.5, to those of other cognitive domains. We calculated the impact of including social cognition on the proportion neuropsychologically classified as MCI., Results: Better social cognition was associated with younger age, female sex, higher education, better general cognition (mini-mental state examination), fewer depressive symptoms, and lower CDR. Adjusting for demographics, associations with mini-mental state examination, depressive symptoms, anxiety symptoms, and subjective cognitive complaints remained significant. The sensitivity and specificity of social cognition for CDR=0.5 were comparable to those of the traditional 5 cognitive domains. Including social cognition as a sixth domain of cognition resulted in a 5% increase in the proportion classified as MCI., Conclusions: Brief objective assessment of social cognition may enhance cognitive assessment of older adults., Competing Interests: M.G. reports grants from National Institute on Aging during the conduct of the study. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

White matter hyperintensities (WMHs) are associated with cognitive decline. Assessing the effect of WMH on WM microstructural changes and its relationships with structural and functional connectivity to multiple cognitive domains are helpful to better understand the pathophysiological processes of cognitive impairment. 65 participants (49 normal and 16 MCI subjects, age: 67.4 ± 8.3 years, 44 females) were studied at 3T. The WMHs and fifty fiber tracts were automatically segmented from the T1/T2-weighted images and diffusion-weighted images, respectively. Tract-profiles of WMH were compared with those of apparent fiber density (AFD). The relationship between AFD and tract connectivity (TC) was assessed. Functional connectivity (FC) between tract ends obtained from resting-state functional MRI was examined in relation to TC. Tract-specific relationships of WMH, TC and FC with a multi-domain neuropsychological test battery and Montreal Cognitive Assessment (MoCA) were also separately assessed by lasso linear regression. Indirect pathways of TC and FC between WMH and multiple cognitive measures were tested using the mediation analysis. Higher WMH loads in WM tracts were locally matched with the reduced AFD, which was related to decrease in TC. However, no direct relationship was found between TC and FC. Tract-specific changes on WMH, TC and FC for each cognitive performance may explain that macro- and microstructural and functional changes are associated differently with each cognitive domain in a fiber specific manner. In these identified tracts, the differences between normal and MCI for WMH and TC were increased, and the relationships of WMH, TC and FC with cognitive outcomes were more significant, compared to the results from all tracts. Indirect pathways of two-step (TC-FC) between WMH and all cognitive domains were significant ( p < 0.0083 with Bonferroni correction), while the separated indirect pathways through TC and through FC were different depending on cognitive domain. Deterioration in specific cognitive domains may be affected by alterations in a set of different tracts that are differently associated with macrostructural, microstructural, and function changes. Thus, assessments of WMH and its associated changes on specific tracts help for better understanding of the interrelationships of multiple changes in cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Aizenstein, Snitz, Cheng, Chang, Roush, Huppert, Cohen, Doman and Becker.)

