Loneliness and Plasma Biomarkers of Neurodegeneration in Community-Dwelling Older Adults: Cross-Sectional and Longitudinal Analyses

BACKGROUND/OBJECTIVE: Loneliness has been linked with cognitive decline and dementia. Studies show relationships between loneliness and neurodegeneration, amyloid, and tau burden. We investigated whether loneliness relates to plasma biomarkers of neurodegenerative processes among cognitively normal or mildly impaired older adults at the population level. SETTING/PARTICIPANTS: A population-based cohort (n = 884) in southwestern Pennsylvania. MEASUREMENTS: Demographics; loneliness and social isolation composite scores, depression symptoms, Clinical Dementia Rating, plasma amyloid beta (Aβ) 42, Aβ40, p-tau181, p-tau217, NfL, GFAP. DESIGN: We examined the associations of loneliness with plasma biomarkers using regression analyses in both cross-sectional and longitudinal models. For cross-sectional analysis, we used data from 884 dementia-free participants at the closest wave to biomarker testing (within 180 days). For longitudinal analysis, we first derived loneliness trajectories from 514 participants with repeated annual loneliness measurements for up to 15 years prior to biomarker testing, then used these trajectories as predictors in regression models examining their associations with plasma biomarkers. RESULTS: Compared with the stable loneliness trajectory, the increasing loneliness trajectory showed nominally higher p-tau181 levels (β = 0.305 log-transformed, 95% CI: 0.022, 0.587; t_476 = 2.112; p = 0.035, uncorrected; multiple comparison-adjusted p = 0.211), adjusting for age, sex, education, social isolation, and depression symptoms. CONCLUSIONS: This exploratory analysis found a nominal association between increasing loneliness and p-tau181 that did not survive correction for multiple comparisons. Findings should be considered hypothesis-generating. If confirmed through replication in larger samples, associations between loneliness patterns and tau pathology could inform understanding of psychosocial contributions to neurodegeneration.