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Background: Diabetes mellitus (DM) is a recognized risk factor for dementia. Because DM is a potentially modifiable condition, greater understanding of the mechanisms linking DM to the clinical expression of Alzheimer’s disease dementia may provide insights into much needed dementia therapeutics. Objective: In this feasibility study, we investigated DM as a dementia risk factor by examining genome-wide distributions of the epigenetic DNA modification 5-hydroxymethylcytosine (5hmC). Methods: We obtained clinical samples from the Rush Memory and Aging Project and used the highly sensitive 5hmC-Seal technique to perform genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) from antemortem serum samples and in genomic DNA from postmortem prefrontal cortex brain tissue from 80 individuals across four groups: Alzheimer’s disease neuropathologically defined (AD), DM clinically defined, AD with DM, and individuals with neither disease (controls). Results: Distinct 5hmC signatures and biological pathways were enriched in persons with both AD and DM versus AD alone, DM alone, or controls, including genes inhibited by EGFR signaling in oligodendroglia and those activated by constitutive RHOA. We also demonstrate the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, an 11-gene weighted model distinguished AD from non-AD/non-DM controls (AUC = 91.8% ; 95% CI, 82.9–100.0%), while a 4-gene model distinguished DM-associated AD from AD alone (AUC = 87.9% ; 95% CI, 77.5–98.3%). Conclusion: We demonstrate in this small sample the feasibility of detecting and characterizing 5hmC in DM-associated AD and of using 5hmC information contained in circulating cfDNA to detect AD in high-risk individuals, such as those with diabetes.

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.

Social engagement is known to improve health; less is known about whether social activities at the core of African American life decrease mortality risk in this minoritized population. This study investigated whether and which aspects of social engagement predict mortality risk in older African Americans.Data from 768 African Americans (aged ∼73 years; nondemented at baseline) participating in the Minority Aging Research Study, a longitudinal community-based, cohort study of aging, was collected between 2004 and 2020 and analyzed in 2020. Participants self-reported late-life social activity, social network size, life space, and purpose in life at baseline and completed approximately 6.5 years of annual follow-up (range=15.70). Cox models included time from baseline to death or censoring and an indicator for death versus censored with age, sex, education, cardiovascular disease risk factor burden, depressive symptomatology, and motor gait performance as covariates.As of March 2020, 25% of participants died (n=192; age at death ∼83 years). In fully adjusted Cox models, mortality risk decreased by 34% (hazard ratio=0.66; 95% CI=0.48, 0.91; p=0.012) for those with higher compared with that for those with lower social activity generally, with community/volunteer-, group-, and socially-related activities specifically driving these results.Engaging in late-life social activity, especially group- and socially-based activities, was most consistently and robustly associated with reduced mortality risk in African Americans regardless of health. These results lay the foundation for considering community-based approaches to increase and/or maintain social participation in older African Americans as a potential means by which to increase longevity in this population.

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.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.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.Defining CR based on the longitudinal differences between person-specific and marginal cognitive levels is a novel and complementary way to quantify CR.

Background Medicare fee-for-service (FFS) claims data are increasingly leveraged for dementia research. Few studies address the validity of recent claim data to identify dementia, or carefully evaluate characteristics of those assigned the wrong diagnosis in claims. Methods We used claims data from 2014 to 2018, linked to participants administered rigorous, annual dementia evaluations in 5 cohorts at the Rush Alzheimer’s Disease Center. We compared prevalent dementia diagnosed through the 2016 cohort evaluation versus claims identification of dementia, applying the Bynum-standard algorithm. Results Of 1 054 participants with Medicare Parts A and B FFS in a 3-year window surrounding their 2016 index date, 136 had prevalent dementia diagnosed during cohort evaluations; the claims algorithm yielded 217. Sensitivity of claims diagnosis was 79%, specificity 88%, positive predictive value 50%, negative predictive value 97%, and overall accuracy 87%. White participants were disproportionately represented among detected dementia cases (true positive) versus cases missed (false negative) by claims (90% vs 75%, respectively, p = .04). Dementia appeared more severe in detected than missed cases in claims (mean Mini-Mental State Exam = 15.4 vs 22.0, respectively, p < .001; 28% with no limitations in activities of daily living versus 45%, p = .046). By contrast, those with “over-diagnosis” of dementia in claims (false positive) had several worse health indicators than true negatives (eg, self-reported memory concerns = 51% vs 29%, respectively, p < .001; mild cognitive impairment in cohort evaluation = 72% vs 44%, p < .001; mean comorbidities = 7 vs 4, p < .001). Conclusions Recent Medicare claims perform reasonably well in identifying dementia; however, there are consistent differences in cases of dementia identified through claims than in rigorous cohort evaluations.

