Biological aging, characterized by cellular and molecular changes, may play a key role in neurodegenerative diseases. While recent proteomic advancements have introduced new aging clocks, widespread validation remains necessary. This study evaluated organ-specific and cognition-enriched proteomic clocks in relation to chronological age and cognitive changes.

We analysed plasma proteomic data from the CHARIOT PRO SubStudy (N= 409), measured via the SomaScan assay ver 4.1 at four time points over three years (month 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages, and compared with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological–chronological age differences) and cognitive performance over 54 months.

The cohort (mean age 71.8 ± 5.5 years, 50.1% female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37–0.8; MAE = 4.2–2.7). Over three years, conventional, organismal, muscle, liver, artery, and immune AgeGaps increased (mean ± SD: 2.1 ± 1.9 to 1.0 ± 2.3). The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar pattens. Higher baseline AgeGap z-scores (i.e., greater biological age) in artery and brain were associated with poorer cognition, measured by the Repeatable Battery for Neuropsychological Status total scores (Coeff. -3.0, 95% CI: -3.4, -2.5 and -1.1, 95% CI: -1.5, -0.6) and Preclinical Alzheimer's Cognitive Composite (Coeff. -0.5, 95% CI: -0.6, -0.4 and -0.14, 95% CI: -0.3, -0.03).

These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging patterns in elucidating Alzheimer’s disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.