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

Biological age can be quantified by composite proteomic scores, called proteomics-based aging clocks (PACs). We investigated whether a discrepancy between chronological and biological age in midlife and late-life is associated with cognition and dementia risk.

We used two longitudinal population-based studies: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA). PACs were created in ARIC at midlife (mean age: 58 years, 57% female, n = 11,758) and late-life (mean age: 77 years, 56% female, n = 4934) using elastic net regression models in two-thirds of dementia-free participants and validated in the remaining one-third of participants. Proteomics-based age acceleration (PAA) was calculated as residuals after regressing PACs on chronological age. We validated the midlife PAC in the MESA cohort (mean age: 62 years, 52% female, n = 5829). We used multivariable linear and Cox proportional hazards regression to assess the association of PAA with cognitive function and dementia incidence, respectively.

In ARIC, every five years, PAA is associated with lower global cognition: difference: -0.11, 95% confidence interval[CI]: -0.16, -0.06) using midlife PAA and difference: -0.17, CI: -0.23, -0.12 using late-life PAA. Midlife PAA is associated with higher dementia risk (hazard ratio[HR]: 1.20 [CI: 1.04, 1.36]) and more prominently when using late-life PAA (HR: 2.14 [CI:1.67, 2.73]). Similar findings are observed in MESA: PAA is associated with lower global cognitive function (difference: -0.08 [CI: -0.14, -0.03]) and higher dementia risk (HR:1.23 [CI: 1.04, 1.46]).

Accelerated biological age is associated with lower cognition and a higher risk of dementia in midlife and more prominently in late life.