Association between hippocampal microglia, AD and LATE-NC, and cognitive decline in older adults.

INTRODUCTION: This study investigates the relationship between microglia inflammation in the hippocampus, brain pathologies, and cognitive decline. METHODS: Participants underwent annual clinical evaluations and agreed to brain donation. Neuropathologic evaluations quantified microglial burden in the hippocampus, amyloid beta (Aß), tau tangles, and limbic age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and other common brain pathologies. Mixed-effect and linear regression models examined the association of microglia with a decline in global and domain-specific cognitive measures, and separately with brain pathologies. Path analyses estimated direct and indirect effects of microglia on global cognition. RESULT: Hippocampal microglia were associated with a faster decline in global cognition, specifically in episodic memory, semantic memory, and perceptual speed. Tau tangles and LATE-NC were independently associated with microglia. Other pathologies, including Aß, were not related. Regional hippocampal burden of tau tangles and TDP-43 accounted for half of the association of microglia with cognitive decline. DISCUSSION: Microglia inflammation in the hippocampus contributes to cognitive decline. Tau tangles and LATE-NC partially mediate this association.

Healthy Lifestyle and Cognition in Older Adults With Common Neuropathologies of Dementia.

Importance: A healthy lifestyle is associated with better cognitive functioning in older adults, but whether this association is independent of the accumulation of dementia-related pathologies in the brain is uncertain. Objective: To determine the role of postmortem brain pathology, including ß-amyloid load, phosphorylated tau tangles, cerebrovascular pathology, and other brain pathologies, in the association between lifestyle and cognition proximate to death. Design, Setting, and Participants: This cohort study used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study with autopsy data from 1997 to 2022 and up to 24 years of follow-up. Participants included 754 deceased individuals with data on lifestyle factors, cognitive testing proximate to death, and a complete neuropathologic evaluation at the time of these analyses. Data were analyzed from January 2023 to June 2023. Exposures: A healthy lifestyle score was developed based on self-reported factors, including noncurrent smoking, at least 150 minutes of physical activity per week, limiting alcohol consumption, a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score higher than 7.5, and a late-life cognitive activity score higher than 3.2. The lifestyle score ranges from 0 to 5, with higher scores reflecting a healthier lifestyle. Main Outcomes and Measures: The global cognitive score was derived from a battery of nineteen standardized tests. Brain pathology measures included ß-amyloid load, phosphorylated tau tangles, global Alzheimer disease pathology, vascular brain pathologies, Lewy body, hippocampal sclerosis, and TAR DNA-binding protein 43. Results: Of 586 included decedents, 415 (70.8%) were female, 171 (29.2%) were male, and the mean (SD) age at death was 90.9 (6.0) years. Higher lifestyle score was associated with better global cognitive functioning proximate to death. In the multivariable-adjusted model, a 1-point increase in lifestyle score was associated with 0.216 (SE = 0.036, P < .001) units higher in global cognitive scores. Neither the strength nor the significance of the association changed substantially when common dementia-related brain pathologies were included in the multivariable-adjusted models. The ß estimate after controlling for the ß-amyloid load was 0.191 (SE = 0.035; P < .001). A higher lifestyle score was associated with lower ß-amyloid load in the brain (ß = -0.120; SE = 0.041; P = .003), and 11.6% of the lifestyle-cognition association was estimated through ß-amyloid load. Conclusions and Relevance: This study found that in older adults, a healthy lifestyle may provide a cognitive reserve to maintain cognitive abilities independently of common neuropathologies of dementia.

Chronic traumatic encephalopathy and aging-related tau astrogliopathy in community-dwelling older persons with and without moderate-to-severe traumatic brain injury.