Due to needs surrounding rigor and reproducibility, subgroup specific disease knowledge, and questions of external validity, data harmonization is an essential tool in population neuroscience of Alzheimer's disease and related dementias (ADRD). Systematic harmonization of data elements is necessary to pool information from heterogeneous samples, and such pooling allows more expansive evaluations of health disparities, more precise effect estimates, and more opportunities to discover effective prevention or treatment strategies. The key goal of this Tutorial in Population Neuroimaging Curriculum, Instruction, and Pedagogy article is to guide researchers in creating a customized population neuroscience of ADRD harmonization training plan to fit their needs or those of their mentees. We provide brief guidance for retrospective data harmonization of multiple data types in this area, including: (1) clinical and demographic, (2) neuropsychological, and (3) neuroimaging data. Core competencies and skills are reviewed, and resources are provided to fill gaps in training as well as data needs. We close with an example study in which harmonization is a critical tool. While several aspects of this tutorial focus specifically on ADRD, the concepts and resources are likely to benefit population neuroscientists working in a range of research areas., Competing Interests: Conflict of interest Author RT is a consultant for Bayer, Astellas, and Happify. Author HS is a full-time employee of the Alzheimer’s Association. Author TH is a member of the Scientific Advisory Board for Vivid Genomics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Alzheimer's disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for., Objective: The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above., Methods: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects., Results: The established association of APOE*4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p = 9.36E-14) and was stronger in females (OR = 2.72; p = 1.74E-10) than in males (OR = 1.88; p = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711/rs148377161 (OR = 3.31; p = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/rs140076909 on chromosome 1 (OR = 4.51; p = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/rs117803234 on chromosome 7 (OR = 3.76; p = 6.93E-08)., Conclusion: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, 18 F-flortaucipir and 18 F-MK-6240, in the same subjects. Methods: 18 F-flortaucipir and 18 F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I-VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80-100 min ( 18 F-flortaucipir) or 70-90 min ( 18 F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated ( r 2 > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for 18 F-MK-6240 than for 18 F-flortaucipir. Cerebellar SUVs were similar for 18 F-MK-6240 and 18 F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with 18 F-flortaucipir and most often in the meninges with 18 F-MK-6240. Conclusion: Both 18 F-MK-6240 and 18 F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. 18 F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: This memory-clinic study joins efforts to study earliest clinical signs and symptoms of Alzheimer's disease and related dementias: subjective reports and objective neuropsychological test performance., Objective: The memory-clinic denoted two clinical "grey zones": 1) subjective cognitive decline (SCD; n = 107) with normal objective test scores, and 2) isolated low test scores (ILTS; n = 74) without subjective complaints to observe risk for future decline., Methods: Initial and annual follow-up clinical research evaluations and consensus diagnosis were used to evaluate baseline characteristics and clinical progression over 2.7 years, compared to normal controls (NC; n = 117)., Results: The ILTS group was on average older than the NC and SCD groups. They had a higher proportion of people identifying as belonging to a minoritized racial group. The SCD group had significantly more years of education than the ILTS group. Both ILTS and SCD groups had increased risk of progression to mild cognitive impairment. Older age, minoritized racial identity, and baseline cognitive classification were risk factors for progression., Conclusion: The two baseline risk groups look different from each other, especially with respect to demographic correlates, but both groups predict faster progression than controls, over and above demographic differences. Varied presentations of early risk are important to recognize and may advance cognitive health equity in aging.

The natural history of Alzheimer's Disease (AD) includes significant alterations in the human connectome, and this disconnection results in the dementia of AD. The organizing principle of our research project is the idea that the expression of cognitive dysfunction in the elderly is the result of two independent processes - the neuropathology associated with AD, and second the neuropathological changes of cerebrovascular disease. Synaptic loss, senile plaques, and neurofibrillary tangles are the functional and diagnostic hallmarks of AD, but it is the structural changes as a consequence of vascular disease that reduce brain reserve and compensation, resulting in an earlier expression of the clinical dementia syndrome. This work is being completed under the auspices of the Human Connectome Project (HCP). We have achieved an equal representation of Black individuals (vs. White individuals) and enrolled 60% Women. Each of the participants contributes demographic, behavioral and laboratory data. We acquire data relative to vascular risk, and the participants also undergo in vivo amyloid imaging, and magnetoencephalography (MEG). All of the data are publicly available under the HCP guidelines using the Connectome Coordinating Facility and the NIMH Data Archive. Locally, we use these data to address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MEG, and in vivo beta amyloid imaging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cohen, Bruña, Chang, Cheng, Doman, Huppert, Kim, Maestu, Roush, Snitz and Becker.)

