Proteomics-based aging clocks in midlife and late-life and risk of dementia.

Background: Biological age can be quantified by composite proteomic scores, called aging clocks. We investigated whether biological age acceleration (a discrepancy between chronological and biological age) in midlife and late-life is associated with cognitive function and risk of dementia. Methods: We used two population-based cohort studies: Atherosclerosis Risk in Communities (ARIC) Study and Multi-Ethnic Study of Atherosclerosis (MESA). Proteomics-based aging clocks (PACs) were created in ARIC at midlife (mean age: 58 years, n=11,758) and late-life (mean age: 77 years, n=4,934) using elastic net regression models in two-thirds of dementia-free participants and validated in the remaining one-third of participants. Age acceleration (AA) was calculated as residuals after regressing PACs on chronological age. We validated the midlife PAC in the MESA cohort (mean age: 62 years, n=5,829). We used multivariable linear and Cox proportional hazards regression to assess the association of AA with cognitive function and dementia incidence, respectively. Results: In ARIC, every five years AA was associated with lower global cognitive function: difference: -0.11, 95% confidence interval (CI): -0.16, -0.06) using midlife AA and difference: -0.17, CI: -0.23, -0.12 using late-life AA. Consistently, midlife AA was associated with higher risk of dementia (hazard ratio [HR]: 1.20 [CI: 1.04, 1.36]) and more prominently when using late-life AA (HR: 2.14 [CI:1.67, 2.73]). Similar findings were observed in the MESA study: every five years AA was associated with lower global cognitive function (difference: -0.08 [CI: -0.14, -0.03]) and higher risk of dementia (HR:1.23 [CI: 1.04, 1.46]). Conclusion: Accelerated biological age - as defined by the plasma proteome - is associated with lower cognitive function and predicts a higher risk of dementia in midlife and more prominently in late-life.