This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI. In contrast, ARTAG was common in older brains (gray matter ARTAG = 77%; white matter ARTAG = 54%; subpial ARTAG = 51%); there were no differences in severity, type, or distribution of ARTAG pathology with respect to history of msTBI. Furthermore, those with msTBI did not have higher levels of PHF-tau tangles density but had higher levels of amyloid-ß load (Estimate = 0.339, SE = 0.164, p = 0.040). These findings suggest that CTE-NC is infrequent while ARTAG is common in the community and that both pathologies are unrelated to msTBI. The association of msTBI with amyloid-ß, rather than with tauopathies suggests differential mechanisms of neurodegeneration in msTBI.

Associations of brain morphology with cortical proteins of cognitive resilience.

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline.

Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure.

BACKGROUND: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [APOE ε4], and diabetes). METHODS AND RESULTS: Data came from 765 community-based older people (91 years old on average at death; 72% women), from 2 ongoing clinical-pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. CONCLUSIONS: Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations.

Changes in an in-vivo classifier of ARTerioloSclerosis (ARTS) with simultaneous change in cognition for older African Americans.

At autopsy, African American decedents often have mixed Alzheimer's and cerebrovascular brain pathologies including arteriolosclerosis. We applied a novel in-vivo classifier of ARTerioloSclerosis (ARTS) in 167 older African Americans (∼75y of age) with > 2 biennial 3 T MRI scans and > 3 years of associated cognitive follow-up to determine if ARTS scores (higher score=higher likelihood of arteriolosclerosis) changed over time and if this change associated with changes in cognition in the same individuals. Mixed effects regression models tested whether ARTS scores increased over time, while simultaneous mixed effects regression models estimated the simultaneous rates of change in both ARTS and cognition and the correlation of these changes. ARTS scores increased over time (estimate=0.030, SE=0.002, p < 0.0001). Faster increases in ARTS were associated with faster rates of global cognitive decline (r = -0.447, p = 0.006) and domain-specific cognitive functions. Applying an in-vivo marker of arteriolosclerosis in an African American cohort revealed that the likelihood of arteriolosclerosis increases over time, and participants whose ARTS scores increased more rapidly tended to have faster than average rates of cognitive decline.

High-throughput digital quantification of Alzheimer disease pathology and associated infrastructure in large autopsy studies.

High-throughput digital pathology offers considerable advantages over traditional semiquantitative and manual methods of counting pathology. We used brain tissue from 5 clinical-pathologic cohort studies of aging; the Religious Orders Study, the Rush Memory and Aging Project, the Minority Aging Research Study, the African American Clinical Core, and the Latino Core to (1) develop a workflow management system for digital pathology processes, (2) optimize digital algorithms to quantify Alzheimer disease (AD) pathology, and (3) harmonize data statistically. Data from digital algorithms for the quantification of ß-amyloid (Aß, n = 413) whole slide images and tau-tangles (n = 639) were highly correlated with manual pathology data (r = 0.83 to 0.94). Measures were robust and reproducible across different magnifications and repeated scans. Digital measures for Aß and tau-tangles across multiple brain regions reproduced established patterns of correlations, even when samples were stratified by clinical diagnosis. Finally, we harmonized newly generated digital measures with historical measures across multiple large autopsy-based studies. We describe a multidisciplinary approach to develop a digital pathology pipeline that reproducibly identifies AD neuropathologies, Aß load, and tau-tangles. Digital pathology is a powerful tool that can overcome critical challenges associated with traditional microscopy methods.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

Objective: To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. Approach: We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. Results: In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Conclusion: Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.

Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia.

BACKGROUND: Assessments of Alzheimer's disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. OBJECTIVE: Test if amyloid-ß (Aß) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. METHODS: Autopsies were obtained in decedents with cognitive testing (n = 300). Aß plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aß were absent in the first 165 cases, it was not assessed in the remaining cases. RESULTS: Age at death was 91 years old. About 90% had Aß in cerebrum and of these, half had Aß in the brainstem. Of the latter, 85% showed Aß in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aß in one or more regions. In a logistic model controlling for demographics, Aß and tau-tangles within the cerebrum, the presence of Aß in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. CONCLUSION: Regional differences in Aß and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

Acculturation in Context and Brain Health in Older Latino Adults: A Diffusion Tensor Imaging Study.

