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

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.

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.

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]).

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.