Background/objective: Poor air quality is implicated as a risk factor for cognitive impairment and dementia. Few studies have examined these associations longitudinally in well-characterized population-based cohorts with standardized annual assessment of both mild cognitive impairment (MCI) and dementia. We investigated the association between estimated ambient fine particulate matter (PM 2.5 ) and risk of incident MCI and dementia in a post-industrial region known for historically poor air quality., Setting/participants: Adults aged 65+ years in a population-based cohort (n = 1572)., Measurements: Census tract level PM 2.5 from Environmental Protection Agency (EPA) air quality monitors; Clinical Dementia Rating (CDR)®., Design: We estimated ambient PM 2.5 exposure (μg/m 3 , single-year and 5-year averages) by geocoding participants' residential addresses to census tracts with daily EPA PM 2.5 measurements from 2002 to 2014. Using Bayesian spatial regression modeling adjusted for age, sex, education, smoking history, and household income, we examined the association between estimated PM 2.5 exposure and risk of incident MCI (CDR = 0.5) and incident dementia (CDR ≥ 1.0)., Results: Modeling estimated single-year exposure, each 1 μg/m 3 higher ambient PM 2.5 was associated with 67% higher adjusted risk of incident dementia (hazard ratio [HR] = 1.669, 95% credible interval [CI]: 1.298, 2.136) and 75% higher adjusted risk of incident MCI (HR = 1.746, 95% CI: 1.518, 2.032). Estimates were higher when modeling 5-year ambient PM 2.5 exposure for incident dementia (HR = 2.082, 95% CI: 1.528, 3.015) and incident MCI (HR = 3.419, 95% CI: 2.806, 4.164)., Conclusions: Higher estimated ambient PM 2.5 was associated with higher risk of incident MCI and dementia, particularly when considering longer-term exposure, and independent of demographic characteristics and smoking history. Targeting poor air quality may be a reasonable population-wide intervention to reduce the risk of cognitive impairment in older adults, particularly in regions exceeding current recommendations for safe exposure to PM 2.5 ., (© 2021 The American Geriatrics Society.)

Introduction: The population of older adults with Alzheimer's disease and Related Dementias (ADRD) is growing larger and more diverse. Prevalence of ADRD is higher in African American (AA) and Hispanic populations relative to non-Hispanic whites (nHW), with larger differences for women compared to men of the same race. Given the public health importance of this issue, we sought to determine if AA and Hispanic women exhibit worse ADRD pathology compared to men of the same race and nHW women. We hypothesized that such differences may explain the discrepancy in ADRD prevalence., Methods: We evaluated 932 articles that measured at least one of the following biomarkers of ADRD pathology in vivo and/or post-mortem: beta-amyloid (Aß), tau, neurodegeneration, and cerebral small vessel disease (cSVD). Criteria for inclusion were: (1) mean age of participants >65 years; (2) inclusion of nHW participants and either AA or Hispanics or both; (3) direct comparison of ADRD pathology between racial groups., Results: We included 26 articles (Aß = 9, tau = 6, neurodegeneration = 16, cSVD = 18), with seven including sex-by-race comparisons. Studies differed by sampling source (e.g., clinic or population), multivariable analytical approach (e.g., adjusted for risk factors for AD), and cognitive status of participants. Aß burden did not differ by race or sex. Tau differed by race (AA < nHW), and by sex (women > men). Both severity of neurodegeneration and cSVD differed by race (AA > nHW; Hispanics < nHW) and sex (women < men). Among the studies that tested sex-by-race interactions, results were not significant., Conclusion: Few studies have examined the burden of ADRD pathology by both race and sex. The higher prevalence of ADRD in women compared to men of the same race may be due to both higher tau load and more vulnerability to cognitive decline in the presence of similar Aß and cSVD burden. AA women may also exhibit more neurodegeneration and cSVD relative to nHW populations. Studies suggest that between-group differences in ADRD pathology are complex, but they are too sparse to completely explain why minority women have the highest ADRD prevalence. Future work should recruit diverse cohorts, compare ADRD biomarkers by both race and sex, and collect relevant risk factor and cognitive data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Royse, Cohen, Snitz and Rosano.)

