Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes

Abstract

Background

The literature supports an attenuation of unfavorable age-related changes, in both cognitive performance and CSF biomarkers of significance to Alzheimer's disease (AD), in association with a functionally advantageous KLOTHO KL-VS genotype (KL-VS_HET).

Objective

To examine whether KL-VS_HET attenuation of unfavorable age-related biomolecular changes is detectable in AD-relevant plasma biomarkers.

Methods

Sample consisted of 298 cognitively unimpaired adults (Mean_AGE = 65 ± 6.8, 67% female) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies with available data of interest. Covariate (sex, education, APOE4+/- status, parental history of AD)-adjusted multivariate regression examined relationships between age group (Younger (N = 140), Older (N = 158); mean split at age 65) and AD-relevant plasma biomarkers [amyloid-β (Aβ) 42/40, phosphorylated tau (pTau)181, pTau217, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)] and whether these relationships differ for KL-VS_HET [N = 86; Younger = 51 (59%), Older = 35 (41%)] compared to non-carriers [KL-VS_NC: N = 212; Younger = 89 (42%), Older = 123 (58%)].

Results

In the pooled sample, older age was associated with less favorable plasma biomarker profiles (all ps ≤ 0.001), except Aβ₄₂ (p = 0.39). When the analyses were stratified by genotype, KL-VS_NC continued to exhibit the same age-related pattern of changes in plasma biomarkers (all ps ≤ 0.009; except Aβ₄₂, p = 0.63), which was attenuated in KL-VS_HET for Aβ₄₀, Aβ_40/42, pTau181, pTau217, and pTau231 (all ps ≥ 0.1).

Conclusions

Unfavorable age-associated changes in core AD plasma biomarkers were attenuated in KLOTHO KL-VS_HET. KL-VS_HET seems to be protective against age-related biomolecular alterations known to confer risk for developing AD.