Washington Heights-Inwood Columbia Aging Project Research Articles

Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease

The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

Physical Activity Moderates the Relationship between Cardiovascular Disease Risk Burden and Cognition in Older Adults

Introduction: Older individuals with a higher cardiovascular disease (CVD) burden have a higher risk for accelerated cognitive decline and dementia. Physical activity (PA) is an inexpensive and accessible preventive measure to CVD, cognitive impairment, and dementia. The current study examined (1) whether PA moderates the relationship between CVD burden and cognition and (2) whether the moderating effect of PA differs by race/ethnicity groups and by APOE-ɛ4 status. Methods: Our cross-sectional study included participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, community-based, longitudinal study on aging and dementia among individuals aged 65 years and older who reside in northern Manhattan. All participants underwent an interview and a neuropsychological assessment for global cognition, memory, language, visuospatial, and speed functioning. Results: In 2,122 older individuals without dementia, having a higher CVD burden was associated with worse cognitive scores for global, language, speed, and visuospatial cognitive functions. PA mitigated the relationship between CVD burden and visuospatial function. Furthermore, PA mitigated the association of CVD burden with global cognition, language, and visuospatial functions in APOE-ɛ4 carriers but not in non-carriers. Discussion/Conclusion: Our study suggests that PA may mitigate the negative association between CVD and cognition, especially in APOE-ɛ4 carriers. The moderating effect of PA did not differ by race/ethnicity.

Periodontitis and brain magnetic resonance imaging markers of Alzheimer's disease and cognitive aging.

We examined the association of clinical, microbiological, and host response features of periodontitis with MRI markers of atrophy/cerebrovascular disease in the Washington Heights Inwood Columbia Aging Project (WHICAP) Ancillary Study of Oral Health. We analyzed 468 participants with clinical periodontal data, microbial plaque and serum samples, and brain MRIs. We tested the association of periodontitis features with MRI features, after adjusting for multiple risk factors for Alzheimer's disease/Alzheimer's disease-related dementia (AD/ADRD). In fully adjusted models, having more teeth was associated with lower odds for infarcts, lower white matter hyperintensity (WMH) volume, higher entorhinal cortex volume, and higher cortical thickness. Higher extent of periodontitis was associated with lower entorhinal cortex volume and lower cortical thickness. Differential associations emerged between colonization by specific bacteria/serum antibacterial IgG responses and MRI outcomes. In an elderly cohort, clinical, microbiological, and serological features of periodontitis were associated with MRI findings related to ADRD risk. Further investigation of causal associations is warranted.

Race/ethnic disparities in mis‐identification of dementia in Medicare claims

AbstractBackgroundStudies have shown that mis‐identification of dementia in Medicare claims is quite common. We extend the literature by examining potential race/ethnic disparities in mis‐identification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment.MethodParticipants were enrolled the Washington Heights‐Inwood Columbia Aging Project (WHICAP), a multiethnic, population‐based, prospective study of cognitive aging in which dementia status is assessed using a rigorous clinical protocol. The current study included 1,178 participants clinically diagnosed with dementia and 3,048 never diagnosed with dementia. ICD‐9‐CM diagnosis codes in all available Medicare claims (1999‐2019) were compared to clinical dementia diagnosis, and categorized into 3 mutually exclusive groups: (1) congruent identification, (2) over‐identification (no clinical dementia, claims‐identified dementia), and (3) under‐identification (clinical dementia, no claims‐identified dementia) during the study period. Race (White, African American/Black, Other) and ethnicity (Hispanic/Latinx, non‐Hispanic/Latinx) were self‐reported. Multinomial logistic regression model was used to examine the relationship between race/ethnicity and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization. Estimated average marginal effects are reported.ResultThe study included 1,520 White, 1,333 African American/Black, and 1,373 participants of other races. 1,985 participants self‐identified as Hispanic, 2,241 non‐Hispanic. Among participants clinically diagnosed with dementia, the proportion who were accurately identified with dementia in Medicare claims were 83.2%, 77.8%, and 73.2% in White, African American/Black, and other races, respectively; 75.9% and 79.7% in Hispanics and non‐Hispanics, respectively. Among participants clinically diagnosed without dementia, the proportion of participants who were accurately identified without dementia in Medicare claims were: 86.1%, 87.3%, and 82.3% in White, African American/Black, and other races, respectively; 82.4% and 87.5% in Hispanics and non‐Hispanics, respectively. After controlling for participant characteristics, multinomial logistics regression results show the probability of over‐identification with dementia was 2.2% higher for African American/Black participants than White (p = 0.05) and 2.7% higher for Hispanic participants than non‐Hispanics (p = 0.03). Differences in under‐identification by race/ethnicity were no longer statistically significant.ConclusionAfrican American/Black and Hispanic participants were more likely to be over‐identified with dementia in Medicare claims.

