Social isolation, loneliness, and blood-based AD/ADRD biomarkers in a nationally-representative study of middle-aged and older adults

ABSTRACT Importance: The biological mechanisms underlying the associations of social isolation and loneliness with dementia risk are not well understood. Objective: To evaluate the relationship of prospectively measured social isolation and loneliness with AD/ADRD blood-based biomarkers. Design: Observational study using the U.S. Health and Retirement Study (2010-2016). Venous blood draws were conducted in 2016 and AD/ADRD biomarkers were released in 2025. We estimated associations of social isolation and loneliness patterns between 2012 and 2014 with continuous biomarkers using linear regressions, accounting for socio-demographic and health covariates. We evaluated effect modification by sex and APOE {varepsilon}4 carrier status. Setting: Population-based Participants: Community-dwelling HRS participants aged 50 years or older (n = 3862). Exposures: Primary exposures were four-category multi-wave variables of persistent, resolving, new-onset, or no social isolation/loneliness across the two exposure waves. Social isolation was classified as "severe" and "moderate-to-severe" based on a 5-item scale including marital status, household size, proximity to children, religious service attendance, and volunteering. Past-week loneliness was measured with a single-item question (yes/no). Main Outcomes and Measures: Neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and the ratio of amyloid beta 42 to amyloid beta 40 (A{beta}42/40), measured in plasma via a Multiplex Simoa Assay and phosphorylated tau (p-tau181), measured in serum via a Simoa Assay. Results: At the analytic baseline, respondents were a mean age of 64 (9.5) years, 59% female, and 25% APOE {varepsilon}4 carriers. Across the two exposure waves, 4% experienced persistent severe social isolation, 16% experienced persistent moderate-to-severe social isolation, and 8% reported persistent loneliness. Multiple patterns of social isolation (vs. no social isolation) were associated with higher NfL, including persistent severe social isolation ({beta}: 0.31), new-onset moderate-to-severe social isolation ({beta}: 0.14), and resolving moderate-to-severe social isolation ({beta}: 0.20). Persistent severe social isolation was associated with lower GFAP ({beta}: -0.31) while persistent loneliness and, for men, new-onset loneliness were associated with higher GFAP ({beta}_persistent: 0.16; {beta}_(new onset_men): 0.25). New-onset severe social isolation was associated with a lower A{beta}42/40 ratio ({beta}: -0.25) while resolving moderate-to-severe social isolation and, for men, persistent severe social isolation were each associated with higher p-tau181 ({beta}_resolving: 0 .11; {beta}_(persistent_men): 0.41). There was some additional variation by APOE {varepsilon}4 carriership, although selective survival is a concern. Conclusions: Social isolation was associated with elevated blood-based biomarkers of neuronal injury, with variation by patterns of exposure over time. Associations between social isolation and loneliness with biomarkers related to astrocyte damage and Alzheimer's disease were less consistent, and varied in sign and magnitude by exposure and sex.