BACKGROUND: Latinos are at higher risk of developing mild cognitive impairment (MCI) and Alzheimer's disease than non-Latino Whites. Acculturation factors may influence this risk, yet there are few studies that have examined associations of acculturation, particularly in the context of socioenvironmental and familial factors, and brain health in older Latinos. OBJECTIVE: To examine potential associations between acculturation in context and brain health in older Latinos. METHODS: Using three previously established composites of acculturation-in-context, (acculturation-related: nativity status, language preference, acculturation scores; contextually-related socioenvironmental: perceived discrimination, loneliness/social isolation, social network size; and familism), and diffusion-tensor imaging (DTI), associations with white matter structural integrity were examined in 92 Latino adults without dementia participating in one of three epidemiological studies of aging. Linear regression models were used to test associations with DTI-derived metrics (fractional anisotropy, FA; trace) as separate outcomes and acculturation composite scores as individual predictors, while adjusting for age, sex, education, scanner, and white matter hyperintensities (voxelwise and total volumes normalized by intracranial volume). RESULTS: Higher scores on the socioenvironmental composite were associated with lower FA in two clusters of left-hemisphere connections. Cluster 1 was dominated by both short association pathways connecting frontal regions and projection pathways connecting frontal regions with the thalamus. Cluster 2 was dominated by long association pathways connecting parietal, frontal, and temporal regions. CONCLUSIONS: This study of older Latino adults demonstrated an association between reduced brain white matter integrity and contextually related socioenvironmental experiences known to increase risk of MCI and Alzheimer's disease.

Dietary Sugar Intake Associated with a Higher Risk of Dementia in Community-Dwelling Older Adults.

BACKGROUND: We have limited evidence for the relationship of high sugar intake with dementia risk. OBJECTIVE: To determine whether high sugar intake is associated with an increased risk of dementia in community-dwelling older adultsMethods:This study included 789 participants of the Rush Memory and Aging Project (community-based longitudinal cohort study of older adults free of known dementia at enrollment), with annual clinical assessments and complete nutrient data (obtained by validated food frequency questionnaire). Clinical diagnosis of dementia is based on the criteria of the joint working group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. We used Cox proportional hazard models. RESULTS: 118 participants developed dementia during 7.3±3.8 years of follow-up. Those in the highest quintile of total sugar intake were twice as likely to develop dementia than those in the lowest quintile (Q5 versus Q1:HR=2.10 (95% CI: 1.05, 4.19) when adjusted for age, sex, education, APOEɛ4 allele, calories from sources other than sugar, physical activity, and diet score. Higher percent calories from sugar were positively associated with dementia risk (ß=0.042, p = 0.0009). In exploratory analyses, the highest versus lowest quintile of fructose and sucrose in the diet had higher dementia risk by 2.8 (95% CI: 1.38, 5.67) and 1.93 (95% CI: 1.05, 3.54) times, respectively. CONCLUSIONS: A higher intake of total sugar or total calories from sugar is associated with increased dementia risk in older adults. Among simple sugars, fructose (e.g., sweetened beverages, snacks, packaged desserts) and sucrose (table sugar in juices, desserts, candies, and commercial cereals) are associated with higher dementia risk.

Global Odds Model with Proportional Odds and Trend Odds Applied to Gross and Microscopic Brain Infarcts.