Introduction: Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults., Methods: A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations., Results: At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions., Discussion: In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study investigated subjective memory complaints in older adults and the roles of setting, response bias, and personality., Design: Cognitively normal older adults from two settings completed questionnaires measuring memory complaints, response bias, and personality., Settings: (A) Neuroimaging study with community-based recruitment and (B) academic memory clinic., Participants: Cognitively normal older adults who (A) volunteer for research (N = 92) or (B) self-referred to a memory clinic (N = 20)., Measurements: Neuropsychological evaluation and adjudication of normal cognitive status were done by the neuroimaging study or memory clinic. This study administered self-reports of subjective memory complaints, response bias, five-factor personality, and depressive symptoms. Primary group differences were examined with secondary sensitivity analyses to control for sex, age, and education differences., Results: There was no significant difference in over-reporting response bias between study settings. Under-reporting response bias was higher in volunteers. Cognitive complaints were associated with response bias for two cognitive complaint measures. Neuroticism was positively associated with over-reporting in evaluation-seekers and negatively associated with under-reporting in volunteers. The relationship was reversed for Extraversion. Under-reporting bias was positively correlated with Agreeableness and Conscientiousness in volunteers., Conclusion: Evaluation-seekers do not show bias toward over-reporting symptoms compared to volunteers. Under-reporting response bias may be important to consider when screening for memory impairment in non-help-seeking settings. The Memory Functioning Questionnaire was less sensitive to reporting biases. Over-reporting may be a facet of higher Neuroticism. Findings help elucidate psychological influences on self-perceived cognitive decline and help seeking in aging and may inform different strategies for assessment by setting.

Objectives: To describe factors associated with driving history, habits, and self-reported driving difficulties of 1982 older adults in a population-based survey., Setting: This was a community setting., Participants: Age-stratified random population sample drawn from publicly available voter registration list., Design: Participants underwent assessments including cognitive testing and self-reported current and past driving status, instrumental activities of daily living, self-rated health, social supports, physical limitations, and depressive symptoms. We built multivariable logistic regression models to identify factors associated with never having driven, having ceased driving, and reporting difficulties while driving., Results: In the multivariable model, "never drivers" were more likely than "ever drivers" to be older, female, less educated and to leave home less frequently. Former drivers were significantly older, more likely to be women, have lower test performance in the cognitive domain of attention, have more instrumental activity of daily living difficulties, leave home less frequently and have visual field deficits in the right eye than current drivers. Current drivers with reported driving difficulties were more likely than those without difficulties to have lower test performance in attention but higher in memory, were more likely to report depressive symptoms and to have both vision and hearing loss., Conclusion: Age, female sex, marital status, and education appear to be associated with driving cessation. Cognitive and functional impairments, mood symptoms and physical health also seem to influence driving cessation and reduction. Our findings may have implications for clinicians in assessing and educating their patients and families on driving safety., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Social cognition indicates the cognitive processes involved in perceiving, interpreting, and processing social information. Although it is one of the six core DSM-5 cognitive domains for diagnosing neurocognitive disorders, it is not routinely assessed in older adults. The Reading the Mind in the Eyes Test assesses Theory of Mind, the social cognition mechanism which forms the root of empathy., Objectives: To describe the distribution of, and factors associated with, scores on a 10-item version of Reading the Mind in the Eyes Test (RMET-10) in older adults., Design: Population-based cross-sectional study., Setting: Small-town communities in Pennsylvania., Participants: Adults aged 66-105 years (N = 902, mean age = 76.6)., Measurements: The assessment included RMET-10, demographics, cognitive screening, literacy, depression symptoms, anxiety symptoms, cognitive composites derived from a neuropsychological test battery, Social Norms Questionnaire, and Clinical Dementia Rating (CDR)., Results: RMET-10 score was normally distributed in our overall study sample. Normative RMET-10 scores among those rated as CDR = 0 were calculated by age, sex, and education. RMET-10 score was significantly higher with younger age, higher education, white race, higher cognitive screening scores, literacy, social norms scores, higher scores in all five domains in cognitive composites, and lower CDR. RMET-10 score was also significantly higher with fewer depression and anxiety symptoms after adjusting for demographics., Conclusions: The RMET is a potentially useful measure of social cognition for use in the research assessment of older adults. With appropriate calibration it should also have utility in the clinical setting., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

