Neighborhood disadvantage reduces cognitive reserve independent of neuropathologic change.

INTRODUCTION: Individuals in socioeconomically disadvantaged neighborhoods exhibit increased risk for impaired cognitive function. Whether this association relates to the major dementia-related neuropathologies is unknown. METHODS: This cross-sectional study included 469 autopsy cases from 2011 to 2023. The relationships between neighborhood disadvantage measured by Area Deprivation Index (ADI) percentiles categorized into tertiles, cognition evaluated by the last Mini-Mental State Examination (MMSE) scores before death, and 10 dementia-associated proteinopathies and cerebrovascular disease were assessed using regression analyses. RESULTS: Higher ADI was significantly associated with lower MMSE score. This was mitigated by increasing years of education. ADI was not associated with an increase in dementia-associated neuropathologic change. Moreover, the significant association between ADI and cognition remained even after controlling for changes in major dementia-associated proteinopathies or cerebrovascular disease. DISCUSSION: Neighborhood disadvantage appears to be associated with decreased cognitive reserve. This association is modified by education but is independent of the major dementia-associated neuropathologies.

Epigenetic age and socioeconomic status contribute to racial disparities in cognitive and functional aging between Black and White older Americans.

Epigenetic age, a biological aging marker measured by DNA methylation, is a potential mechanism by which social factors drive disparities in age-related health. Epigenetic age gap is the residual between epigenetic age measures and chronological age. Previous studies showed associations between epigenetic age gap and age-related outcomes including cognitive capacity and performance on some functional measures, but whether epigenetic age gap contributes to disparities in these outcomes is unknown. We use data from the Health and Retirement Study to examine the role of epigenetic age gap in racial disparities in cognitive and functional outcomes and consider the role of socioeconomic status (SES). Epigenetic age measures are GrimAge or Dunedin Pace of Aging methylation (DPoAm). Cognitive outcomes are cross-sectional score and two-year change in Telephone Interview for Cognitive Status (TICS). Functional outcomes are prevalence and incidence of limitations performing Instrumental Activities of Daily Living (IADLs). We find, relative to White participants, Black participants have lower scores and greater decline in TICS, higher prevalence and incidence rates of IADL limitations, and higher epigenetic age gap. Age- and gender-adjusted analyses reveal that higher GrimAge and DPoAm gap are both associated with worse cognitive and functional outcomes and mediate 6-11% of racial disparities in cognitive outcomes and 19-39% of disparities in functional outcomes. Adjusting for SES attenuates most DPoAm associations and most mediation effects. These results support that epigenetic age gap contributes to racial disparities in cognition and functioning and may be an important mechanism linking social factors to disparities in health outcomes.

Racial Differences in Clinical Presentation in Individuals Diagnosed With Frontotemporal Dementia.

Importance: Prior research suggests there are racial disparities in the presentation of dementia, but this has not been investigated in the context of frontotemporal dementia (FTD). Objective: To explore racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms in individuals with a diagnosis of FTD. Design, Setting, and Participants: This exploratory cross-sectional study of National Alzheimer's Coordinating Center (NACC) data collected between June 2005 to August 2021 evaluated Asian, Black, and White individuals with a diagnosis of FTD (behavioral variant FTD or primary progressive aphasia). Excluded were races with limited data, including American Indian or Alaska Native (n = 4), Native Hawaiian or other Pacific Islander (n = 3), other (n = 13), and unknown (n = 24), and participants with symptom duration more than 4 SDs above the mean. Main Outcomes and Measures: Racial differences at initial NACC visit were examined on Clinical Dementia Rating Dementia Staging Instrument plus NACC Frontotemporal Lobar Degeneration Behavior & Language Domains (FTLD-CDR), Functional Assessment Scale, and Neuropsychiatric Inventory using regression models. Matching was also performed to address the imbalance between racial groups. Results: The final sample comprised 2478 individuals, of which 59 (2.4%) were Asian, 63 (2.5%) were Black, and 2356 (95.1%) were White. The mean (SD) age at initial visit was 65.3 (9.4) years and symptom duration at initial visit was 67.5 (35.6) months. Asian and Black individuals were considerably underrepresented, comprising a small percent of the sample. Black individuals had a higher degree of dementia severity on FTLD-CDR (ß = 0.64; SE = 0.24; P = .006) and FTLD-CDR sum of boxes (ß = 1.21; SE = 0.57; P = .03) and greater functional impairment (ß = 3.83; SE = 1.49; P = .01). There were no differences on FTLD-CDR and Functional Assessment Scale between Asian and White individuals. Black individuals were found to exhibit a higher frequency of delusions, agitation, and depression (delusions: odds ratio [OR], 2.18; 95% CI, 1.15-3.93; P = .01; agitation: OR, 1.73; 95% CI, 1.03-2.93; P = .04; depression: OR, 1.75; 95% CI, 1.05-2.92; P = .03). Asian individuals were found to exhibit a higher frequency of apathy (OR, 1.89; 95% CI, 1.09-3.78; P = .03), nighttime behaviors (OR, 1.72; 95% CI, 1.01-2.91; P = .04), and appetite/eating (OR, 1.99; 95% CI, 1.17-3.47; P = .01) compared to White individuals. Conclusions and Relevance: This exploratory study suggests there are racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms. Future work must address racial disparities and their underlying determinants as well as the lack of representation of racially minoritized individuals in nationally representative dementia registries.

