Grey matter ageing-related tau astrogliopathy: associations with brain pathologies and cognitive decline.

Grey matter ageing-related tau astrogliopathy (ARTAG) pathology is common in aged brains and detected in multiple brain regions. However, the associations of grey matter ARTAG with Alzheimer's disease and other common age-related proteinopathies, in addition to clinical phenotypes, including Alzheimer's dementia and cognitive decline, remain unclear. We examined 442 decedents (mean age at death = 90 years, males = 32%) from three longitudinal community-based clinical-pathological studies. Using AT8 immunohistochemistry, grey matter ARTAG pathology was counted in the superior frontal region, anterior temporal tip and amygdala and summarized as a severity score ranging from zero (none) to six (severe). Alzheimer's disease and other common age-related neuropathologies were also evaluated. The diagnosis of Alzheimer's dementia was based on clinical evaluations; annual tests of cognitive performance were summarized as global cognition and five cognitive domains. Multivariable logistic regression tested the associations of grey matter ARTAG pathology with an array of age-related neuropathologies. To evaluate associations of grey matter ARTAG pathology with Alzheimer's dementia and cognitive decline, we used logistic regression and linear mixed-effect models. Grey matter ARTAG pathology was seen in 324 (73%) participants, of which 303 (68%) participants had ARTAG in the amygdala, 246 (56%) in the anterior temporal tip and 137 (31%) in the superior frontal region. Grey matter ARTAG pathology from each of the three regions was associated with a pathological diagnosis of Alzheimer's disease and limbic-predominant age-related TAR DNA-binding protein 43 encephalopathy-neuropathological change but not with vascular pathology. In fully adjusted models that controlled for demographics, Alzheimer's disease and common age-related pathologies, an increase in severity of grey matter ARTAG pathology in the superior frontal cortex, but not in the amygdala or the anterior temporal tip, was associated with higher odds of Alzheimer's dementia and faster decline in global cognition, episodic memory and semantic memory. These results provide compelling evidence that grey matter ARTAG, specifically in the superior frontal cortex, contributes to Alzheimer's dementia and cognitive decline in old age.

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.

Cerebral arteriolosclerosis, lacunar infarcts, and cognition in older Black adults.

INTRODUCTION: Older Black adults are at risk of cerebral small vessel disease (CSVD), which contributes to dementia risk. Two subtypes of CSVD, arteriolosclerosis and ischemic lacunar infarcts, have been independently linked to lower cognition and higher dementia risk, but their combined effects on cognition in older Black adults are unclear. METHODS: Mixed models were used to examine the associations of in vivo measures of arteriolosclerosis (ARTS) and ischemic lacunar infarcts to cognitive level and change in 370 older Black adults without dementia.  RESULTS: Modeled together, higher ARTS load accounted for lower levels of global cognition, episodic memory, semantic memory, and perceptual speed, whereas higher infarct load accounted for lower levels of working memory. There were no associations with rate of cognitive change. DISCUSSION: Both arteriolosclerosis and ischemic infarcts impact the cognitive health of older Black adults, but arteriolosclerosis affects cognition more broadly and offers promise as an in vivo biomarker of dementia risk. HIGHLIGHTS: Older Black adults are at risk of cerebral small vessel disease (CSVD) and dementia. Examined magnetic resonance imaging-derived measure of arteriolosclerosis (ARTS), infarcts, and cognition. ARTS load was widely associated with lower cognition after adjusting for infarct load. Infarct load was specifically associated with lower complex attention. More within-Black in vivo studies of CSVD subtypes and cognition are needed.

A multilayer network analysis of Alzheimer's disease pathogenesis: Roles for p-tau, synaptic peptides, and physical activity.

INTRODUCTION: In the aging brain, cognitive abilities emerge from the coordination of complex pathways arising from a balance between protective lifestyle and environmental factors and accumulation of neuropathologies. METHODS: As part of the Rush Memory and Aging Project (n = 440), we measured accelerometer-based actigraphy, cognitive performance, and after brain autopsy, selected reaction monitoring mass spectrometry. Multilevel network analysis was used to examine the relationships among the molecular machinery of vesicular neurotransmission, Alzheimer's disease (AD) neuropathology, cognition, and late-life physical activity. RESULTS: Synaptic peptides involved in neuronal secretory function were the most influential contributors to the multilayer network, reflecting the complex interdependencies among AD pathology, synaptic processes, and late-life cognition. Older adults with lower physical activity evidenced stronger adverse relationships among phosphorylated tau peptides, markers of synaptic integrity, and tangle pathology. DISCUSSION: Network-based approaches simultaneously model interdependent biological processes and advance understanding of the role of physical activity in age-associated cognitive impairment. HIGHLIGHTS: Network-based approaches simultaneously model interdependent biological processes. Secretory synaptic peptides were influential contributors to the multilayer network. Older adults with lower physical activity had adverse relationships among pathology. There was interdependence among phosphorylated tau, synaptic integrity, and tangles. Network methods elucidate the role of physical activity in cognitive impairment.