A true understanding of the distribution and functional correlates of Alzheimer's disease pathology in dementia-free older adults requires a population-based perspective. Here we report initial findings from a sample of 102 cognitively unimpaired participants (average age 77.2 years, 54.9% women, 13.7% APOE*4 carriers) recruited for neuroimaging from a larger representative population-based cohort participating in an ongoing longitudinal study of aging, the Monongahela-Youghiogheny Healthy Aging Team (MYHAT). All participants scored < 1.0 on the Clinical Dementia Rating (CDR) Scale, with 8 participants (7.8%) scoring CDR = 0.5. Participants completed a positron emission tomography scan using the tracers [C-11]Pittsburgh Compound-B (PiB) and [F-18]AV-1451 to estimate amyloid and tau deposition. PiB positivity was defined on a regional basis using established standardized uptake value ratio cutoffs (SUVR; cerebellar gray matter reference), with 39 participants (38.2%) determined to be PiB(+). Health history, lifestyle, and cognitive abilities were assessed cross-sectionally at the nearest annual parent MYHAT study visit. A series of adjusted regression analyses modeled cognitive performance as a function of global PiB SUVR and [F-18]AV-1451 SUVR in Braak associated regions 1, 3/4, and 5/6. In comparison to PiB(-) participants (n = 63), PiB(+) participants were older, less educated, and were more likely to be APOE*4 carriers. Global PiB SUVR was significantly correlated with [F-18]AV-1451 SUVR in all Braak-associated regions (r = .38-0.53, p < .05). In independent models, higher Global PiB SUVR and Braak 1 [F-18]AV-1451 SUVR were associated with worse performance on a semantic interference verbal memory test. Our findings suggest that brain amyloid is common in a community-based setting, and is associated with tau deposition, but both pathologies show few associations with concurrent cognitive performance in a dementia-free sample., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11 C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.

Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer's disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates., Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations., Methods: We measured brain activation during the "face-name" memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education., Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education., Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve.

Background: Subjective cognitive decline (SCD) is recognized as a risk stage for Alzheimer's disease (AD) and other dementias, but its prevalence is not well known. We aimed to use uniform criteria to better estimate SCD prevalence across international cohorts., Methods: We combined individual participant data for 16 cohorts from 15 countries (members of the COSMIC consortium) and used qualitative and quantitative (Item Response Theory/IRT) harmonization techniques to estimate SCD prevalence., Results: The sample comprised 39,387 cognitively unimpaired individuals above age 60. The prevalence of SCD across studies was around one quarter with both qualitative harmonization/QH (23.8%, 95%CI = 23.3-24.4%) and IRT (25.6%, 95%CI = 25.1-26.1%); however, prevalence estimates varied largely between studies (QH 6.1%, 95%CI = 5.1-7.0%, to 52.7%, 95%CI = 47.4-58.0%; IRT: 7.8%, 95%CI = 6.8-8.9%, to 52.7%, 95%CI = 47.4-58.0%). Across studies, SCD prevalence was higher in men than women, in lower levels of education, in Asian and Black African people compared to White people, in lower- and middle-income countries compared to high-income countries, and in studies conducted in later decades., Conclusions: SCD is frequent in old age. Having a quarter of older individuals with SCD warrants further investigation of its significance, as a risk stage for AD and other dementias, and of ways to help individuals with SCD who seek medical advice. Moreover, a standardized instrument to measure SCD is needed to overcome the measurement variability currently dominant in the field.

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 -5 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 -27 ). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10 -5 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.

To characterize the influence of apolipoprotein-E (APOE) genotype on cerebral Aβ load and longitudinal Aβ trajectories, [ 11 C]Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants with known APOE genotype. Serial [ 11 C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies Alzheimer's disease risk through a direct influence on amyloidogenic processes, which manifests as an earlier age of onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR-DNA binding protein of 43kDA (TDP-43) in Alzheimer's disease (AD) patients., Methods: The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA-Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37-95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP-43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE-4 allele, and presence of Lewy bodies (LB)., Results: HS was present in 18% (n = 64) and TDP-43 in 51.5% (n = 185) of the patients. HS and TDP-43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP-43. Age at onset was not associated with TDP-43 or HS. HS was associated with duration of symptoms and LB, TDP-43, and atherosclerosis in the CW. TDP-43 was associated with duration of symptoms, LB, and HS., Interpretation: HS and TDP-43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP-43 are part of the later neuropathological changes in AD., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)