Total and posterior cerebral blood flow is associated with white matter hyperintensity volume and Alzheimer’s‐like patterns of brain atrophy in older adults

AbstractBackgroundSmall vessel cerebrovascular disease, often visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scans, contributes to risk, progression, and, possibly, pathogenesis of Alzheimer’s disease (AD). When considered in the context of previous neuroimaging biomarker work in AD, WMH appear to colocalize with other markers of disease risk and progression, including metabolic changes, atrophy, and tau pathology, in areas perfused by the posterior circulation. In the current study, we used a novel MR‐based method, termed phase contrast, to quantitate total cerebral blood flow in anterior and posterior circulations and test its relationship with WMH volume and an AD‐like pattern of brain atrophy in older, community‐dwelling adults.MethodTwo hundred forty‐five older adult participants (77±5.6 mean±SD age, 66% women, 42% Latinx, 30% Black, and 28% White individuals) in the Washington Heights Inwood Columbia Aging Project (WHICAP) received T1‐weighted, T2‐weighted (FLAIR), and phase contrast MR imaging. 2D phase contrast imaging can be used to quantify absolute blood flow rates with cross‐sectional velocity‐encoding of major vasculature leading into the brain. Blood flow rates in the anterior circulation (carotid arteries) and posterior circulation (vertebral arteries) were derived with Medis QFlow 4.0. WMH volume and cortical thickness in AD‐signature regions were derived with in‐house software and FreeSurfer v6.0, respectively. Separate general linear models tested the association of total, anterior, and posterior blood flow rates with WMH volumes and AD‐signature cortical thickness.ResultLower total cerebral blood flow was associated with increased total WMH volume (β = ‐0.14, p<0.05, 95%CI [‐1.37E‐2, ‐7.32E‐4]), an effect that was stronger for posterior flow (β_posterior = ‐0.17, 95%CI [‐3.7E‐2, 2.5E3], β_anterior = ‐0.11, 95%CI [‐1.9E‐2, 5.4E3]). Lower posterior blood flow specifically was associated with lower AD‐signature cortical thickness, but only in older participants (age interaction term: β = ‐3.14, p<0.01, 95%CI [‐2.0E‐4, ‐3.5E‐5]).ConclusionLower total cerebral blood flow, particularly in the posterior circulation, is associated with increased WMH volume and decreased cortical thickness, two neuroimaging markers that are implicated in risk and progression of AD. Future work that examines whether or how diminished total cerebral blood flow accounts for the colocalization of AD biomarkers across modalities will provide insight into the vascular contributions to AD.

4 Associations Between Education, Emotional and Instrumental Support, and Cognitive Function in Black, White, and Latinx Older Adults