Background: Literacy is more consistently reported than education as protective against dementia in developing regions. Objective: To study the association of verbal literacy, numeracy, and music literacy with dementia in older Black and White Brazilians with a broad spectrum of education. Methods: We studied 1,818 Black, Mixed-race, and White deceased Brazilians 65 years or older at death (mean = 79.64). Data were retrospectively obtained within 36 hours after death in a face-to-face interview with an informant, usually a family member. Dementia was classified using the Clinical Dementia Rating (CDR) scale. Three forms of literacy were ascertained: verbal literacy (10 questions: reading and writing), numeracy (3 questions: multiplication, percentages, and use of a calculator), and music literacy (1 question: reading music). Black (11%) and Mixed-race (23%) older adults were combined in analyses. Models adjusted for age and sex. Results: Dementia was identified in 531 people. Participants had 0 to 25 years of education (median = 4). More literacy was associated with lower odds of dementia (all p≤0.039). Participants that read music had about half the odds of having dementia. Participants in the highest quartile of numeracy and verbal literacy had respectively 27%and 15%lower odds of having dementia compared to the lowest quartile. Literacy was lower in Blacks (p 0.237). In secondary analyses, playing instruments without reading music was not associated with dementia (p = 0.887). Conclusion: In a large sample of Brazilians, verbal literacy, numeracy, and music literacy were associated with lower odds of dementia. The effect was similar across races.

Background We tested the hypothesis that indices of Alzheimer’s disease and related dementia (ADRD) pathologies may explain associations between change in body mass index (BMI) and cognitive decline in old age. Method We used data from 436 older decedents participating in a prospective longitudinal cohort study who had undergone annual cognitive and BMI assessments and postmortem collection of indices of 12 brain pathologies. We identified ADRD brain pathologies associated with BMI range, a previously published metric of change in BMI. We employed sigmoidal mixed-effect models of cognitive decline to examine the associations of change in BMI and cognitive decline with and without terms for ADRD brain pathologies. Results Average age at baseline was 78.6 years, SD = 6.5 years with 64% female. On average, 9 cognitive assessments were obtained with average age at death 88.4 years (SD = 6.2 years). Change in BMI as measured by BMI range was associated with cognitive decline (θ 2 = 0.260). β-Amyloid, hippocampal sclerosis, and substantia nigra neuronal loss were associated with BMI range. β-Amyloid strongly attenuated the association of BMI range with cognitive decline. Hippocampal sclerosis showed only partial attenuation of the association of BMI range and cognitive decline and nigral neuronal loss did not attenuate this association. Conclusion Changes in BMI and cognitive decline in older adults may be affected by similar mechanisms underlying the accumulation of brain pathologies like β-amyloid in aging brains. Elucidating the molecular mechanisms underlying these associations may provide novel targets for developing interventions that maintain brain health and metabolic homeostasis in old age.

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.

More than 50 million older people worldwide are suffering from dementia, and this number is estimated to increase to 150 million by 2050. Greater caregiver burdens and financial impacts on the healthcare system are expected as we wait for an effective treatment for dementia. Researchers are constantly exploring new therapies and screening approaches for the early detection of dementia. Artificial intelligence (AI) is widely applied in dementia research, including machine learning and deep learning methods for dementia diagnosis and progression detection. Computerized apps are also convenient tools for patients and caregivers to monitor cognitive function changes. Furthermore, social robots can potentially provide daily life support or guidance for the elderly who live alone. This review aims to provide an overview of AI applications in dementia research. We divided the applications into three categories according to different stages of cognitive impairment: (1) cognitive screening and training, (2) diagnosis and prognosis for dementia, and (3) dementia care and interventions. There are numerous studies on AI applications for dementia research. However, one challenge that remains is comparing the effectiveness of different AI methods in real clinical settings.

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.

