Differential correlations of changes in in vivo neuroimaging markers of hippocampal volume and arteriolosclerosis with declining financial and health literacy in old age.

Financial and health literacy is essential for older adults to navigate complex decision processes in late life. However, the neurobiological basis of age-related decline in financial and health literacy is poorly understood. This study aimed to characterize progression of neurodegenerative and vascular conditions over time, and to assess how these changes coincide with declining financial and health literacy in old age. Data came from 319 community-living older adults who were free of dementia at baseline, and underwent annual literacy assessments, as well as biennial 3-Tesla neuroimaging scans. Financial and health literacy was assessed using a battery of 32 items. Two in vivo neuroimaging markers of neurodegenerative and cerebrovascular conditions were used, i.e., hippocampal volume and the ARTS marker of arteriolosclerosis. A multivariate linear mixed effects model estimated the simultaneous changes in financial and health literacy, hippocampal volume, and the ARTS score. Over a mean of 7 years of follow-up, these older adults experienced a significant decline in financial and health literacy, a significant reduction in hippocampal volume, and a significant progression in ARTS score. Individuals with faster hippocampal atrophy had faster decline in literacy. Similarly, those with faster progression in ARTS also had faster decline in literacy. The correlation between the rates of hippocampal atrophy and declining literacy, however, was stronger than the correlation between the progression of ARTS with declining literacy. These findings suggest that neurodegeneration and, to a lesser extent, cerebrovascular conditions are correlated with declining financial and health literacy in old age.

Associations between structural neuroimaging markers of Alzheimer's risk and scam susceptibility.

Older adults with greater scam susceptibility are at greater risk for mild cognitive impairment and incident Alzheimer's dementia, regardless of baseline cognition. This, combined with documented associations between scam susceptibility and beta amyloid at death suggests that scam susceptibility may be an earlier indicator of pathological aging than cognition. Little, however, is known about whether in vivo neuroimaging markers of early-stage risk for Alzheimer's dementia are also related to scam susceptibility; such knowledge will inform upon the associations of neurodegenerative processes with scam susceptibility and may help identify vulnerable individuals. Participants were 472 community-based adults without dementia (age ~ 81y; 75% women) from the Rush Memory and Aging Project. Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess the cortical thickness 'signature' of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden, respectively. Scam susceptibility was measured using a questionnaire that assessed behaviors associated with vulnerability to fraud and scams. Demographically-adjusted linear effects regression models determined the relationship of each neuroimaging measure, first separately and then combined, with scam susceptibility. Reduced AD-CT was associated with higher levels of scam susceptibility (estimate=-0.10, standard error = 0.03, p = 0.002). WMH burden was not associated with scam susceptibility either alone or when combined in the same model as AD-CT (p-values ≥ 0.14). Results for AD-CT persisted after the inclusion of WMH burden. AD-CT was associated with scam susceptibility in older adults without dementia possibly signaling an in vivo profile of this behavior.

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.

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.

Metformin, age-related cognitive decline, and brain pathology.

The objective of this study was to evaluate the relation of metformin with change in cognition and brain pathology. During a mean of 8 years (SD = 5.5) of annual follow-up visits, 262/3029 participants were using metformin at any time during the study. Using a linear-mixed effect model adjusted for age, sex, and education, metformin users had slower decline on a score of global cognition compared to non-users (estimate = 0.017, SE = 0.007, p = 0.027). Analyses of cognitive domains showed a slower decline in episodic memory and semantic memory specifically. In sensitivity analysis, when examining any diabetes medication use vs none, no association was observed of any diabetes medication use with cognitive function. In the autopsy subset of 1584 participants, there was no difference in the level of Alzheimer's disease (AD) pathology or the presence of infarcts (of any size or location) between groups of metformin users vs non-users. However, in additional analyses, metformin users had higher odds of subcortical infarcts, and lower odds of atherosclerosis and arteriosclerosis.

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.

The Relationship of MRI-Derived Alzheimer's and Cerebrovascular-Related Signatures With Level of and Change in Health and Financial Literacy.