Brain and spinal cord arteriolosclerosis and its associations with cerebrovascular disease risk factors in community-dwelling older adults.

Arteriolosclerosis is common in older brains and related to cognitive and motor impairment. We compared the severity of arteriolosclerosis and its associations with cerebrovascular disease risk factors (CVD-RFs) in multiple locations in the brain and spinal cord. Participants (n = 390) were recruited in the context of a longitudinal community-based clinical-pathological study, the Rush Memory and Aging Project. CVD-RFs were assessed annually for an average of 8.7 (SD = 4.3) years before death. The annual assessments included systolic (SBP) and diastolic (DBP) blood pressure, diabetes mellitus (DM), low- and high-density lipoprotein cholesterol, triglyceride, body mass index, and smoking. Postmortem pathological assessments included assessment of arteriolosclerosis severity using the same rating scale in three brain locations (basal ganglia, frontal, and parietal white matter regions) and four spinal cord levels (cervical, thoracic, lumbar and sacral levels). A single measure was used to summarize the severity of spinal arteriolosclerosis assessments at the four levels due to their high correlations. Average age at death was 91.5 (SD = 6.2) years, and 73% were women. Half showed arteriolosclerosis in frontal white matter and spinal cord followed by parietal white matter (38%) and basal ganglia (27%). The severity of arteriolosclerosis in all three brain locations showed mild-to-moderate correlations. By contrast, spinal arteriolosclerosis was associated with brain arteriolosclerosis only in frontal white matter. Higher DBP was associated with more severe arteriolosclerosis in all three brain locations. DM was associated with more severe arteriolosclerosis only in frontal white matter. Controlling for DBP, higher SBP was inversely associated with arteriolosclerosis in parietal white matter. Blood cholesterol and triglyceride, high body mass index, or smoking were not related to the severity of arteriolosclerosis in any brain region. None of the CVD-RFs were associated with the severity of spinal arteriolosclerosis. These data indicate that severity of arteriolosclerosis and its associations with CVD-RFs may vary in different CNS locations.

Brain copper may protect from cognitive decline and Alzheimer's disease pathology: a community-based study.

Copper is an essential micronutrient for brain health and dyshomeostasis of copper could have a pathophysiological role in Alzheimer's disease (AD), however, there are limited data from community-based samples. In this study, we investigate the association of brain copper (assessed using ICP-MS in four regions -inferior temporal, mid-frontal, anterior cingulate, and cerebellum) and dietary copper with cognitive decline and AD pathology burden (a quantitative summary of neurofibrillary tangles, diffuse and neuritic plaques in multiple brain regions) at autopsy examination among deceased participants (N = 657; age of death: 90.2(±6.2)years, 70% women, 25% APOE-ɛ4 carriers) in the Rush Memory and Aging Project. During annual visits, these participants completed cognitive assessments using a 19-test battery and dietary assessments (using a food frequency questionnaire). Regression, linear mixed-effects, and logistic models adjusted for age at death, sex, education, and APOE-ε4 status were used. Higher composite brain copper levels were associated with slower cognitive decline (ß(SE) = 0.028(0.01), p = 0.001) and less global AD pathology (ß(SE) = -0.069(0.02), p = 0.0004). Participants in the middle and highest tertile of dietary copper had slower cognitive decline (T2vs.T1: ß = 0.038, p = 0.0008; T3vs.T1: ß = 0.028, p = 0.01) than those in the lowest tertile. Dietary copper intake was not associated with brain copper levels or AD pathology. Associations of higher brain copper levels with slower cognitive decline and with less AD pathology support a role for copper dyshomeostasis in AD pathogenesis and suggest that lower brain copper may exacerbate or indicate disease severity. Dietary and brain copper are unrelated but dietary copper is associated with slower cognitive decline via an unknown mechanism.

Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy.

Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC50 ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer's disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele's heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.

Longitudinal change in serial position scores in older adults with entorhinal and hippocampal neuropathologies.

OBJECTIVE: Serial position scores on verbal memory tests are sensitive to early Alzheimer's disease (AD)-related neuropathological changes that occur in the entorhinal cortex and hippocampus. The current study examines longitudinal change in serial position scores as markers of subtle cognitive decline in older adults who may be in preclinical or at-risk states for AD. METHODS: This study uses longitudinal data from the Religious Orders Study and the Rush Memory and Aging Project. Participants (n = 141) were included if they did not have dementia at enrollment, completed follow-up assessments, and died and were classified as Braak stage I or II. Memory tests were used to calculate serial position (primacy, recency), total recall, and episodic memory composite scores. A neuropathological evaluation quantified AD, vascular, and Lewy body pathologies. Mixed effects models were used to examine change in memory scores. Neuropathologies and covariates (age, sex, education, APOE e4) were examined as moderators. RESULTS: Primacy scores declined (ß = -.032, p < .001), whereas recency scores increased (ß = .021, p = .012). No change was observed in standard memory measures. Greater neurofibrillary tangle density and atherosclerosis explained 10.4% of the variance in primacy decline. Neuropathologies were not associated with recency change. CONCLUSIONS: In older adults with hippocampal neuropathologies, primacy score decline may be a sensitive marker of early AD-related changes. Tangle density and atherosclerosis had additive effects on decline. Recency improvement may reflect a compensatory mechanism. Monitoring for changes in serial position scores may be a useful in vivo method of tracking incipient AD.

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.

Brain vitamin D forms, cognitive decline, and neuropathology in community-dwelling older adults.

INTRODUCTION: Vitamin D purportedly protects against cognitive decline and dementia based on observational data using circulating 25-hydroxyvitamin D (25(OH)D). Little is known about vitamin D in the human brain and the association with dementia or neuropathology. METHODS: Decedents of the Rush Memory and Aging Project (n = 290) had vitamin D concentrations measured in four brain regions. Associations with cognitive and neuropathological outcomes were estimated using linear and logistic regression. RESULTS: The main form of vitamin D in all brain regions measured was 25(OH)D3 . Higher brain 25(OH)D3 concentrations were associated with a 25% to 33% lower odds of dementia or mild cognitive impairment (MCI) at the last visit before death (all P ≤ .031). However, brain 25(OH)D concentrations were not associated with any post-mortem neuropathology outcome studied. DISCUSSION: Higher brain 25(OH)D3 concentrations were associated with better cognitive function prior to death. Additional research is needed to clarify the specific mechanisms underlying this potentially protective relationship.

Complex Profiles of Cerebrovascular Disease Pathologies in the Aging Brain and Their Relationship With Cognitive Decline.

BACKGROUND AND PURPOSE: Cerebrovascular disease (CVD) pathologies including vessel disease (atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and tissue injury (macroinfarcts and microinfarcts) each contribute to Alzheimer and other forms of dementia. CVD is often a complex mix of neuropathologies, with little known about the frequencies of differing combinations or their associations with cognition. METHODS: We investigated 32 possible CVD combinations (3 types of vessel disease and 2 types of tissue injury) using autopsy data from 1474 decedents (≈88 years at death; 65% female) of Rush Alzheimer's Disease Center studies. We determined frequencies of all 32 CVD combinations and their relationships with global and domain-specific cognitive decline using mixed-effect models adjusted for demographics, neuropathologies, time before death, and interactions of these variables with time. RESULTS: Of the 1184 decedents with CVD neuropathology (80% of the total sample), 37% had a single CVD (67-148 decedents/group) while 63% had mixed CVD profiles (11-54 decedents/group). When considered as 2 distinct groups, the mixed CVD profile group (but not the single CVD profile group) showed a faster cognitive decline across all domains assessed compared with decedents without CVD neuropathology. Most mixed CVD profiles, especially those involving both atherosclerosis and arteriolosclerosis, showed faster cognitive decline than any single CVD profile considered alone; specific mixed CVD profiles differentially associated with individual cognitive domains. CONCLUSIONS: Mixed CVD, more common than single CVD, is associated with cognitive decline, and distinct mixed CVD profiles show domain-specific associations with cognitive decline. CVD is not monolithic but consists of heterogenous person-specific combinations with distinct contributions to cognitive decline.