Objective:Higher education is strongly associated with better cognitive function in older adults. Previous research has also showed that positive psychosocial factors, such as selfefficacy and emotional and instrumental support, are beneficial for late-life cognition. There is prior evidence of a buffering effect of self-efficacy on the relationship between educational disadvantage and poor cognition in older adults, however it is not known if other psychosocial factors modify the schooling-cognition relationship. We hypothesized that higher levels of emotional and instrumental support will diminish the association between lower education and lower cognitive test scores among older adults.Participants and Methods:553 older adults without dementia (42.1% non-Latinx Black, 32.2% non-Latinx White, 25.7% Latinx; 63.2% women; average age 74.4 (SD 4.3)) from the Washington Heights-Inwood Columbia Aging Project. Neuropsychological tests assessed four cognitive domains (language, memory, psychomotor processing speed, and visuospatial function). Self-reported emotional and instrumental support were assessed with measures from NIH Toolbox. Linear regression estimated interactions between education and the two support measures on cognition in models stratified by cognitive domain and racial and ethnic group. Covariates included age, sex/gender, and chronic health conditions (e.g. heart disease, stroke, cancer, etc.).Results:Education was associated with cognition across racial and ethnic groups. For every one year of schooling, the processing speed z-score composite was 0.33 higher among Latinx participants, 0.10 among non-Latinx Black participants, and 0.03 higher among non-Latinx White participants. The education-cognition relationship was generally similar across cognitive domains with larger effects in non-Latinx Black and Latinx participants than in White participants. Low education was associated with slower processing speed among Black participants with low emotional support (B = 0.224, 95% CI [0.014, 0.096]), but there was no association between low education and processing speed among Black older adults with high levels of emotional support (beta for interaction = -.142, 95% CI [-0.061, -0.001]). A similar pattern of results was observed for instrumental support (beta for interaction = -.207, 95% CI [-0.064, 0.010]). There were no interactions between support and education on other cognitive domains or among Latinx and White participants.Conclusions:We found that higher levels of emotional and instrumental support attenuate the detrimental effect of educational disadvantages on processing speed in older Black adults. This may occur via benefits of social capital, which provides access to health resources and knowledge, increased social interaction, an emotional outlet allowing the ability to better cope with stress. Longitudinal analyses are needed to examine temporal patterns of associations. In addition, improving equitable access to high quality schools will improve later-life cognitive outcomes for future generations of older adults. However, for the growing number of Black older adults who will not experience the benefits of structural improvements in the education system, emotional and instrumental support may represent a modifiable psychosocial factor to reduce their disproportionate burden of cognitive morbidity.

3 Does External Locus of Control Moderate the Intergenerational Transmission of Dementia Risk Among Non-Latinx Black and Non-Latinx White Middle-Aged Adults?

Objective:People whose parents had dementia or memory impairment are at higher risk for later-life cognitive impairment themselves. One goal of our research is to identify factors that either increase the risk of or protect against family history of dementia over the life course. External locus of control has been associated with lower cognitive function in middle-aged and older adults. Previous findings have shown that adults racialized as Black have relatively high levels of external locus of control due to inequity and racism. We hypothesized that lower parental memory would be associated with lower offspring memory among Non-Latinx Black and Non-Latinx White (hereafter Black and White, respectively) adults; and associations would be stronger among participants with higher levels of external locus of control.Participants and Methods:Participants comprised 594 adults racialized as Black or White (60.3% Black; 62% women; aged 56.1 ± 10.4; 15.3 ± 2.7 years of education) from the Offspring Study who are the adult children of participants in the Washington Heights Inwood Columbia Aging Project (WHICAP). Parental memory was residualized for age (74.3 ± 6.0) and education (13.7 ± 3.1). Self-reported external locus of control was assessed using 8 items from the the perceived control questionnaire. Memory was assessed with the Selective Reminding Test, and a composite of total and delayed recall scores were computed. Linear regression quantified the interaction between parental memory and external locus of control on memory in models stratified by race, and adjusted for age, sex/gender, and number of chronic health diseases.Results:Among Black participants (n=358), there were no main effects of parental memory or locus of control on offspring memory. However, lower parental memory was associated with lower offspring memory among Black participants with high levels of external locus of control (standardized estimate=0.36, p=0.02, 95%CI [0.05, 0.67]). Associations were attenuated and non-significant at lower levels of control. Among White participants (n=236), there was a main effect of parental memory on offspring memory, and this association did not vary by levels of external locus of control.Conclusions:Poor parental memory, which reflects risk for later-life cognitive impairment and dementia, was associated with lower memory performance among White middle-aged participants. Among Black participants, this association was observed among those with high levels of external locus of control only. Economic and social constraints shape levels of external locus of control and are disproportionately experienced by Black adults. In the face of greater external locus of control, a cascade of psychological and biological stress-related processes may be triggered and make Black adults’ memory function more vulnerable to the detrimental impact of parent-related dementia risk. Longitudinal analyses are needed to clarify temporal associations. Nonetheless, these findings suggest that reducing social and economic inequities disproportionately experienced by Black adults may dampen the effect of intergenerational transmission of dementia risk on cognition.