ImportanceWith 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.ObjectiveTo characterize trends in pathways underlying dementia by examining prevalence of postmortem neuropathologies in birth cohorts across 25 years.Design, Setting, and ParticipantsTwo 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 (1930) years of birth were excluded.ExposuresFour categories of year of birth: 1905-1914, 1915-1919, 1920-1924, and 1925-1930.Main Outcomes and MeasuresOutcomes 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.ResultsOverall, 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 Conclusion and RelevanceIn 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.

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, β = 0.106, p = 0.002), similarly in Blacks and Whites (β(interaction) = 0.046, p = 0.526). More NLEs were also associated with higher neuroticism (β = 0.071, p < 0.0001), in Whites but not in Blacks (β(interaction) = −0.048, p = 0.006). Neuroticism was associated with higher odds of dementia (OR = 1.658, β = 0.506, p=

The purpose of the current study was to investigate the association between self-reported physical activity (minutes/week) and cognitive functioning in a sample of African American older adults living with HIV. A secondary analysis of baseline data collected from clinically stable African American older adults living with HIV (aged >50 years; N = 124) enrolled in the Rush Center of Excellence on Disparities in HIV and Aging study was conducted. Participants completed a battery of 19 cognitive function tests that were used to create summary scores of global cognition and five cognitive domains. Physical activity was measured using a modified self-report questionnaire derived from a national health survey. Average self-reported number of weekly minutes spent in light physical activity was 290.6 minutes and for moderate/vigorous physical activity was 314.67 minutes. Number of weekly minutes of light physical activity was significantly positively associated with visuospatial ability; however, no associations were found between moderate/vigorous physical activity and any cognitive domain. Contrary to expectations, our findings do not support a relationship between moderate/vigorous physical activity and cognitive function in African American older adults living with HIV. [ Journal of Gerontological Nursing, 47 (12), 27–34.]

Background There is no practical dementia risk score in the clinical setting. Objective To derive and validate a score obtained by a rapid and simple assessment, which guides primary care providers in predicting the risk of dementia among older adults. Design A total of 4178 participants from three longitudinal cohorts (mean age at baseline = 76.8 [SD = 7.6] years), without baseline dementia, followed annually for a median of 10 years (IQR: 5 to16 years, Reverse Kaplan-Meier). Participants To derive the score, we used data from 1,780 participants from the Rush Memory and Aging Project (93% White). To validate the score, we used data from 1,299 participants from the Religious Order Study (92% White), and to assess generalizability, 679 participants from the Minority Aging Research Study (100% Black). Measurements Clinician-based dementia diagnosis at any time after baseline and predictive variables associated with dementia risk that can be collected in a primary care setting: demographics, clinical indicators, medical history, memory complaints, cognitive and motor tests, and questions to assess functional disability, depressive symptoms, sleep, social isolation, and genetics (APOE e4 and AD polygenic risk score). Results At baseline, age, memory complaint, the ability to handle finances, the recall of the month, recall of the room, and recall of three words, were associated with the cumulative incidence of dementia, in the derivation cohort. The discrimination of the RADaR (Rapid Risk Assessment of Dementia) was good for the derivation and external-validation cohorts (AUC3 years = 0.82–0.86), compared to the overall discrimination of age alone (AUC3 years = 0.73), a major risk factor for dementia. Adding genetic data did not increase discrimination. Limitations Participants were volunteers, may not represent the general population. Conclusions The RADaR, derived from community-dwelling older persons, is a brief and valid tool to predict dementia risk at 3 years in older White and Black persons.

OBJECTIVE To test the hypothesis that Alzheimer's disease and related neuropathologies contribute to the association between hospitalization and cognitive decline in old age. METHODS As part of a longitudinal clinical-pathologic cohort study, 526 older persons (mean age at death = 90.9 years, 71% female) without dementia at baseline completed annual cognitive testing and were autopsied at death. Hospitalization information was obtained from linked Medicare claims records. Neuropathologic examination assessed β-amyloid burden, tau tangle density, neocortical Lewy bodies, hippocampal sclerosis, chronic gross and microscopic cerebral infarcts, and transactive response DNA binding protein 43 kDa. RESULTS Over a mean of 5.1 years, a total of 1,383 hospitalizations occurred, and the mean annual rate of hospitalization was 0.5 (standard deviation = 0.6, median = 0.4). Higher rate of hospitalization was not directly related to higher burden for any of the neuropathologic markers. Higher rate of hospitalization was associated with more rapid cognitive decline (estimate = -0.042, standard error [SE] = 0.012, p