Medical and epidemiological researchers commonly study ordinal measures of symptoms or pathology. Some of these studies involve two correlated ordinal measures. There is often an interest in including both measures in the modeling. It is common to see analyses that consider one of the measures as a predictor in the model for the other measure as outcome. There are, however, issues with these analyses including biased estimate of the probabilities and a decreased power due to multicollinearity (since they share some predictors). These issues create a necessity to examine both variables as simultaneous outcomes, by assessing the marginal probabilities for each outcome (i.e. using a proportional odds model) and the association between the two outcomes (i.e. using a constant global odds model). In this work we extend this model using a parsimonious option when the constraints imposed by assumptions of proportional marginal odds and constant global odds do not hold. We compare approaches by using simulations and by analyzing data on brain infarcts in older adults. Age at death is a marginal predictor of gross infarcts and also a marginal predictor of microscopic infarcts, but does not modify the association between gross and microscopic infarcts.

Effects of Cerebrovascular and Lewy Body Pathology on Parkinsonian Signs in Community-Dwelling Older Adults.

BACKGROUND AND OBJECTIVES: The roles of Lewy body (LB) and separately of cerebrovascular disease (CVD) pathologies in the severity of parkinsonian signs are well recognized in old age. We investigated whether the 2 pathologies act synergistically to further potentiate the severity of parkinsonism beyond their separate effects. METHODS: We used postmortem data of decedents from 3 longitudinal community-based studies of aging who underwent annual clinical evaluation to assess parkinsonian signs using 26 items of the motor portion of a modified Unified Parkinson Disease Rating Scale. A summary score was developed from each item score to construct a global parkinsonian score, with a higher score indicating more severe parkinsonism. A detailed neuropathologic evaluation was performed to identify LB, Alzheimer disease pathology, nigral neuronal loss, atherosclerosis, macroscopic infarcts, and other CVD pathologies (arteriolosclerosis, cerebral amyloid angiopathy, and microscopic infarcts). A series of regression models with terms for LB, CVD pathology, and the interaction of LB with CVD pathologies was fit for global parkinsonism proximate to death and for individual parkinsonian signs scores including, parkinsonian gait, rigidity, tremor, and bradykinesia. RESULTS: In 1,753 participants (mean age at death = 89 years; 68% women), LB was observed in 26% of participants, and CVD pathologies were present in more than two-thirds of participants. LB and 3 CVD pathologies (atherosclerosis, arteriolosclerosis, and macroscopic infarcts) were each independently associated with the severity of global parkinsonism proximate to death (LB: ß = 0.318, SE = 0.08, p < 0.001; atherosclerosis: ß = 0.373, SE = 0.079, p < 0.001; arteriolosclerosis: ß = 0.253, SE = 0.078, p = 0.001; macroscopic infarcts: ß = 0.333, SE = 0.077, p < 0.001). A linear regression model adjusted for demographics, CVD, and neurodegenerative pathologies showed interaction between LB and macroscopic infarcts (ß = 0.463, SE = 0.168, p = 0.006), with LBs being associated with worse global parkinsonism when macroinfarcts are present. Similar interactions were found for atherosclerosis and LBs (ß = 0.371, SE = 0.173, p = 0.032) and for parkinsonian gait as the outcome (macroscopic infarcts: ß = 0.662, SE = 0.239, p = 0.005; atherosclerosis: ß = 0.509, SE = 0.246, p = 0.038). Findings were not affected when the 66 participants with a clinical diagnosis of Parkinson disease were excluded. By contrast, there were no interactions between LB and other CVD pathologies or between atherosclerosis and macroscopic infarcts for global parkinsonism proximate to death. DISCUSSION: These findings suggest that atherosclerosis and macroscopic infarcts interact with LB pathology to increase the severity of parkinsonism beyond their additive effects in older persons.

Primacy and recency effects in verbal memory are differentially associated with post-mortem frontal cortex p-tau 217 and 202 levels in a mixed sample of community-dwelling older adults.