Racial/Ethnic Disparities in Misidentification of Dementia in Medicare Claims: Results from the Washington Heights-Inwood Columbia Aging Project.

Misidentification of dementia in Medicare claims is quite common. We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment. Participants were enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999-2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization. Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p = 0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p = 0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant. African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims.

Semantic item-level metrics relate to future memory decline beyond existing cognitive tests in older adults without dementia.

In normal aging, the cognitive domain of semantic memory remains preserved, while the domain of episodic memory declines to some extent. In Alzheimer's disease dementia, both semantic and episodic memory become impaired early in the disease process. Given the need to develop sensitive and accessible cognitive markers for early detection of dementia, we investigated among older adults without dementia whether item-level metrics of semantic fluency related to episodic memory decline above and beyond existing neuropsychological measures and total fluency score. Participants were drawn from the community-based Washington Heights-Inwood Columbia Aging Project cohort (N = 583 English speakers, Mage = 76.3 ± 6.8) followed up to five visits across up to 11 years. We examined the association of semantic fluency metrics with subsequent declines in memory performance using latent growth curve models covaried for age and recruitment wave. Results showed that item-level metrics (e.g., lexical frequency, age of acquisition, and semantic neighborhood density) were associated with a decline in episodic memory-even when covarying for other cognitive tests-while the standard total score was not. Moderation analyses showed that the relationship of semantic fluency metrics with memory decline did not differ across race, sex/gender, or education. In conclusion, item-level data hold a wealth of information with potential to reveal subtle semantic memory impairment, which tracks with episodic memory impairment, among older adults without dementia beyond existing neuropsychological measures. Implementation of psycholinguistic metrics may point to cognitive tools that have better prognostic value or are more sensitive to cognitive change in the context of clinical trials or observational studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Racial and ethnic differences in the relationship between financial worry and white matter hyperintensities in Latinx, non-Latinx Black, and non-Latinx White older adults

Socioeconomic status (SES) is associated with white matter hyperintensities (WMHs) and contributes to racial and ethnic health disparities. However, traditional measures of SES may not accurately represent individual financial circumstances among non-Latinx Black and Latinx older adults due to longstanding structural inequities. This study examined associations between multiple SES indicators (education, income, subjective financial worry) and WMHs across non-Latinx Black, Latinx, and non-Latinx White older adults in the Washington Heights-Inwood Columbia Aging Project (N = 662). Latinx participants reported the lowest SES and greatest financial worry, while Black participants evidenced the most WMHs. Greater financial worry was associated with higher WMHs volume above and beyond education and income, which were not associated with WMHs. However, this association was only evident among Latinx older adults. These results provide evidence for the minority poverty hypothesis and highlight the need for systemic socioeconomic interventions to alleviate brain health disparities in older adulthood.

Influence of Socioeconomic Opportunity Disparities on Sex/Gender Inequalities in Cognitive Decline

