Organ-specific proteomic aging and cognitive performance: implications for risk prediction of Alzheimer’s disease and related dementias in older adults
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background and objectives
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 change.
Methods
We analyzed plasma proteomic data from the CHARIOT PRO SubStudy (N = 409), measured using the SomaScan assay (version 4.1) at four time points over three years (months 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages and compared them with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological−chronological age differences) and cognitive performance over 54 months.
Results
The cohort (mean age: 71.8 ± 5.5 years; 50.1 % female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37–0.80; MAE = 4.2–2.7). Over three years, AgeGaps increased across the conventional, organismal, muscle, liver, artery, and immune systems, ranging from 2.1 ± 1.9 to 1.0 ± 2.3 years. The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar patterns. Higher baseline AgeGap z-scores (i.e., greater biological age) in the artery and brain were associated with poorer cognition, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status Total Scores (Coeff. −3.0, 95 % CI: −3.4, −2.5; and −1.1, 95 % CI: −1.5, −0.6) and the Preclinical Alzheimer's Cognitive Composite (Coeff. −0.5, 95 % CI: −0.6, −0.4; and −0.14, 95 % CI: −0.3, −0.03).
Conclusions
These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid in the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging signatures in elucidating Alzheimer’s disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.
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 change.
Methods
We analyzed plasma proteomic data from the CHARIOT PRO SubStudy (N = 409), measured using the SomaScan assay (version 4.1) at four time points over three years (months 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages and compared them with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological−chronological age differences) and cognitive performance over 54 months.
Results
The cohort (mean age: 71.8 ± 5.5 years; 50.1 % female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37–0.80; MAE = 4.2–2.7). Over three years, AgeGaps increased across the conventional, organismal, muscle, liver, artery, and immune systems, ranging from 2.1 ± 1.9 to 1.0 ± 2.3 years. The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar patterns. Higher baseline AgeGap z-scores (i.e., greater biological age) in the artery and brain were associated with poorer cognition, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status Total Scores (Coeff. −3.0, 95 % CI: −3.4, −2.5; and −1.1, 95 % CI: −1.5, −0.6) and the Preclinical Alzheimer's Cognitive Composite (Coeff. −0.5, 95 % CI: −0.6, −0.4; and −0.14, 95 % CI: −0.3, −0.03).
Conclusions
These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid in the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging signatures in elucidating Alzheimer’s disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.
Date Issued
2025-11-01
Date Acceptance
2025-07-05
Citation
The Journal of Prevention of Alzheimer's Disease, 2025, 12 (9)
ISSN
2426-0266
Publisher
Elsevier
Journal / Book Title
The Journal of Prevention of Alzheimer's Disease
Volume
12
Issue
9
Copyright Statement
© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of SERDI Publisher. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
10.1016/j.tjpad.2025.100274
Publication Status
Published
Article Number
100274
Date Publish Online
2025-07-22