OBJECTIVE: The cortical thickness "signature" of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden have each been associated with cognitive aging and incident AD and related dementias. Less is known about how these structural neuroimaging markers associate with other critical behaviors. We investigated associations of AD-CT and WMH volumes with a composite index of health and financial literacy given that the ability to access, understand, and utilize health and financial information significantly influences older adults' health outcomes. DESIGN, SETTING, PARTICIPANTS: Participants were 303 adults without dementia (age∼80 years; 74% women) from the Rush Memory and Aging Project. MEASUREMENTS: Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess AD-CT and WMH volumes, respectively. Literacy was measured using questions designed to assess comprehension of health and financial information and concepts, yielding a total literacy score. Multivariable linear mixed effects regression models determined the relationship of each neuroimaging marker, first separately and then combined, with the level of and change in literacy. RESULTS: Reduced AD-CT and higher WMH at baseline were each associated with lower levels of literacy; only AD-CT was associated with the rate of decline in literacy over time. The association of AD-CT with change in literacy persisted when both neuroimaging markers were included in the same model. CONCLUSIONS: The cortical thickness signature of AD predicts changes in health and financial literacy in nondemented older adults suggesting that the multidimensional construct of health and financial literacy relies on specific brain networks implicated in AD.

The status of digital pathology and associated infrastructure within Alzheimer's Disease Centers.

Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health's Alzheimer's Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows.

TDP-43 Pathology in the Setting of Intermediate and High Alzheimer's Disease Neuropathologic Changes: A Preliminary Evaluation Across Ethnoracial Groups.

BACKGROUND: Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer's disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White cohorts. OBJECTIVE: We sought to evaluate the presence of TDP-43 pathology across ethnoracial groups utilizing the National Alzheimer's Coordinating Center; a database containing data from over 29 institutions across the United States. Cases (N = 1135: Hispanics/Latinos = 29, African Americans/Black Americans = 51, Asians/Asian Americans = 10, American Indians/Alaskan Natives = 2, non-Hispanic White = 1043) with intermediate/high AD having data on TDP-43 pathology in the amygdala, hippocampus, entorhinal cortex, and neocortex were included. METHODS: TDP-43 pathology frequency in each neuroanatomic region among ethnoracial groups were compared using generalized linear mixed effects models with center as a random effect adjusting for age at death, education, and gender. RESULTS: Although groups were imbalanced, there was no significant difference across ethnoracial groups based on TDP-43 pathology (p = 0.84). With respect to neuroanatomical regions evaluated, there were no significant differences across ethnoracial groups (p-values > 0.06). There were also no significant differences for age at death and gender ratios across ethnoracial groups based on TDP-43 pathology. Although not statistically significant, TDP-43 pathology was present less often in Hispanic/Latinos (34%) when compared to non-Hispanic Whites (46%). CONCLUSION: While this is a preliminary evaluation, it highlights the need for diverse cohorts and on TDP-43 pathology research across ethnoracial groups. This is the first study to our knowledge having a focus on the neuroanatomical distribution of TDP-43 deposits in Hispanic/Latino decedents with AD.

Well-Being and Cognitive Resilience to Dementia-Related Neuropathology.

Not all older adults with dementia-related neuropathology in their brains experience cognitive decline or impairment. Instead, some people maintain relatively normal cognitive functioning despite neuropathologic burden, a phenomenon called cognitive resilience. Using a longitudinal, epidemiological, clinical-pathologic cohort study of older adults in the United States (N = 348), the present research investigated associations between well-being and cognitive resilience. Consistent with preregistered hypotheses, results showed that higher eudaimonic well-being (measured via the Ryff Psychological Well-Being Scale) and higher hedonic well-being (measured via the Satisfaction with Life Scale) were associated with better-than-expected cognitive functioning relative to one's neuropathological burden (i.e., beta-amyloid, neurofibrillary tangles, Lewy bodies, vascular pathologies, hippocampal sclerosis, and TDP-43). The association of eudaimonic well-being in particular was present above and beyond known cognitive resilience factors (i.e., socioeconomic status, education, cognitive activity, low neuroticism, low depression) and dementia risk factors (i.e., apolipoprotein E [ApoE] genotype, medical comorbidities). This research highlights the importance of considering eudaimonic well-being in efforts to prevent dementia.

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.

Association of Stroke and Cerebrovascular Pathologies With Scam Susceptibility in Older Adults.