INTRODUCTION: Serial position effects in verbal memory are associated with in vivo fluid biomarkers and neuropathological outcomes in Alzheimer's disease (AD). To extend the biomarker literature, associations between serial position scores and postmortem levels of brain phosphorylated tau (p-tau) were examined, in the context of Braak stage of neurofibrillary tangle progression. METHOD: Participants were 1091 community-dwelling adults (Mage = 80.2, 68.9% female) from the Rush University Religious Orders Study and Memory and Aging Project who were non-demented at enrollment and followed for a mean of 9.2 years until death. The CERAD Word List Memory test administered at baseline and within 1 year of death was used to calculate serial position (primacy, recency) and total recall scores. Proteomic analyses quantified p-tau 217 and 202 from dorsolateral prefrontal cortex samples. Linear regressions assessed associations between cognitive scores and p-tau with Braak stage as a moderator. RESULTS: Cognitive status proximal to death indicated 34.7% were unimpaired, 26.2% met criteria for MCI, and 39.0% for dementia. Better baseline primacy recall, but not recency recall, was associated with lower p-tau 217 levels across Braak stages. Delayed recall showed a similar pattern as primacy. There was no main effect of immediate recall, but an interaction with Braak stages indicated a negative association with p-tau 217 level only in Braak V-VI. Within 1 year of death, there were no main effects for cognitive scores; however, recency, immediate and delayed recall scores interacted with Braak stage showing better recall was associated with lower p-tau 217 only in Braak V-VI. No associations were observed with p-tau 202. CONCLUSIONS: Primacy recall measured in non-demented adults may be sensitive to emergent tau phosphorylation that occurs in the earliest stages of AD. Serial position scores may complement the routinely used delayed recall score and p-tau biomarkers to detect preclinical AD.

Neuropathologic correlates of cerebral microbleeds in community-based older adults.

Cerebral microbleeds (CMBs) appearing as hypointense foci on T2*-weighted magnetic resonance images are small hemorrhages that have been linked to cognitive decline and increased mortality. However, the neuropathologic correlates of CMBs in community-based older adults are poorly understood. The present study investigated the association of age-related neuropathologies with CMBs in community-based older adults. Cerebral hemispheres from 289 participants of the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Rush Alzheimer's Disease Clinical Core underwent ex vivo MRI and detailed neuropathologic examination. Following Bonferroni correction, CMBs in the cerebrum overall and in the frontal lobe were associated with cerebral amyloid angiopathy, CMBs in the frontal lobe were also associated with arteriolosclerosis, and CMBs in the basal ganglia showed a borderline significant association with microinfarcts. These findings suggest that CMBs can aid in the prediction of small vessel disease in community-based older adults. Finally, CMBs were not associated with dementia, suggesting that CMBs in community-based older adults may not be linked to substantial cognitive impairment.

Late-life depressive symptoms and white matter structural integrity within older Black adults.

Introduction: Older Black adults experience a high burden of depressive symptoms and cerebrovascular disease but the specific neurobiological substrates underlying the association between late-life depressive symptoms and brain integrity are understudied, particularly in within-group designs. Methods: Using the Center for Epidemiologic Studies Depression Scale and diffusion-tensor imaging, within-Black variation in the association between late-life depressive symptoms and white matter structural integrity was examined in 297 older Black participants without dementia that were enrolled across three epidemiological studies of aging and dementia. Linear regression models were used to test associations with DTI metrics (fractional anisotropy, trace of the diffusion tensor) as the outcomes and depressive symptoms as the predictor, while adjusting for age, sex, education, scanner, serotonin-reuptake inhibitor use, total volume of white-matter hyperintensities normalized by intracranial volume, and presence of white-matter hyperintensities at the voxel level. Results: Higher level of self-reported late-life depressive symptoms was associated with greater diffusion-tensor trace (reduced white matter integrity) in connections between commissural pathways and contralateral prefrontal regions (superior and middle frontal/dorsolateral prefrontal cortex), association pathways connecting dorsolateral prefrontal cortex with insular, striatal and thalamic regions, and association pathways connecting the parietal, temporal and occipital lobes and the thalamus. Discussion: This study demonstrated a discernable pattern of compromised white matter structural integrity underlying late-life depressive symptoms within older Black adults.