BACKGROUND: Brain proteins, including Insulin-like Growth Factor Binding Protein 5 (IGFBP-5), have been associated with cognitive dysfunction in aging. Mechanisms linking depression with cognition are poorly understood. We hypothesize that the association of depressive symptoms with cognition is mediated or modified by brain proteins. METHODS: IGFBP-5, HSPB2, AK4, ITPK1 and PLXNB1 were measured in dorsolateral prefrontal cortex in 1057 deceased participants, who underwent annual assessments of depressive symptoms and cognition for a mean of 8.9 years. The average number of depressive symptoms per year before a dementia diagnosis was calculated for each person. RESULTS: A one standard deviation above the mean IGFBP-5 was associated with a 14% higher odds of having more depressive symptoms (p0.070). LIMITATIONS: Participants were volunteers and self-selection bias limits the generalizability of our findings. In addition, we used self-reported data on depressive symptoms. However, we also used data on depression medications as sensitivity analyses to confirm findings. CONCLUSIONS: In old age, brain IGFBP-5 is associated with depressive symptoms and cognition. The association of depressive symptoms with cognitive decline is conditional on IGFBP-5.

ObjectiveTo determine whether emergent and urgent (nonelective) hospitalizations are associated with faster acceleration of cognitive decline compared to elective hospitalizations, accounting for prehospital decline.MethodsData came from the Rush Memory and Aging Project, a prospective cohort study of community-dwelling older persons without baseline dementia. Annual measures of cognition via a battery of 19 tests were linked to 1999 to 2010 Medicare claims records.ResultsOf 777 participants, 460 (59.2%) were hospitalized over a mean of 5.0 (SD = 2.6) years; 222 (28.6%) had at least one elective and 418 (53.8%) at least one nonelective hospitalization. Mixed-effects regression models estimated change in global cognition before and after each type of hospitalization compared to no hospitalization, adjusted for age, sex, education, medical conditions, length of stay, surgery, intensive care unit, and comorbidities. Persons who were not hospitalized had a mean loss of 0.051 unit global cognition per year. In comparison, there was no significant difference in rate of decline before (0.044 unit per year) or after (0.048 unit per year) elective hospitalizations. In contrast, decline before nonelective hospitalization was faster (0.076 unit per year; estimate = −0.024, SE = 0.011, p = 0.032), and accelerated by 0.036 unit (SE = 0.005, p < 0.001) to mean loss of 0.112 unit per year after nonelective hospitalizations, more than doubling the rate in those not hospitalized.ConclusionsNonelective hospitalizations are related to more dramatic acceleration in cognitive decline compared to elective hospitalizations, even after accounting for prehospital decline. These findings may inform which hospital admissions pose the greatest risk to the cognitive health of older adults.

Background: Few data are available on associations of antiphospholipid (aPL) antibodies with cognitive and motor decline in aging, and cerebrovascular disease on in vivo neuroimaging and postmortem neuropathology. Methods: This longitudinal, clinical-pathologic study (aPL antibodies, brain infarcts, and cognitive and motor decline in aging), was derived from 2 ongoing community-based cohort studies. A panel of 3 aPL antibodies was assayed in serum from 956 older individuals (mean age = 81.1 years; 72% women). Serum was also tested in a subset for markers of inflammation (C-reactive protein [CRP]) and blood-brain barrier breakdown (matrix metalloproteinases, MMPs). Annual clinical evaluations documented cognitive (17 neuropsychological tests) and motor function including parkinsonism. Cerebrovascular disease data were derived from in vivo neuroimaging and postmortem neuropathologic evaluations (699 individuals). We examined associations of aPL with cognitive and motor decline, other serum markers, neuroimaging, and neuropathology. Results: Of 956 individuals, 197 (20.6%) had aPL positivity, defined as positivity on any of the assays, at the time of first measurement. During a mean follow-up of 6.6 years (SD 4), overall aPL positivity was not associated with change in global cognition (estimate = –0.005, SE 0.011; p = 0.622) or parkinsonian signs (estimate = –0.003, SE 0.017; p = 0.860). aPL were not associated with serum CRP or MMPs (both p > 0.268). aPL were not associated with in vivo brain magnetic resonance imaging white matter hyperintensities or infarcts (both p > 0.376). Among those autopsied, aPL were not associated with pathologically confirmed brain infarcts, or cerebral atherosclerosis or arteriolosclerosis (all p≥ 0.447). Conclusions: In older individuals followed longitudinally, aPL do not relate to cognitive or motor decline, inflammation, or cerebrovascular disease on in vivo neuroimaging or postmortem neuropathology.

