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

Alzheimers Dement (N Y). 2025 Aug 8;11(3):e70133. doi: 10.1002/trc2.70133. eCollection 2025 Jul-Sep.

ABSTRACT

INTRODUCTION: Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves 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 related 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 noncarriers (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, apolipoprotein E (APOE) 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO_2peak and KLOTHO genotype on CSF core AD biomarker levels (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 pTau₁₈₁, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS_HET and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.

HIGHLIGHTS: KLOTHO KL-VS_HET and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)-related changes.Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL-VS_HET.More fit KL-VS_HET also has lower levels of pTau and less neuroinflammation.

PMID:40787159 | PMC:PMC12333875 | DOI:10.1002/trc2.70133