Cognitive decline and hippocampal functional connectivity within older Black adults.

While there has been a proliferation of neuroimaging studies on cognitive decline in older non-Hispanic White adults, there is a dearth of knowledge regarding neuroimaging correlates of cognitive decline in Black adults. Resting-state functional neuroimaging approaches may be particularly sensitive to early cognitive decline, but there are no studies that we know of that apply this approach to examining associations of brain function to cognition in older Black adults. We investigated the association of cognitive decline with whole-brain voxel-wise functional connectivity to the hippocampus, a key brain region functionally implicated in early Alzheimer's dementia, in 132 older Black adults without dementia participating in the Minority Aging Research Study and Rush Memory and Aging Project, two longitudinal studies of aging that include harmonized annual cognitive assessments and magnetic resonance imaging brain imaging. In models adjusted for demographic factors (age, education, sex), global cognitive decline was associated with functional connectivity of the hippocampus to three clusters in the right and left frontal regions of the dorsolateral prefrontal cortex. In domain-specific analyses, decline in semantic memory was associated with functional connectivity of the hippocampus to bilateral clusters in the precentral gyrus, and decline in perceptual speed was inversely associated with connectivity of the hippocampus to the bilateral intracalcarine cortex and the right fusiform gyrus. These findings elucidate neurobiological mechanisms underlying cognitive decline in older Black adults and may point to specific targets of intervention for Alzheimer's disease.

Relationship of Blood Pressure and White Matter Hyperintensity Burden With Level of and Change in Cognition in Older Black Adults.

OBJECTIVE: Elevations in blood pressure (BP) and associated white matter hyperintensities (WMHs) are chronic comorbid conditions among older Black adults. We investigated whether WMHs modify the association between late-life BP and cognition within older Black adults. METHODS: A total of 167 Black adults (age, ~75 years; without dementia at baseline) participating in neuroimaging studies at the Rush Alzheimer's Disease Center were evaluated for BP markers of cardiovascular health, including systolic BP, diastolic BP, pulse pressure, mean arterial pressure (MAP), and hypertension, and were assessed for global and domain-specific cognition at baseline and annually for up to 8 years. WMHs adjusted for intracranial volume were quantified at baseline. RESULTS: Models adjusted for relevant confounders and the interaction of these variables with time revealed differential associations between BP markers and baseline cognition; however, only elevated diastolic BP predicted faster cognitive, that is, episodic memory, decline (estimate = -0.002, standard error = 0.0009, p = .002). Although WMH burden did not modify the association between diastolic BP and episodic memory decline, it did interact with diastolic BP to lower episodic memory at baseline (estimate = -0.051, standard error = 0.012, p = .0001); that is, greater WMHs combined with higher diastolic BP resulted in the lowest baseline episodic memory scores. A similar profile was noted for WMHs, MAP, and baseline episodic memory. Hypertension was neither associated with cognition nor modified by WMH burden after multiple comparisons correction. CONCLUSION: Late-life diastolic BP was associated with faster rates of episodic memory decline in older Black adults; together with higher WMH burden, it (and MAP) lowered the point at which individuals begin their course of decline toward pathological aging.

Acute versus chronic inflammatory markers and cognition in older black adults: Results from the Minority Aging Research Study.

Peripheral inflammation is elevated in older Black adults, an elevation which prior work has suggested may be due to chronic stress associated with systemic racism and related adverse cardiovascular health conditions. Inflammation is also involved in the pathogenic processes of dementia; however, limited (and mixed) results exist concerning inflammation and cognitive decline in Black adults. We characterized patterns of inflammation and their role in cognitive decline in 280 older Black adults (age = 72.99 ± 6.00 years; 69.6% female) from the Minority Aging Research Study (MARS) who were without dementia at baseline and followed between 2 and 15 years (mean = 9 years). Participants completed a blood draw at baseline and annual cognitive evaluations. Serum was assayed for 9 peripheral inflammatory markers; 19 neuropsychological test scores were used to create indices of global cognition and five cognitive domains. Principal component analysis with varimax rotation characterized patterns of inflammation with factor loadings > 0.6 per component contributing to two composite scores representing acute/upstream and chronic/downstream inflammation. These composites were used as separate predictors in linear mixed regression models to determine associations with level and change in cognition adjusting for relevant covariates. Higher baseline upstream/acute inflammation associated with lower baseline semantic memory (p = .040) and perceptual speed (p = .046); it was not related to cognitive decline. By contrast, higher baseline downstream/chronic inflammation associated with faster declines in global cognition (p = .010), episodic (p = .027) and working memory (p = .006); it was not related to baseline cognition. For older Black adults, chronic, but not acute, inflammation may be a risk factor for changes in cognition.

