Sex differences in the impact of genetic and clinical risk factors for Alzheimer's disease in midlife
Year: 2025
Type: article
Study design: Observational Study
Abstract: Background Preclinical risk for Alzheimer's disease (AD), including amyloid-β (Aβ) deposition, begins 10–15 years prior to diagnosis. In addition to genetics, hypertension, type 2 diabetes, and depression in midlife are major risk factors for AD. Objective Here, we assessed sex differences in associations of AD risk status with memory circuitry function and AD pathology in midlife. Methods High- (HR) and low-risk (LR) participants (N = 99; ages 52–71 years) were recruited from the Mass General Brigham Biobank. HR participants have genetic risk ( APOE4 ) plus hypertension, type 2 diabetes, and/or depression; LR participants have no genetic or clinical risk. Participants underwent neuropsychological assessments of verbal, associative, and working memory, functional MRI (fMRI) scans while completing a working memory and verbal encoding task, and PET imaging scans. Aβ deposition was detected using PET C-11PiB and calculated as distribution volume ratio. Results HR status was significantly associated with lower scores in associative memory, altered fMRI BOLD activity in memory circuitry regions, and higher Aβ deposition, primarily in women. Further, altered task-based fMRI activity was related to worse memory performance and higher Aβ accumulation in women. While some effects were observed in men, effect sizes were smaller and did not survive correction for multiple comparisons. Conclusions Results demonstrated that genetic and clinical risk factors can help identify in a sex-dependent manner those in midlife who are at increased risk of developing AD to target for early intervention.
Source: Journal of Alzheimer s Disease
Authors: Kyoko Konishi, Dylan S Spets, Paris Fisher, Sarah Aroner, Sarah M Sant, Dmitry Prokopenko, Hrishikesh Lokhande, Rohit Patel, Harlyn Aizley, Brianna Smith, Anne Remington, Emma Spooner, Alexandra Touroutoglou, Jonathan Rosand, Steven Arnold, Hang Lee, Bradford Dickerson, Rudolph E Tanzi, Tanuja Chitnis, Jill M Goldstein
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Harvard NeuroDiscovery Center, BrightFocus Foundation, Harvard University, Harvard Catalyst, National Institutes of Health, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, Office of Research on Women's Health, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1243485958, G1639885399, G1689526078, G1717162763, G2032961523, G2086695793, G265784363, Impact of Depression on Alzheimer's disease: Prenatal Immune Origins and Shared Impact of Sex, G4880724714, G6241284220, G8230212765, G855671392, G8909023964, G9000032172, G9000065669, G9000082636, G9000089793, Development of Clinical Algorithm to Identify Risk for Alzheimer's disease in Early Midlife, Impact of sex differences in immune function on shared risk for cardiometabolic disorder & Alzheimer's disease, Hormones and Genes in Women's Health: Bench to Bedside
OpenAlex ID: W4413297188