AbstractBackgroundState‐level socioeconomic opportunity disparities have been linked to health outcomes. We examined whether early‐life exposure to state‐level socioeconomic opportunity disparities between women and men influences the pattern of sex/gender inequalities in cognitive decline.MethodParticipants were 2,394 U.S.‐born non‐Latinx Black and non‐Latinx White women and men enrolled in the Washington Heights/Inwood Columbia Aging Project (WHICAP), who were dementia free at their baseline study visit. Age at first cognitive assessment ranged from 61‐101 and the average follow‐up time was 4.8 years. Cognitive outcomes were level and trajectory on memory and language scores. A socioeconomic opportunity disparity index (SODI) was created using census data on sex/gender disparities in labor force participation, occupational status, and educational attainment between the years 1900 to 1960 (birth year range for WHICAP participants). The SODI ranged from 0 to 1, with higher scores reflecting wider sex/gender disparities in socioeconomic opportunities. SODI values were linked to WHICAP individual data via birth year and state. Multiple‐group growth curve modeling was used to examine interactions between sex/gender and SODI on cognitive trajectories across racial groups. All models accounted for age, childhood SES, and state of birth, as well as differential study attrition due to death.ResultSmaller disparities in state‐level opportunity were associated with 1) higher baseline cognitive test performance across groups and 2) slower memory and language decline for Black women and White women and men. Women demonstrated an advantage over men on cognitive measures and we expected women’s advantage to be more pronounced in states with lower opportunity disparities. This pattern held true for Black individuals with regards to memory and language level and for memory decline among White individuals. However, White women’s advantage over White men on baseline memory was more pronounced in states with higher opportunity disparities.ConclusionBeing born in a state where socioeconomic opportunities were more equally distributed among women and men was positively linked to cognitive outcomes later in life. Our results suggest that this relationship varies across men and women depending on their race, contributing to different patterns of sex/gender inequalities in late‐life cognitive trajectories.

Associations between intergenerational transmission of AD, type 2 diabetes, and cognitive function among non‐Hispanic Black adults in midlife

AbstractBackgroundType 2 diabetes (T2D) and parental history of Alzheimer’s disease (AD) are independent risk factors for late‐life cognitive impairment. The presence of T2D may strengthen the association of parental AD risk on cognition through pathways of vascular function, insulin signaling, and amyloid β/tau metabolism. Examining the independent and interactive association of parental AD risk and T2D on cognitive function, specifically in non‐Hispanic Black adults may advance our understanding of their contribution to the disproportionate rates of AD in this group. We hypothesize that parental AD risk and T2D would be independently associated with worse cognition and that the association between parental AD risk and cognition would be stronger in participants with T2D.MethodParticipants comprised non‐Hispanic Black adults (N = 331; 25.8% with T2D; Table 1) in the Offspring Study who are the adult children of participants in the Washington Heights Inwood Columbia Aging Project (WHICAP). AD risk was operationalized as parental memory performance residualized for age and education and assessed at their last WHICAP visit. Participant T2D was based on self‐reported physician diagnosis and cognition was assessed with measures of attention, language, and memory. Cognitive test scores were residualized for age and education (Table 1). Linear regression models quantified the independent associations and interaction of AD risk and T2D on offspring cognition.ResultT2D was associated with lower language (B = ‐0.13, 95% CI: [‐0.55, ‐0.08]) and memory (B = ‐0.45, 95% CI: [‐0.72, ‐0.17]) scores, but AD risk was not associated with cognition in any domain. However, AD risk was associated with lower language scores among participants without T2D, but not in participants with T2D (B = ‐0.36, 95% CI [‐0.71, ‐0.02]; Figure 1). No interaction was observed for AD risk and T2D with memory and attention (Figure 2).ConclusionOur results suggest that among middle‐aged non‐Hispanic Black adults, AD risk is associated with lower language performance in individuals without T2D. The association between AD risk and cognition may be masked by exposure to risk factors, such as T2D.

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample.

