Biological age acceleration associates with Alzheimer's disease plasma biomarker levels

Abstract

Introduction: Epigenetic clocks associate with neuropathology and Alzheimer's disease (AD) clinical risk, but findings are mixed regarding whether clocks associate with blood-based biomarkers and in non-European populations.

Methods: We calculated biological age and age acceleration from blood methylation data in 704 older Hispanic adults and tested associations with clinical diagnosis and antemortem biomarker levels.

Results: Age acceleration was significantly associated with sex, clinical diagnosis, and levels of eight plasma biomarkers, including P-tau217 levels. Additionally, biomarker associations trended more significantly among APOE-ε4 non-carriers. We also identified that methylation levels in CD4 and CD8 T-cell types are associated with age acceleration.

Discussion: We demonstrated that biological age acceleration, measured in blood, in a Hispanic cohort enriched for preclinical individuals, can stratify clinical AD risk and is associated with plasma AD biomarker levels.

Highlights: Blood-based aging clocks associate with Alzheimer's disease plasma biomarker levels. Biological aging appears relevant to pathological aging in apolipoprotein E (APOE) -ε4 non-carriers. Immune T-cell composition relates to biological aging.

Keywords: Alzheimer's disease; age acceleration; biological aging; epigenetic clocks; methylation; plasma biomarkers; preclinical disease; risk stratification.

FIGURE 1

Biological age is correlated with chronological age. Biological age (DNAm) derived from (A) Horvath and (B) Hannum blood‐based epigenetic clocks of aging are correlated with chronological age in a Hispanic cohort enriched for individuals with preclinical Alzheimer's disease.

FIGURE 2

Biological aging is significantly associated with sex. Both biological age [DNAm; (A)] and age acceleration (B) derived from epigenetic clocks are significantly associated with sex. (A, B) Men have both a slightly older biological age and a slightly faster biological age acceleration as compared to women.

FIGURE 3

Biological aging is significantly associated with clinical diagnosis. Biological age [DNAm; (A)] derived from epigenetic clocks is not associated with clinical diagnosis, but age acceleration (B) is significantly associated. While those with a clinical Alzheimer's disease diagnosis do not have a statistically significant older biological age than clinical controls (A), clinical cases do have a faster age acceleration as compared to their age‐matched healthy counterparts (B).

FIGURE 4

Biological age and age acceleration are significantly associated with Alzheimer's disease plasma biomarker levels. (A) Biological age and (B) age acceleration, both derived from epigenetic clocks, are significantly associated with eight out of nine plasma biomarkers tested, with each biomarker name listed on the y‐axis. (A, B) The x‐axis on both panels shows 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 gray.

FIGURE 5

Biological aging is significantly associated with immune cell‐type proportions. Red, white, and pink coloring represents the strength of effect size, represented by beta values (rescaled in the 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. 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 epigenetic clocks show that memory CD4 T‐cells, naïve CD8 T‐cells, and memory B‐cells are significantly associated with both biological age and age acceleration.