Contributions of neighborhood social environment and air pollution exposure to Black-White disparities in epigenetic aging.

Racial disparities in many aging-related health outcomes are persistent and pervasive among older Americans, reflecting accelerated biological aging for Black Americans compared to White, known as weathering. Environmental determinants that contribute to weathering are poorly understood. Having a higher biological age, measured by DNA methylation (DNAm), than chronological age is robustly associated with worse age-related outcomes and higher social adversity. We hypothesize that individual socioeconomic status (SES), neighborhood social environment, and air pollution exposures contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm). We perform retrospective cross-sectional analyses among 2,960 non-Hispanic participants (82% White, 18% Black) in the Health and Retirement Study whose 2016 DNAm age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing DNAm age on chronological age. We observe Black individuals have significantly accelerated DNAm aging on average compared to White individuals according to GrimAge (239%) and DPoAm (238%). We implement multivariable linear regression models and threefold decomposition to identify exposures that contribute to this disparity. Exposure measures include individual-level SES, census-tract-level socioeconomic deprivation and air pollution (fine particulate matter, nitrogen dioxide, and ozone), and perceived neighborhood social and physical disorder. Race and gender are included as covariates. Regression and decomposition results show that individual-level SES is strongly associated with and accounts for a large portion of the disparity in both GrimAge and DPoAm aging. Higher neighborhood deprivation for Black participants significantly contributes to the disparity in GrimAge aging. Black participants are more vulnerable to fine particulate matter exposure for DPoAm, perhaps due to individual- and neighborhood-level SES, which may contribute to the disparity in DPoAm aging. DNAm aging may play a role in the environment "getting under the skin", contributing to age-related health disparities between older Black and White Americans.

Dual targeting of IGF-1R and ErbB3 as a potential therapeutic regimen for ovarian cancer.

Therapeutically targeting receptor tyrosine kinases has proven to be paramount to overcoming chemotherapy resistance in several cancer indications, improving patient outcomes. Insulin-Like Growth Factor Receptor 1 (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) have been implicated as two such drivers of resistance, however their simultaneous role in ovarian cancer chemotherapy resistance remains poorly elucidated. The aim of this work is to determine the effects of dual IGF-1R/ErbB3 inhibition on ovarian cancer cell signaling, growth, and in vivo efficacy. Assessment of in vitro chemotherapy response across a panel of ovarian cancer cell lines revealed that increased IGF-1R cell surface expression correlates with decreased sensitivity to chemotherapy, and that growth induced by IGF-1R and ErbB3 ligands is blocked by the tetravalent bispecific antibody targeting IGF-1R and ErbB3, istiratumab. In vitro chemotherapy treatment increased ovarian cancer cell line capacity to activate prosurvival PI3K signaling in response to ligand, which could be prevented with istiratumab treatment. Furthermore, in vivo efficacy of standard of care chemotherapies using a xenograft model of ovarian cancer was potentiated with istiratumab. Our results suggest a role for IGF-1R and ErbB3 in driving chemotherapy resistance of ovarian cancer.