Biological Age and Age Acceleration Predict Alzheimer's Disease Plasma Biomarker Levels

Abstract

Epigenetic clocks can predict pathological aging associated with Alzheimer's disease (AD) risk, albeit findings are mixed regarding if clocks are predictive in blood and in non-European populations. We constructed epigenetic clocks from blood methylation data in 704 older Hispanic adults and tested the association with a clinical diagnosis of AD and plasma biomarker levels. Biological age and age acceleration, the rate of biological aging, were significantly associated with sex, clinical diagnosis, and levels of eight plasma biomarkers, including P-Tau217 levels. Additionally, biomarker associations trended more significant among APOE-ε4 non-carriers. We also identified that methylation levels in CD4 and CD8 T-cell types are associated with biological aging and showed slightly stronger associations in men. We demonstrate that biological aging, in blood, in a Hispanic cohort of both demented and non-demented individuals, can stratify AD risk, predicting plasma biomarker levels even in preclinical disease.

Figure 1.. Biological age is significantly associated with chronological age.

Biological age (DNAm) derived from A) Horvath and B) Hannum epigenetic aging clocks are significantly associated with chronological age in a Hispanic cohort of individuals with clinical Alzheimer's disease and age-matched healthy controls.

Figure 2.. Biological aging is significantly associated with biological sex.

Both biological age (DNAm) derived from A) Horvath and B) Hannum epigenetic clocks and age acceleration derived from C) Horvath and D) Hannum clocks are significantly associated with sex. Shown in panels A-D, men have both a slightly older biological age and a faster biological age acceleration as compared to women. P-values shown on the boxplots are derived from a simple t-test between sexes for biological age and age acceleration, respectively.

Figure 3.. Biological aging is significantly associated with clinical diagnosis.

Both biological age (DNAm) derived from A) Horvath and B) Hannum epigenetic clocks and age acceleration derived from C) Horvath and D) Hannum clocks are significantly associated with clinical diagnosis. Shown in panels A-D, those with a clinical Alzheimer’s disease diagnoses have both an older biological age and a faster biological age acceleration as compared to their aged-matched healthy counterparts. P-values shown on the boxplots are derived from a simple t-test between groups for biological age and age acceleration, respectively.

Figure 4.. Biological aging is significantly associated with Alzheimer’s disease plasma biomarker levels.

A) Biological age and B) age acceleration both derived from Horvath and Hannum epigenetic clocks are significantly associated with 8 out of 9 plasma biomarkers tested, with each biomarker listed on the x-axis. Both panels A and B show a 95% confidence interval calculated from the beta and standard error from each model. Age type is denoted by the shape and color of each plotted beta point estimate, with all nonsignificant results in grey.

Figure 5.. Biological aging is significantly associated with immune cell-type proportions.

Red, white, and pink coloring represents strength of effect size, represented by beta values (re-scaled in figure from −1 to 1 for visualization purposes) from each model, and the black labeled values in each box represent the false-discovery-rate-adjusted p-values from each model. As shown, chronological aging is associated with multiple immune cell types (first row). Both biological age (second and third rows) and age acceleration (fourth and fifth rows) derived from Horvath and Hannum clocks show that CD4 and CD8 T-cells are significantly associated with both biological age and with rate of biological aging.