Amyloid-β positivity is less prevalent in cognitively unimpaired KLOTHO KL-VS heterozygotes

Background: Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VS_HET) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau).

Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk.

Methods: The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; Mean_Age(SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; Mean_Age(SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status.

Results: A+ prevalence was lower in KL-VS_HET (p = 0.05), with no differences in T + prevalence (p = 0.52). KL-VS_HET also had marginally lower odds of being A + T- (p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40).

Conclusions: KL-VS_HET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD.