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

Background: 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.

Methods: 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.

Results: 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]).

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