Background: Self-reported discrimination is a source of psychosocial stress that has been previously associated with poor cognitive function in older African Americans without dementia. Objective: Here, we examine the association of discrimination with dementia and cognitive impairment in racially diverse older Brazilians. Methods: We included 899 participants 65 years or older (34.3% Black) from the Pathology, Alzheimer’s and Related Dementias Study (PARDoS), a community-based study of aging and dementia. A structured interview with informants of the deceased was conducted. The interview included the Clinical Dementia Rating (CDR) Scale for the diagnosis of dementia and cognitive impairment proximate to death and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) as a second measure of cognitive impairment. Informant-reported discrimination was assessed using modified items from the Major and Everyday Discrimination Scales. Results: Discrimination was reported by informants of 182 (20.2%) decedents and was more likely reported by informants of Blacks than Whites (25.3% versus 17.6%, p = 0.006). Using the CDR, a higher level of informant-reported discrimination was associated with higher odds of dementia (OR: 1.24, 95% CI 1.08 –1.42, p = 0.002) and cognitive impairment (OR: 1.21, 95% CI: 1.06 –1.39, p = 0.004). Similar results were observed using the IQCODE (estimate: 0.07, SE: 0.02, p = 0.003). The effects were independent of race, sex, education, socioeconomic status, major depression, neuroticism, or comorbidities. Conclusion: Higher level of informant-reported discrimination was associated with higher odds of dementia and cognitive impairment in racially diverse older Brazilians.

Background and Purpose: The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies. Methods: We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies. Results: Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07–1.13], P P =0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04–1.11], P P =0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy. Conclusions: A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.

Background The purpose of this study was to identify correlates of perceived stress among older African Americans. Methods and findings Guided by the National Institute on Aging’s (NIA) Health Disparities Research Framework, we grouped correlates into four levels–environmental, sociocultural, behavioral, and biological, and performed a cross-sectional analysis using ordinal logistic regression models. Participants included 722 African Americans [mean age = 73.61 years (SD = 6.33)] from the Minority Aging Research Study (MARS). Several protective correlates from environmental (e.g., larger life space), sociocultural (e.g., larger social network size), behavioral (e.g., more purpose in life), and biological (e.g., higher global cognition) levels were associated with a lower odds of having higher levels of perceived stress. Conclusions Perceived stress was associated with established and novel correlates from every level. Future research is needed to examine how changes in these correlates may impact perceived stress in older African Americans.

BACKGROUND: Literacy is more consistently reported than education as protective against dementia in developing regions. OBJECTIVE: To study the association of verbal literacy, numeracy, and music literacy with dementia in older Black and White Brazilians with a broad spectrum of education. METHODS: We studied 1818 Black, Mixed-race, and White deceased Brazilians 65 years or older at death (mean=79.64). Data were retrospectively obtained within 36 hours after death in a face-to-face interview with an informant, usually a family member. Dementia was classified using the Clinical Dementia Rating (CDR) scale. Three forms of literacy were ascertained: verbal literacy (10 questions: reading and writing), numeracy (3 questions: multiplication, percentages, and use of a calculator), and music literacy (1 question: reading music). Black (11%) and Mixed-race (23%) older adults were combined in analyses. Models adjusted for age and sex. RESULTS: Dementia was identified in 531 people. Participants had 0 to 25 years of education (median=4). More literacy was associated with lower odds of dementia (all p≤0.039). Participants that read music had about half the odds of having dementia. Participants in the highest quartile of numeracy and verbal literacy had respectively 27% and 15% lower odds of having dementia compared to the lowest quartile. Literacy was lower in Blacks (p0.237). In secondary analyses, playing instruments without reading music was not associated with dementia (p=0.887). CONCLUSION: In a large sample of Brazilians, verbal literacy, numeracy, and music literacy were associated with lower odds of dementia. The effect was similar across races.

