Older more fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles

medRxiv [Preprint]. 2025 Mar 3:2025.02.27.25323056. doi: 10.1101/2025.02.27.25323056.

ABSTRACT

INTRODUCTION: While hallmarked by the accumulation of β-amyloid plaques (Aβ) and neurofibrillary tangles (tau) in the brain, Alzheimer's disease (AD) is a multifactorial disorder that involves additional pathological events, including neuroinflammation, neurodegeneration and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL-VS_HET). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes, both in general and specifically with regard to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO_2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS_HET compared to non-carriers (KL-VS_NC).

METHODS: The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (N=136; Mean_AGE(SD)=62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, APOE4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO_2peak and KLOTHO genotype on core AD biomarker levels in CSF [phosphorylated tau 181 (pTau₁₈₁), Aβ₄₂/Aβ₄₀, pTau₁₈₁/Aβ₄₂]. Analyses were repeated for CSF biomarkers of neurodegeneration [total tau (tTau), α-synuclein (α-syn), neurofilament light polypeptide (NfL)], synaptic dysfunction [neurogranin (Ng)], and neuroinflammation [glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed in myeloid cells (sTREM2), chitinase-3-like protein 1 (YKL-40), interleukin 6 (IL-6), S100 calcium-binding protein B (S100B)].

RESULTS: The interaction between VO_2peak and KL-VS_HET was significant for tTau (P=0.05), pTau₁₈₁ (P=0.03), Ng (P=0.02), sTREM2 (P=0.03), and YKL-40 (P=0.03), such that lower levels of each biomarker were observed for KL-VS_HET who were more fit. No significant KL-VSxVO_2peak interactions were observed for Aβ₄₂/Aβ₄₀, pTau₁₈₁/Aβ₄₂, α-syn, NfL, GFAP, IL-6 or S100B (all Ps>0.09).

CONCLUSIONS: We report a synergistic relationship between KL-VS_HET and CRF with regard to pTau₁₈₁, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS_HET and better cardiovascular fitness against unfavorable AD-related changes. Their potentially shared biological mechanisms will require future investigations.

PMID:40093256 | PMC:PMC11908295 | DOI:10.1101/2025.02.27.25323056