Importance: Scam susceptibility is associated with adverse financial and health outcomes, including an increased risk of cognitive decline and dementia. Very little is known about the role of cerebrovascular pathologies with scam susceptibility. Objective: To examine the association of diverse cerebrovascular pathologies (globally and regionally) with scam susceptibility. Design, setting, and Participants: This clinical-pathological cohort study included participants from 2 ongoing studies of aging that began enrollment in 1994 and 1997. In 2010, participants were enrolled in the decision-making and behavioral economics substudy and were followed up for a mean (SD) of 3.4 (2.6) years prior to death. From 1365 older persons with clinical evaluations, 69 were excluded for having dementia at baseline. From 538 older persons who died, 408 had annual assessments for scam susceptibility, cardiovascular risk burden, and cognitive function and consented to brain donation for detailed neuropathologic examination. Data were analyzed from June 2021 through September 2022. Exposures: Neuropathologic examination identified the presence of macroscopic and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and common neurodegenerative pathologies (Alzheimer disease, limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, and Lewy bodies). Results: There was a total of 408 participants. The mean (SD) age at death was 91 (6.1) years, the mean (SD) amount of education was 15.6 (3.1) years, and 297 (73%) were women. Participants included 4 Latino individuals (1%), 7 non-Latino Black individuals (2%), and 397 non-Latino White individuals (97%). The frequency of participants with macroscopic infarcts was 38% (n = 154), microinfarcts was 40% (n = 163), and moderate to severe vessel disease; specifically, atherosclerosis was 20% (n = 83), arteriolosclerosis was 25% (n = 100), and cerebral amyloid angiopathy was 35% (n = 143). In linear regression models adjusted for demographics and neurodegenerative pathologies, macroscopic infarcts were associated with greater scam susceptibility (estimate [SE], 0.18 [0.07]; P = .009). This association persisted after adjusting for cardiovascular risk burden and global cognition. Regionally, infarcts localized to the frontal, temporal, and occipital lobes and thalamus were associated with greater scam susceptibility. Neither arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy, nor microinfarcts were associated with scam susceptibility. Conclusions and Relevance: Cerebrovascular pathologies, specifically cerebral infarcts, is linked with greater scam susceptibility in older adults, independent of common neurodegenerative diseases such as Alzheimer disease. Future studies examining in vivo magnetic resonance imaging markers of cerebrovascular pathologies with scam susceptibility and related decision-making outcomes will be important.

Frequency and Underlying Pathology of Pure Vascular Cognitive Impairment.

Importance: It is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies. Objective: To identify participants without AD and other neurodegenerative pathologies and determine the extent to which cerebrovascular disease pathologies were associated with cognitive impairment. Design, Setting, and Participants: This clinical pathological study included participants from 2 ongoing community-based cohorts that began enrollment in 1994 and 1997. Prior to death, participants were observed for a mean (SD) of 8.4 (5.3) years with annual assessments. From 2096 participants who died, 1799 (85.8%) underwent autopsy and 1767 had complete postmortem pathological examination data at the time of data analyses. To identify participants without neurodegenerative pathologies, we categorized them in 3 subgroups. A vascular subgroup was composed of participants without significant levels of neurodegenerative brain pathologies. A neurodegenerative subgroup was composed of participants without significant levels of cerebrovascular disease pathologies. A mixed subgroup was composed of the rest of the participants. Data were analyzed from May 2021 to July 2022. Exposures: Brain pathology indices obtained by postmortem pathological assessments. Main Outcomes and Measures: The primary outcome was cognitive impairment defined by presence of mild cognitive impairment or dementia. The secondary outcome was cognition assessed by 19 neuropsychological tests. Results: Of 1767 included participants, 1189 (67.3%) were women, and the mean (SD) age at death was 89.4 (6.6) years. In the vascular subgroup (n = 369), cognitive impairment was present in 156 participants (42.3%) and was associated with cerebrovascular disease pathologies (macroinfarcts: odds ratio [OR], 2.05; 95% CI, 1.49-2.82; P < .001; arteriolosclerosis in basal ganglia: OR, 1.35; 95% CI, 1.04-1.76; P = .03) but not AD or other neurodegenerative pathologies, an indication of pure VCI. In mixed-effects models including all the pathologies, only macroinfarcts were associated with a faster cognitive decline rate (estimate, -0.019; SE, 0.005; P < .001) in the vascular subgroup. Further analyses identified macroinfarcts in the frontal white matter to be associated with faster cognitive decline rate when macroinfarcts of cortical and subcortical brain regions were examined in a single model. Conclusions and Relevance: In this study, pure VCI was not rare. Macroinfarcts, specifically in frontal white matter, were the main cerebrovascular disease pathologies associated with cognitive decline in pure VCI.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Association of small vessel disease with tau pathology.

Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical ß-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with ß-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with ß-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with ß-amyloid. AWS arteriolosclerosis was not associated with ß-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not ß-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.

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.

Association of Amyloid-ß Pathology with Decision Making and Scam Susceptibility.

BACKGROUND: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer's disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia. METHODS: Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-ß and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy. RESULTS: In linear regression models adjusted for demographics, amyloid-ß pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02). CONCLUSION: Accumulating AD pathology, particularly amyloid-ß, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.

Brain insulin signaling and cerebrovascular disease in human postmortem brain.

Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS616IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.