Background: Vascular mechanisms may contribute to the accumulation of AD pathology. Objective: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association. Methods: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau. Results: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r = –0.00, p = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = –0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = –0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP. Conclusion: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

BACKGROUND/OBJECTIVES: The purpose of this study was to: (1) examine relationships between body mass index (BMI) stability and cognitive decline in older African Americans; and (2) investigate differences in the relationships between women and men. DESIGN: The present study is a secondary data analysis of the Minority Aging Research Study, which is a longitudinal, cohort study of risk factors for cognitive decline and Alzheimerʼs disease among older African Americans living in the Chicago, IL, area. The study entails annual clinical evaluations, including measures of 19 neuropsychological tests that represent five cognitive domains, including episodic, semantic, and working memory, perceptual speed, and visuospatial ability. PARTICIPANTS: Participants (n = 671; mean age = 73.5 years; standard deviation = 6.2 years) were included in the present analysis if they were dementia free at baseline and completed at least two clinical evaluations, on average 1 year apart, that included valid cognitive and BMI assessments. RESULTS: Mixed-effects models showed higher baseline BMI was related to slower global cognitive decline, whereas changes in BMI (instability) were related to faster global cognitive decline. These effects were the same for four of five cognitive domains and remained after controlling for various health characteristics. However, women and men did not differ in any of the relationships. CONCLUSION: Higher BMI is related to slower cognitive decline in older African Americans, but greater BMI instability is related to faster decline. Stability of BMI should be considered in the cognitive aging of African Americans. J Am Geriatr Soc 68:2662–2667, 2020.

ObjectiveTo test the hypothesis that an inverse association exists between diabetes mellitus (DM) and hemoglobin A1C (A1C) with transactive response DNA binding protein 43 (TDP-43) levels in older adults.MethodsWe leveraged antemortem and postmortem data of decedents from 3 community-based clinical–pathologic studies. DM status, A1C levels, and medications for DM were documented annually. TDP-43 cytoplasmic inclusions, evaluated in 6 brain regions using immunohistochemistry, were used to obtain a semiquantitative TDP-43 score (0–5) in each region, and scores were averaged across regions to obtain a TDP-43 severity score. We used linear regressions to test the association of DM and A1C with the TDP-43 severity score.ResultsOn average, participants (n = 817) were 90 years old at the time of death, three-fourths were women, and one-fourth had DM. The mean A1C was 6.0% (SD 0.6). TDP-43 was observed in 54% of participants, and the mean TDP-43 score was 0.7 (range 0–4.5). A higher level of A1C was associated with a lower TDP-43 score (estimate −0.156, SE 0.060, p = 0.009), while DM had a borderline inverse association with the TDP-43 score (estimate −0.163, SE 0.087, p = 0.060). The association of higher levels of A1C with lower TDP-43 scores persisted after further adjustment by APOE ε4, vascular risk factors, stroke, and hypoglycemic medications. Exclusion of the oldest old participants did not change the results.ConclusionOverall, the results suggest that a high level of A1C is associated with less TDP-43 proteinopathy in older persons while the relationship of DM with TDP-43 needs further study.

OBJECTIVE: To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. METHODS: This clinical–pathologic study was derived from a community-based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme-linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. RESULTS: Brain insulin receptor substrate-1 (IRS1) phosphorylation (pS(307)IRS1/total IRS1) and serine/threonine-protein kinase (AKT) phosphorylation (pT(308)AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT(308)AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT(308)AKT1 was associated with a lower level of global cognitive function (estimate = −0.212, standard error = 0.097; p = 0.031). INTERPRETATION: Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function.