This prospective study seeks to examine the utility of subjective cognitive decline (SCD) as a marker of future progression to dementia in a community-based cohort of non-Latinx White, non-Latinx Black, and Latinx individuals. Debate surrounds the utility of SCD, the subjective perception of decline in one's cognition before such impairment is evident in traditional neuropsychological assessments, as an early indicator of impending Alzheimer disease. Unfortunately, most studies examining SCD have been conducted in non-Latinx White samples and commonly exclude groups of individuals shown to be most vulnerable to dementia. Participants were enrolled into this cohort study from the Washington Heights-Inwood Columbia Aging Project if they were cognitively unimpaired, had baseline measurement of SCD, and self-identified as non-Latinx White, non-Latinx Black, or Latinx. SCD was measured as a continuous sum of 10 items assessing cognitive complaints. Competing risk models tested the main effects of baseline SCD on progression to dementia. Models were adjusted for age, sex/gender, years of education, medical comorbidity burden, enrollment cohort, and baseline memory test performance with death jointly modelled as a function of race/ethnicity. A total of 4,043 (1,063 non-Latinx White, 1,267 non-Latinx Black, and 1,713 Latinx) participants were selected for this study with a mean age of 75 years, 67% women, and with a mean follow-up of 5 years. Higher baseline SCD was associated with increased rates of incident dementia over time in the full sample (hazard ratio [HR] 1.085, CI 1.047-1.125, p < 0.001) and within Latinx (HR 1.084, CI 1.039-1.130, p < 0.001) and non-Latinx Black individuals (HR 1.099, CI 1.012-1.194, p = 0.024). Overall results of this study support SCD as a prodromal marker of dementia in a multiracial community sample, and in Latinx and non-Latinx Black individuals in particular. Because models examining the risk of dementia were adjusted for baseline memory test performance, the results support the idea that SCD, a subjective reflection of one's own current cognitive functioning, contributes information above and beyond standard memory testing. Current findings highlight the importance of carefully evaluating any memory concerns raised by older adults during routine visits and underscore the potential utility of screening older adults for SCD.

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults

Neuroimaging studies have documented racial and ethnic disparities in brain health in old age. It remains unclear whether these disparities are apparent in midlife. To assess racial and ethnic disparities in magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration in midlife and late life. Data from 2 community-based cohort studies, Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Offspring Study of Racial and Ethnic Disparities in Alzheimer Disease (Offspring), were used. Enrollment took place from March 2011 and June 2017, in WHICAP and Offspring, respectively, to January 2021. Of the 822 Offspring and 1254 WHICAP participants approached for MRI scanning, 285 and 176 refused participation in MRI scanning, 36 and 76 were excluded for contraindications/ineligibility, and 4 and 32 were excluded for missing key variables, respectively. Cortical thickness in Alzheimer disease-related regions, white matter hyperintensity (WMH) volume. The final sample included 1467 participants. Offspring participants (497 [33.9%]) had a mean (SD) age of 55 (10.7) years, had a mean (SD) of 13 (3.5) years of education, and included 117 Black individuals (23.5%), 348 Latinx individuals (70%), 32 White individuals (6.4%), and 324 women (65.2%). WHICAP participants (970 [66.1%]) had a mean (SD) age of 75 (6.5) years, had a mean (SD) of 12 (4.7) years of education, and included 338 Black individuals (34.8%), 389 Latinx individuals (40.1%), 243 White individuals (25.1%), and 589 women (65.2%). Racial and ethnic disparities in cerebrovascular disease were observed in both midlife (Black-White: B = 0.357; 95% CI, 0.708-0.007; P = .046) and late life (Black-Latinx: B = 0.149, 95% CI, 0.068-0.231; P < .001; Black-White: B = 0.166; 95% CI, 0.254-0.077; P < .001), while disparities in cortical thickness were evident in late life only (Black-Latinx: B = -0.037; 95% CI, -0.055 to -0.019; P < .001; Black-White: B = -0.064; 95% CI -0.044 to -0.084; P < .001). Overall, Black-White disparities were larger than Latinx-White disparities for cortical thickness and WMH volume. Brain aging, or the association of age with MRI measures, was greater in late life compared with midlife for Latinx (cortical thickness: B = 0.006; 95% CI, 0.004-0.008; P < .001; WMH volume: B = -0.010; 95% CI, -0.018 to -0.001; P = .03) and White (cortical thickness: B = 0.005; 95% CI, 0.002-0.008; P = .001; WMH volume: B = -0.021; 95% CI -0.043 to 0.002; P = .07) participants but not Black participants (cortical thickness: B = 0.001; 95% CI, -0.002 to 0.004; P =.64; WMH volume: B = 0.003; 95% CI, -0.010 to 0.017; P = .61), who evidenced a similarly strong association between age and MRI measures in midlife and late life. In this study, racial and ethnic disparities in small vessel cerebrovascular disease were apparent in midlife. In Latinx and White adults, brain aging was more pronounced in late life than midlife, whereas Black adults showed accelerated pattern of brain aging beginning in midlife.

Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample

We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69–96 years; 62% women; 31%/49%/20% Non–Hispanic White/Non–Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non–Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non–Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group. Importantly, treatment strategies exist to minimize vascular contributions to cognitive decline.

Longitudinal associations between racial discrimination and hippocampal and white matter hyperintensity volumes among older Black adults

RationaleNon-Hispanic Black older adults are at higher risk of Alzheimer's disease and related dementias (ADRD) than non-Hispanic Whites, which reflects racial disparities in both brain and cognitive health. Discrimination may contribute to these disparities, but much of the research on discrimination and ADRD outcomes is cross-sectional and/or does not disaggregate experiences of discrimination by attribution. Focusing specifically on racial discrimination and considering longitudinal brain outcomes may advance our understanding of the role of discrimination in explaining disproportionate rates of ADRD among non-Hispanic Black older adults. MethodsIn total, 221 non-Hispanic Black participants in the Washington Heights-Inwood Columbia Aging Project completed multiple measures of discrimination at one time point and structural magnetic resonance imaging (MRI) scans at two time points. Everyday discrimination and lifetime discrimination were operationalized first as aggregate experiences of discrimination (regardless of identity attributions) and then as racial discrimination per se. MRI outcomes included hippocampal and white matter hyperintensity (WMH) volumes. Latent difference score models estimated associations between the discrimination measures and each MRI outcome over four years. ResultsAggregate discrimination (regardless of attributions) was not associated with either outcome. Lifetime racial discrimination was associated with lower initial hippocampal volume. Everyday racial discrimination was associated with faster accumulation of WMH over time. ConclusionsRacial discrimination may be detrimental for brain aging among non-Hispanic Black older adults, which may contribute to their disproportionate dementia burden. Disaggregating discrimination by attribution may clarify research on racial inequalities in brain and cognitive aging, as racial discrimination appears to be particularly toxic.

Association Between Mediterranean Diet and Functional Status in Older Adults: A Longitudinal Study Based on the Washington Heights-Inwood Columbia Aging Project.

Current evidence on the association between Mediterranean diet (MeDi) intake and activities of daily living (ADL) is limited and inconsistent in older adults. This study included 1 696 participants aged ≥65 years in the Washington Heights-Inwood Community Aging Project study. The MeDi score was calculated based on data collected from the Willett's semiquantitative food frequency questionnaire. The multivariable-adjusted Cox regression model was applied to examine the association of MeDi score with risks of disability in basic (BADL) and instrumental ADL (IADL), as well as the overall ADL (B-IADL). Eight hundred and thirty-two participants with incident ADL disability were identified over a median follow-up of 5.39 years. The continuous MeDi score was significantly associated with decreased risk of disability in B-IADL (hazard ratio = 0.95, 95% confidence interval = 0.91-0.99, p = .018) in a model adjusted for age, sex, race/ethnicity, educational level, and dietary calories intake but was no longer significant after additionally adjusted for multiple comorbidities and physical activities (0.97 [0.93, 1.01], p = .121). The continuous MeDi score was significantly associated with decreased risk of disability in B-IADL (0.92 [0.85, 1.00], p = .043) and BADL (0.90 [0.82, 0.99], p = .030) in non-Hispanic Whites, but not in non-Hispanic Blacks and Hispanics (p > .05 for all). Higher MeDi score was associated with decreased risk of ADL disability, particularly in non-Hispanic Whites.

Evaluation of stroke as a potential moderator of polygenic risk in Alzheimer's disease among non-Hispanic white and Caribbean Hispanic participants.

