Peripheral immune signatures predict cognitive decline in older adults: a population-based cohort study

Peripheral immune dysregulation has increasingly been associated with cognitive impairment and dementia, yet large-scale prospective evidence linking cellular immunophenotypes to long-term cognitive outcomes in community-representative older adults remains limited.

We profiled 24 peripheral immune subsets by flow cytometry in 9008 older adults from the Health and Retirement Study (HRS). Among 4464 participants classified as cognitively normal (CN) at baseline, we prospectively examined incident CIND/dementia (CIND, cognitively impaired no dementia) and six-year cognitive trajectories, constructed an Immune Risk Score (IRS) from baseline peripheral immune-cell features using bootstrap stability-selected elastic-net Cox regression, and characterised correlations with plasma biomarkers related to amyloid, tau, neural injury, astroglial activation, and inflammation.

Participants classified as CIND/dementia were characterised by a coordinated immunosenescence signature of naïve CD4+ and CD8+ T-cell and naïve B-cell depletion, with expansion of effector-memory T-cell and memory B-cell. CD56hi NK cells and naïve B cells independently predicted reduced cognitive impairment risk after full covariate adjustment (HR = 0.92, 95% CI: 0.86-0.98 and HR = 0.92, 95% CI: 0.87-0.98). Higher IRS independently predicted incident CIND/dementia (HR = 1.63; 95% CI, 1.28-2.09) and faster decline across global cognition, episodic memory, and working memory and correlated more strongly with GDF-15, NfL, and GFAP than with amyloid or tau pathology.

Peripheral immune profiles independently predict incident CIND/dementia and multi-domain cognitive decline in older adults, with associations preferentially reflecting neuroinflammatory rather than amyloid-tau burden. These findings support further evaluation of peripheral immunophenotyping as a complementary approach to cognitive impairment risk assessment.