Neighborhood-level social vulnerability and individual-level cognitive and motor functioning over time in older non-Latino Black and Latino adults.

Introduction: Despite known health disparities in cognitive aging, a comprehensive rationale for the increased burden in older minoritized populations including non-Latino Black and Latino adults has yet to be elucidated. While most work has focused on person-specific risk, studies are increasingly assessing neighborhood-level risk. We evaluated multiple aspects of the environmental milieu that may be critical when considering vulnerability to adverse health outcomes. Methods: We investigated associations between a Census-tract derived Social Vulnerability Index (SVI) and level of and change in cognitive and motor functioning in 780 older adults (590 non-Latino Black adults, ∼73 years old at baseline; 190 Latinos, ∼70 years old baseline). Total SVI scores (higher = greater neighborhood-level vulnerability) were combined with annual evaluations of cognitive and motor functioning (follow-up ranged from 2 to 18 years). Demographically-adjusted mixed linear regression models tested for associations between SVI and cognitive and motor outcomes in analyses stratified by ethno-racial group. Results: For non-Latino Black participants, higher SVI scores were associated with lower levels of global cognitive and motor functioning-specifically, episodic memory, motor dexterity and gait-as well as longitudinal change in visuospatial abilities and hand strength. For Latinos, higher SVI scores were associated with lower levels of global motor functioning only-specifically, motor dexterity; there were no significant associations between SVI and change in motor functioning. Discussion: Neighborhood-level social vulnerability is associated with cognitive and motor functioning in non-Latino Black and Latino older adults, although associations appear to contribute to level more so than longitudinal change.

Association of Mediterranean-DASH Intervention for Neurodegenerative Delay and Mediterranean Diets With Alzheimer Disease Pathology.

BACKGROUND AND OBJECTIVES: Diet may reduce Alzheimer dementia risk and slow cognitive decline, but the understanding of the relevant neuropathologic mechanisms remains limited. The association of dietary patterns with Alzheimer disease (AD) pathology has been suggested using neuroimaging biomarkers. This study examined the association of Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean dietary patterns with ß-amyloid load, phosphorylated tau tangles, and global AD pathology in postmortem brain tissue of older adults. METHODS: Autopsied participants of the Rush Memory and Aging Project with complete dietary information (collected through a validated food frequency questionnaire) and AD pathology data (ß-amyloid load, phosphorylated tau tangles, and global AD pathology [summarized neurofibrillary tangles and neuritic and diffuse plaques]) were included in this study. Linear regression models controlled for age at death, sex, education, APOE-ε4 status, and total calories were used to investigate the dietary patterns (MIND and Mediterranean diets) and dietary components associated with AD pathology. Further effect modification was tested for APOE-ε4 status and sex. RESULTS: Among our study participants (N = 581, age at death: 91.0 ± 6.3 years; mean age at first dietary assessment: 84.2 ± 5.8 years; 73% female; 6.8 ± 3.9 years of follow-up), dietary patterns were associated with lower global AD pathology (MIND: ß = -0.022, p = 0.034, standardized ß = -2.0; Mediterranean: ß = -0.007, p = 0.039, standardized ß = -2.3) and specifically less ß-amyloid load (MIND: ß = -0.068, p = 0.050, standardized ß = -2.0; Mediterranean: ß = -0.040, p = 0.004, standardized ß = -2.9). The findings persisted when further adjusted for physical activity, smoking, and vascular disease burden. The associations were also retained when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded. Those in the highest tertile of green leafy vegetables intake had less global AD pathology when compared with those in the lowest tertile (tertile 3 vs tertile 1: ß = -0.115, p = 0.0038). DISCUSSION: The MIND and Mediterranean diets are associated with less postmortem AD pathology, primarily ß-amyloid load. Among dietary components, higher green leafy vegetable intake was associated with less AD pathology.

The association of MIND diet with cognitive resilience to neuropathologies.