Relationship of Purpose in Life to Dementia in Older Black and White Brazilians.

OBJECTIVES: To test the hypothesis that higher level of purpose in life is associated with lower likelihood of dementia and mild cognitive impairment (MCI) in older Brazilians. METHODS: As part of the Pathology, Alzheimer's and Related Dementias Study (PARDoS), informants of 1,514 older deceased Brazilians underwent a uniform structured interview. The informant interview included demographic data, the Clinical Dementia Rating scale to diagnose dementia and MCI, the National Institute of Mental Health Diagnostic Interview Schedule for depression, and a 6-item measure of purpose in life, a component of well-being. RESULTS: Purpose scores ranged from 1.5 to 5.0 with higher values indicating higher levels of purpose. On the Clinical Dementia Rating Scale, 940 persons (62.1%) had no cognitive impairment, 121 (8.0%) had MCI, and 453 (29.9%) had dementia. In logistic regression models adjusted for age at death, sex, education, and race, higher purpose was associated with lower likelihood of MCI (odds ratio = .58; 95% confidence interval [CI]: .43, .79) and dementia (odds ratio = .49, 95% CI: .41, .59). Results were comparable after adjusting for depression (identified in 161 [10.6%]). Neither race nor education modified the association of purpose with cognitive diagnoses. CONCLUSIONS: Higher purpose in life is associated with lower likelihood of MCI and dementia in older black and white Brazilians.

Quantifying longitudinal cognitive resilience to Alzheimer's disease and other neuropathologies.

INTRODUCTION: Cognitive resilience (CR) has been defined as the continuum of better (or worse) than expected cognition, given the degree of neuropathology. To quantify this concept, existing approaches focus on either cognitive level at a single time point or slopes of cognitive decline. METHODS: In a prospective study of 1215 participants, we created a continuous measure of CR defined as the mean of differences between estimated person-specific and marginal cognitive levels over time, after accounting for neuropathologies. RESULTS: Neuroticism and depressive symptoms were associated with all CR measures (P-values < .012); as expected, cognitive activity and education were only associated with the cognitive-level approaches (P-values < .0002). However, compared with the existing CR measures focusing on a single measure or slopes of cognition, our new measure yielded stronger relations with risk factors. DISCUSSION: Defining CR based on the longitudinal differences between person-specific and marginal cognitive levels is a novel and complementary way to quantify CR.

Proteomic identification of select protein variants of the SNARE interactome associated with cognitive reserve in a large community sample.

Age-related neuropathologies progressively impair cognitive abilities by damaging synaptic function. We aimed to identify key components within the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery associated with cognitive performance and estimate their potential contribution to brain reserve in old age. We used targeted SRM proteomics to quantify amounts of 60 peptides, encoded in 30 different genes, in postmortem specimens of the prefrontal cortex from 1209 participants of two aging studies, with available antemortem cognitive evaluations and postmortem neuropathologic assessments. We found that select (but not all) proteoforms are strongly associated with cognitive function and the burden of Alzheimer's disease (AD) pathology. Specifically, greater abundance of STX1A (but not other syntaxins), SYT12, full-length SNAP25, and the GABAergic STXBP1 variant were robustly associated with better cognitive performance. By contrast, greater abundance of other presynaptic proteins (e.g., STXBP5 or tomosyn, STX7, or SYN2) showed a negative influence on cognition. Regression models adjusting for demographic and pathologic variables showed that altered levels of these protein species explained 7.7% additional between-subject variance in cognition (more than any individual age-related neuropathology in the model), suggesting that these molecules constitute key elements of brain reserve. Network analyses indicated that those peptides associated with brain reserve, and closest to the SNARE fusogenic activity, showed greater centrality measures and were better connected in the network. Validation assays confirmed the selective loss of the STX1A (but not STX1B) isoform in cognitively impaired cases. In rodent and human brains, STX1A was selectively located at glutamatergic terminals. However, in AD brains, STX1A was redistributed adjacent to neuritic pathology, and markedly expressed in astrocytes. Our study provides strong evidence, indicating that select presynaptic proteins are key in maintaining brain reserve. Compromised ability to sustain expression levels of these proteins may trigger synaptic dysfunction and concomitant cognitive impairment.