While body mass index (BMI) is higher in black compared to white persons, little is known about BMI and change in cognition in cohorts with a large proportion of blacks. We examine relations of BMI with decline in global cognition and five cognitive domains, in older blacks and whites, and determine whether relations differ by race.Participants were 2,134 persons without baseline dementia (33% black; 75% women; mean age =77.9 [range 53-100] and education = 14.7 years, Mini-Mental State Examination = 28.0), enrolled in one of two longitudinal, community-based cohort studies of aging (Minority Aging Research Study; Rush Memory and Aging Project). Summary scores of global cognition and five domains were based on 19 neuropsychological tests administered annually. Mixed-effects models, controlling for age, sex, education, and race, were used to examine the relation of baseline BMI to change in cognition.Baseline BMI = 28.4 units (30.3 in blacks [95% confidence interval (CI): 27.2-27.7]; 27.4 in whites [95% CI: 29.8-30.7]). During a mean annual follow-up of 6 years (SD = 4), lower baseline BMI was related to faster decline in global cognition (p = .002), and semantic memory (p.001) and episodic memory (p = .004), but not working memory, perceptual speed, or visuospatial ability (all p.08). The relationship of BMI with change in cognition was not modified by race (all p.09).Late-life lower BMI relates to faster rates of decline in cognition, specifically semantic memory and episodic memory, in both blacks and whites. The effect of BMI on cognition appears to be similar in both racial groups.

Background Research indicates that stress is linked to cognitive dysfunction. However, few community-based studies have explored the relationship between perceived stress and cognitive decline, and fewer still have utilized cognitive domains rather than a global measure of cognition. Objective We examined the relation between perceived stress and the rate of decline in different cognitive domains. Methods Participants were older African Americans without dementia from the Minority Aging Research Study (MARS; N = 467, mean age: 73 years, SD: 6.1 years). A battery of 19 cognitive tests was administered at baseline and at annual intervals for up to 9 years (mean follow-up: 4 years), from which composite measures of global cognitive function and five specific cognitive domains were derived. The four-item Cohen's Perceived Stress Scale (PSS) was also administered at baseline. Results In linear mixed-effects models adjusted for age, sex, education, and vascular risk factors, higher perceived stress was related to faster declines in global cognition (β = −0.019; SE: 0.008; t (1951) = −2.46), episodic memory (β = −0.022; SE: 0.011; t (1954) = −1.99), and visuospatial ability (β = −0.021; SE: 0.009; t (1939) = −2.38) all p Conclusions Results indicate that older African Americans with higher levels of perceived stress have more rapid declines in global cognition than those with lower levels, most notably for episodic memory and visuospatial ability.

We examined the relationship of diabetes and hemoglobin A1C (A1C) to 2 common causes of dementia. The study included 1228 subjects who underwent annual clinical evaluations and a brain autopsy at death, as part of a Rush longitudinal cohort study of aging. A total of 433 subjects had A1C data available. Neuropathologic evaluations documented the size and location of infarcts. Modified silver stain-based Alzheimer disease (AD) measures included global and regional scores. We used regression analyses to examine associations of diabetes and A1C with overall and regional neuropathology. Diabetes [odds ratio (OR)=0.94; 95% confidence interval (CI), 0.73-1.20) and A1C (OR=0.83; 95% CI, 0.62-1.10) were not associated with global AD pathology across the brain, nor with overall or individual measures of neuropathology in mesial temporal or neocortical regions separately (all P>0.05). Diabetes was associated with a higher odds of any infarct (OR=1.43; 95% CI, 1.07-1.90), and particularly with gross (OR=1.53; 95% CI, 1.14-2.06) but not microinfarcts (P=0.06), and subcortical (OR=1.79; 95% CI, 1.34-2.39) but not cortical infarcts (P=0.83). In summary, we found no relationship of diabetes or A1C with global or regional AD pathology, including in the mesial temporal lobe. Diabetes is associated with gross subcortical infarcts. Our results suggest that the diabetes-dementia link is based on subcortical vascular pathology and not on regional AD pathology.

The purpose of our review was to analyze evidence related to physical activity (PA) and cognitive health in people living with HIV (PLWH), appraise psychometric characteristics of study measures, and calculate effect sizes. A computerized database search of the literature published between 1996 and 2017 was examined for correlational and observational studies that included a sample of PLWH, measured PA, and measured cognitive health. Seven articles met the sampling criteria. Of which, six studies used a cross-sectional design; one used a longitudinal design. All but one found significant positive associations between PA and cognitive health in PLWH. Four studies showed a moderate to high effect for PA on cognitive function (Cohen's d values = 0.45-0.58). None reported sample-specific reliability and validity estimates for PA and cognitive health instruments. PA is a modifiable factor that may delay the onset of cognitive impairment and decline among PLWH.