INTRODUCTION: Cognitive resilience (CR) can be defined as the continuum of better through worse than expected cognition, given the degree of neuropathology. The relation of healthy diet patterns to CR remains to be elucidated. METHODS: Using longitudinal cognitive data and post mortem neuropathology from 578 deceased older adults, we examined associations between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet at baseline and two standardized CR measures reflecting higher cognitive levels over time (CR Level ¯ $_{\overline {{\rm{Level}}}} $ ), and slower decline (CRSlope ), than expected given neuropathology. RESULTS: Compared to individuals in the lowest tertile of MIND score, those in the top tertile had higher CR Level ¯ $_{\overline {{\rm{Level}}}} $ (mean difference [MD] = 0.34; 95% confidence interval [CI] = 0.14, 0.55) and CRSlope (MD = 0.27; 95% CI = 0.05, 0.48), after multivariable adjustment. Overall MIND score was more strongly related to CR than the individual food components. DISCUSSION: The MIND diet is associated with both higher cognition and slower rates of cognitive decline, after controlling for neuropathology, indicating the MIND diet may be important to cognitive resilience.

Trends in Postmortem Neurodegenerative and Cerebrovascular Neuropathologies Over 25 Years.

Importance: With rapid aging of the US population, understanding trends over time in dementia occurrence is essential to public health planning and intervention; this understanding includes trends in neuropathologies underlying clinical dementia. Objective: To characterize trends in pathways underlying dementia by examining prevalence of postmortem neuropathologies in birth cohorts across 25 years. Design, Setting, and Participants: Two longitudinal cohorts, the Religious Orders Study and the Rush Memory and Aging Project, with autopsy data from 1997 to 2022 with up to 27 years follow-up were analyzed. Deceased individuals with complete postmortem neuropathology evaluations were included, and 177 individuals with most distant (<1905) or recent (>1930) years of birth were excluded. Exposures: Four categories of year of birth: 1905-1914, 1915-1919, 1920-1924, and 1925-1930. Main Outcomes and Measures: Outcomes included pathologic diagnosis of Alzheimer disease (AD), global AD pathology, amyloid load, tau tangles, neocortical Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy neuropathological change, atherosclerosis, arteriolosclerosis, gross chronic infarcts, and chronic microinfarcts. For comparison, pathologies in each birth epoch were age-standardized to age distribution of the cohorts. χ2 Tests were used for categorical outcomes, and analysis of variance was used to compare means across birth epochs. Results: Overall, 1554 participants were examined (510 [33%] male; median [range] age at death, 90 [66-108] years). Participants were distributed fairly evenly across birth epochs (1905-1914: n = 374; 1915-1919: n = 360; 1920-1924: n = 466; 1925-1930: n = 354). Across year of birth groups, no differences were found in prevalence of pathologic AD diagnosis; age-standardized prevalence fluctuated between 62% and 68% in the birth cohorts (χ2 test: P = .76 across birth epochs). Similarly, no differences were found in mean levels of global AD pathology, although there was greater density specifically of tau tangles in later birth cohorts (eg, age-standardized mean [SD], 1.53 [1.20] years for the 1905-1914 cohort and 1.87 [1.47] years for the 1925-1930 cohort; analysis of variance test: P = .01 across birth cohorts). There were no differences over time in other neurodegenerative pathologies. In contrast, atherosclerosis and arteriosclerosis were dramatically lower over time; for example, age-standardized prevalence of moderate to severe atherosclerosis ranged from 54% among those born from 1905-1914 to 22% for 1925-1930 (χ2 test: P < .001 across birth epochs). Conclusion and Relevance: In this study, few differences in neurodegenerative pathologies were found, but there may be worse levels of tau tangles across birth cohorts over 25 years. This indicates that any improvements over time in clinical dementia observed by cohorts are likely in part associated with improved resilience to pathology rather than reduced AD pathology. Finally, vessel pathologies were markedly lower over birth cohorts, indicating the assocation with brain health of populationwide improvements in several vascular risk factors.