Recent studies have evaluated Alzheimer's disease (AD) associated with cerebrovascular and cardiovascular risk factors. Stroke history mediates association between late-onset AD and cardiovascular disease risk factors (Tosto et al., 2016). Our research investigated stroke as a potential moderator between polygenic risk score (PRS) and Alzheimer's disease. Participants were enrolled in the multi-ethnic Washington Heights-Inwood Columbia Aging Project (WHICAP). 653 non-Hispanic white and 2285 Caribbean Hispanic participants were included based on GWAS data and stroke status (self-reported history of stroke or MRI-visualized stroke). A concordance analysis assessed stroke group agreement. PRS from GWAS statistics was calculated for both populations. Following calculation of moderators by stroke status on population-specific PRS, binomial logistic regression models were conducted. Model outcome was Alzheimer's disease, which incorporated four diagnoses: Pure Alzheimer's disease, Probable Alzheimer's disease with Stroke, Alzheimer's disease with Parkinsonism, and Atypical Alzheimer's disease. Another set of models was conducted for the Caribbean Hispanic population towards a general outcome of Alzheimer's disease alone. Concordance analyses among all 4987 WHICAP participants showed Cohen's kappa of -0.033 and p of 0.001* (p* < 0.05), indicating no concordance between self-reported and MRI-visualized stroke groups; this is consistent with observation by Reitz et al., 2009. Within the Caribbean Hispanic population, MRI-visualized stroke models for Alzheimer's disease (four types) showed moderator significance (p of 0.002*, 0.007*, and 0.001* for Models 1, 2, 3 respectively) and MRI-visualized stroke models towards generalized Alzheimer's disease showed moderator significance (p of 0.152, 0.041*, and 0.020* for Models 1, 2, 3 respectively). Stroke is likely to be an important moderator of PRS and Alzheimer's disease risk in MRI-visualized stroke models, while a self-reported history of stroke was not related.

The impact of cerebrovascular disease on blood‐based biomarkers of Alzheimer’s disease

AbstractBackgroundThe development of ultrasensitive assays for blood‐based biomarkers may allow for detection of Alzheimer’s disease (AD)‐related pathology in large‐scale community‐based cohorts. We previously showed in the Washington Heights Inwood Columbia Aging Project (WHICAP) an association of plasma biomarker concentrations with clinical and pathological AD diagnosis, and that MRI markers of cerebrovascular disease, particularly parietal lobe white matter hyperintensities (WMH), increase the risk and progression of clinical AD. Here, we test the hypothesis that cerebrovascular disease has a direct impact on AD‐related pathology by examining the association of MRI markers of cerebrovascular disease and plasma biomarker concentrations in WHICAP.MethodAmong 300 WHICAP participants with available structural MRI (mean age 81.87+6.45 years, 67% women, 33.3% non‐Hispanic white, 33.3% African American, 33.3% Hispanic, 42% with cognitive impairment) we used SIMOA and MSD technology to measure plasma concentrations of Aβ42, Aβ40, ptau181, ptau217, total tau, and NfL from banked plasma samples. MRI scans were analyzed for regional WMH, presence of infarct, and presence of microbleeds. We first examined bivariate correlations between MRI cerebrovascular measures and plasma biomarker concentrations. For markers that were associated, we conducted demographically adjusted analyses and examined interactions with cognitive diagnostic status.ResultIncreased parietal lobe WMH, specifically, was associated with higher ptau181 (r=0.21, p=0.008) and ptau217 (r=0.13, p=0.05) concentrations. Increased WMH in frontal, temporal, and parietal regions was associated with increased NfL concentrations (rs=0.21‐0.25, ps&lt;0.001‐0.002). Presence of one or more microbleed was associated with increased NfL (r=0.19, p=0.02). In adjusted models the associations of regional WMH with ptau181 and NfL concentrations were independent of and did not interact with diagnosis.ConclusionMarkers of small vessel cerebrovascular disease, particularly parietal lobe WMH, are associated with AD blood‐based biomarkers of phosphorylated tau pathology and neurodegeneration.

Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults

Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Total and regional WMH volumes. The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized β = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: β = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: β = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: β = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: β = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: β = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: β = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004). In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.