Nicole Schupf’s research while affiliated with Columbia University and other places

Introduction New Alzheimer's disease (AD) treatments have created an urgent need for accurate early diagnosis of high‐risk adults with Down syndrome (DS), distinguishing prodromal DS‐AD symptoms from lifelong cognitive impairments. Often, clinicians will need to evaluate dementia status during a single assessment, and here we describe empirically supported methods effective under such circumstances. Methods Archived data collected between 1987 and 2017 included longitudinal findings for 144 individuals maintaining cognitive stability and 126 developing prodromal DS‐AD. Response operating characteristic analyses compared groups, defined by the presence/absence of prodromal DS‐AD, for a single assessment. Results Groups differed on all measures without adjusting for developmental history, 0.717 < areas under the curve < 0.859, Ps < 0.0001. The balance between sensitivity and specificity improved slightly when developmental histories were considered. Discussion The present study demonstrated that one‐time assessments can inform clinical judgments when diagnosing adults at risk for DS‐AD. Knowledge of developmental history is valuable but non‐essential. Highlights Non‐overlapping distributions were observed for preclinical and prodromal Alzheimer's disease (AD) groups. Receiver operating characteristic area under the curve analyses were in the acceptable to excellent range for all measures. Performance was sensitive to both the severity of intellectual disability and the stage of Down syndrome‐AD progression. Episodic memory tests were sensitive to the transition from preclinical to prodromal AD. Performance results at a single time point can inform dementia status decisions.

Background Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD. Method Data for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound‐B (PIB) scans, ABC‐DS had PIB or florbetapir. Nonlinear cross‐sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member. Result Data from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non‐carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups. Conclusion ADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

Background Structural determinants of health may be important drivers of late‐life cognitive decline and dementia risk for women who have a disproportionate burden of Alzheimer’s disease (AD). This study examines how early life exposure to structural sexism influences cognitive trajectories among women racialized as Black and White. Method This study analyzed longitudinal data from two cohort studies: the Washington Heights‐Inwood Columbia Aging Project (WHICAP) and the Health and Retirement Study (HRS). Eligible participants were aged 60+, US born, non‐Latinx, and dementia‐free at their baseline cognitive assessment. Confirmatory factor analysis produced a latent variable of state‐level structural sexism comprised of 6 US Census‐derived indicators representing sex/gender disparities in access to economic, political, cultural, and reproductive health resources. Latent variable scores, per US state, were generated for each year between 1902 ‐ 1954 and linked with WHICAP and HRS participants using birth year and state. Cognitive outcomes were level and change in memory performance. Stratified mixed‐effects models were used to examine associations between structural sexism and memory trajectories across women and men. Interaction terms were included to examine associations by racialized group. Result Exposure to higher levels of structural sexism was associated with lower baseline memory performance among WHICAP women and a more rapid rate of memory decline among women in both studies. For women, the difference in rate of memory decline between being born in the state with the highest structural sexism versus the state with the lowest structural sexism was equivalent to 8 to 9 years of cognitive aging. Associations between structural sexism and baseline memory were stronger among Black women compared with White women for both studies. Conclusion This study provides some of the first insights into the relationship between structural sexism and late‐life cognitive aging outcomes. Results suggest that, among US‐born Black and White women, early‐life exposure to structural sexism negatively impacts late‐life memory trajectories. Structural determinants are actionable risk factors that can be modified through policy changes. A deeper understanding of the pathways linking structural sexism to AD risk can inform the development of future policy interventions to improve late‐life cognitive health among women.

