Mapping sex‐specific associations of adiposity with age‐related cognitive decline and multimodal Alzheimer's pathology
Jingjing Zhang, Dan Liu, Yueran Yang, Xiaoyu Lou, Hongwei Ren, Wei Tan, Yan Zeng,Abstract
INTRODUCTION
The adiposity–cognition relationship in aging is controversial. This study aimed to assess its sex‐ and age‐specific associations with Alzheimer’s disease (AD) pathology using multimodal biomarkers.
METHODS
In two longitudinal cohorts (Hubei Memory and Aging Cohort Study [HMACS], n = 2,349; Alzheimer’s Disease Neuroimaging Initiative [ADNI], n = 1,858), we assessed body fat via Clínica Universidad de Navarra‐Body Adiposity Estimator (CUN‐BAE) and performed sex‐/age‐stratified analyses using multimodal biomarkers (plasma, cerebrospinal fluid [CSF], Positron Emission Computed Tomography [PET]).
RESULTS
In adults ≥65 years of age, higher baseline and increasing CUN‐BAE were associated with lower risk of AD‐related mild cognitive impairment (MCI) and dementia, with stratified analyses suggesting distinct patterns by sex and age; however, formal interaction tests were non‐significant. Each 1% increase in ΔCUN‐BAE at ages 70–74 was associated with lower normal cognition (NC)‐to‐MCI transition risk by 20%. In females, higher CUN‐BAE associated with lower phosphorylated tau 217 (p‐tau217) and nonlinearly with amyloid beta (Aβ)42 with an inflection point near 37.6%. In males, increasing adiposity correlated with lower p‐tau217 and neurofilament light chain (NfL). Neuroimaging revealed inverse associations with Aβ deposition in females and with tau deposition in Aβ‐positive males with MCI.
DISCUSSION
Higher adiposity was associated with lower incidence of AD‐related decline and less pronounced pathology; stratified exploratory analyses suggested patterns by age and sex, although formal interaction tests were non‐significant. However, these observational findings do not support recommendations of blindly increasing body fat for dementia prevention.