Neuroticism, negative life events, and dementia in older White and Black Brazilians.

OBJECTIVE: Exposure to negative life events (NLEs) and neuroticism are associated with dementia. It is unknown whether neuroticism explains or modifies the association of NLEs with dementia in older Black and White Brazilians. METHODS: A total of 1747 decedents 65 years and older White and Black (11% Black and 23% Mixed) Brazilians, 53% women, were included in the analyses. Data were obtained in a face-to-face interview with an informant (71% their children) who knew the decedents for 47 years on average. Dementia was classified using the Clinical Dementia Rating. NLEs were assessed with a 10-item scale involving common problems (e.g., death, illness, alcoholism, and financial). Neuroticism was assessed with a 6-item neuroticism scale adapted from the NEO Five-Factor Inventory. Models adjusted for age, sex, and education. Black and mixed-race were combined in the analyses. RESULTS: NLEs (median of 2) were more common in Blacks than Whites (2.04 vs. 1.82, p = 0.007). More NLEs increased the odds of dementia (OR = 1.112, ß = 0.106, p = 0.002), similarly in Blacks and Whites (ß interaction  = 0.046, p = 0.526). More NLEs were also associated with higher neuroticism (ß = 0.071, p < 0.0001), in Whites but not in Blacks (ß interaction  = -0.048, p = 0.006). Neuroticism was associated with higher odds of dementia (OR = 1.658, ß = 0.506, p=<0.001), in Whites but not in Blacks (ß interaction  = -0.420, p = 0.040). Overall, 34% of the effect of NLEs on dementia was associated with the underlying neuroticism trait in Whites (65%, Indirect OR = 1.060, p < 0.001) but no association was evident in Blacks (6%, Indirect OR = 1.008, p = 0.326). Neuroticism did not moderate the association of NLEs with dementia (OR = 0.979, ß = -0.021, p = 0.717). CONCLUSION: The association of NLEs and dementia is partially explained by neuroticism in older White but not in Blacks Brazilians.

The link between social and emotional isolation and dementia in older black and white Brazilians.

OBJECTIVE: To examine the link between social and emotional isolation and likelihood of dementia among older black and white Brazilians. DESIGN: Cross-sectional clinical-pathological cohort study. SETTING: Medical center in Sao Paulo, Brazil. PARTICIPANTS: As part of the Pathology, Alzheimer's and Related Dementias Study, we conducted uniform structured interviews with knowledgeable informants (72% children) of 1,493 older (age > 65) Brazilian decedents. MEASUREMENTS: The interview included measures of social isolation (number of family and friends in at least monthly contact with decedent), emotional isolation (short form of UCLA Loneliness Scale), and major depression plus the informant portion of the Clinical Dementia Rating Scale to diagnose dementia and its precursor, mild cognitive impairment (MCI). RESULTS: Decedents had a median social network size of 8.0 (interquartile range = 9.0) and a median loneliness score of 0.0 (interquartile range = 1.0). On the Clinical Dementia Rating Scale, 947 persons had no cognitive impairment, 122 had MCI, and 424 had dementia. In a logistic regression model adjusted for age, education, sex, and race, both smaller network size (odds ratio [OR] = 0.975; 95% confidence interval [CI]: 0.962, 0.989) and higher loneliness (OR = 1.145; 95% CI: 1.060, 1.237) were associated with higher likelihood of dementia. These associations persisted after controlling for depression (present in 10.4%) and did not vary by race. After controlling for depression, neither network size nor loneliness was related to MCI. CONCLUSION: Social and emotional isolation are associated with higher likelihood of dementia in older black and white Brazilians.

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

BACKGROUND AND PURPOSE: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed. METHODS: This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline. RESULTS: EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, P=0.0017) and diabetes mellitus (odds ratio=1.73, P=0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, P=0.016) and microscopic infarcts (odds ratio=1.79, P=0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, P=0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, P=0.048) and visuospatial abilities (estimate=-0.11, P=0.016) at the time of death. CONCLUSIONS: EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.