Background Subjective social status in the US (SSS) is related to physical, mental, and cognitive health independent of socioeconomic status, yet few studies have assessed SSS in one’s community or examined how SSS may function differentially across the intersection of race and gender. This study aimed to assess the relationships between SSS‐US, SSS‐community, brain health, and cognitive reserve utilizing an intersectional lens to extend the literature on social determinants of Alzheimer’s disease and related dementia (ADRD) risk. Methods Participants were 867 older adults from the Washington Heights‐Inwood Columbia Aging Project (WHICAP). SSS relative to the US and one’s community were based on the MacArthur Scale of SSS. Brain health was operationalized as total volume of white matter hyperintensities (WMH), total gray matter volume, total hippocampal volume, and mean cortical thickness across nine AD signature regions. Cognitive reserve was operationalized as residual variance in an episodic memory composite after accounting for all brain health measures. Separate multiple linear regressions assessed unique relationships between the two SSS predictors and the brain health and cognitive reserve outcomes while adjusting for sociodemographics. Multiplicative interaction terms examined whether associations involving SSS were moderated by sex/gender, race/ethnicity, and their intersection. Results There were no relationships between SSS‐community or SSS‐US and brain health across the full sample. Among White women, higher SSS‐community was associated with lower WMH (B = ‐0.33, p = 0.047). Among Black men, higher SSS‐community was associated with lower hippocampal volume (B = ‐0.31, p = 0.04). In sensitivity analyses, higher SSS‐community was associated with lower hippocampal volume among older (B = ‐0.30, p = 0.048), but not younger (B = ‐0.21, p = 0.37) Black men. Neither SSS‐US nor SSS‐community was associated with cognitive reserve. Conclusions This study highlights the value of assessing community standing in addition to US standing to understand social determinants of ADRD risk, as community standing may be more predictive of brain health. From an intersectional lens, community standing may be most strongly related to cerebrovascular health among White women, who appeared more sensitive to both low and high community standing. Counterintuitive findings among Black men likely reflect selective survival. Further research should explore longitudinal relationships between community standing and brain health.

INTRODUCTION We investigated whether early life exposure to state‐level structural sexism influenced late‐life memory trajectories among United Staes (U.S.) ‐born women and men and determined whether associations differed between racialized groups. METHODS Participants were from the Washington Heights‐Inwood Columbia Aging Project (WHICAP; N = 2314) and Health and Retirement Study (HRS; N = 18,631). State‐level structural sexism was measured via U.S. census and administrative data and linked to participants in each study by birth year and state. RESULTS Exposure to greater structural sexism was associated with lower baseline memory performance among WHICAP women and HRS men and faster memory decline among women in both studies. Women born in the state with the highest structural sexism showed memory decline like that of those who were 9 years older. Structural sexism‐baseline memory associations were stronger among Black women than White women. DISCUSSION Early life exposure to structural sexism negatively impacts late‐life memory trajectories among women. Highlights A longitudinal measure captured state‐level structural sexism from 1900 to 1960. Exposure to structural sexism was associated with worse late‐life memory outcomes. Associations were strongest among women for memory decline. The negative impact on memory performance was stronger among Black women. Lowering structural sexism may, in turn, reduce memory decline among women.

Objective:Being married may protect late-life cognition. Less is known about living arrangement among unmarried adults and mechanisms such as brain health (BH) and cognitive reserve (CR) across race and ethnicity or sex/gender. The current study examines (1) associations between marital status, BH, and CR among diverse older adults and (2) whether one’s living arrangement is linked to BH and CR among unmarried adults. Method:Cross-sectional data come from the Washington Heights-Inwood Columbia Aging Project (N = 778, 41% Hispanic, 33% non-Hispanic Black, 25% non-Hispanic White; 64% women). Magnetic resonance imaging (MRI) markers of BH included cortical thickness in Alzheimer’s disease signature regions and hippocampal, gray matter, and white matter hyperintensity volumes. CR was residual variance in an episodic memory composite after partialing out MRI markers. Exploratory analyses stratified by race and ethnicity and sex/gender and included potential mediators. Results:Marital status was associated with CR, but not BH. Compared to married individuals, those who were previously married (i.e., divorced, widowed, and separated) had lower CR than their married counterparts in the full sample, among White and Hispanic subgroups, and among women. Never married women also had lower CR than married women. These findings were independent of age, education, physical health, and household income. Among never married individuals, living with others was negatively linked to BH. Conclusions:Marriage may protect late-life cognition via CR. Findings also highlight differential effects across race and ethnicity and sex/gender. Marital status could be considered when assessing the risk of cognitive impairment during routine screenings.

Background Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Interpretation Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. Funding 10.13039/100000002National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), 10.13039/501100023864NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.

Background: Previous research has identified multiple risk and protective factors for late onset Alzheimer’s disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines. Objective: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles. Methods: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories (“Stable-High,” “Stable-Low,” “Decliner,” “Rapid Decliner”) using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington Heights-Inwood Columbia Aging Project. Results: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-ɛ4 only incurred independent risk in the rapidly declining group. Conclusion: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient’s unique cognitive history.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer’s disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer’s disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer’s disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer’s Biomarkers Consortium–Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer’s disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer’s disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer’s disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer’s disease in adults with Down syndrome.