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

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-VSHET). 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 (VO2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VSHET compared to noncarriers (KL-VSNC).

METHODS

The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (n = 136; MeanAGE(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 VO2peak 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 VO2peak and KL-VSHET 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-VSHET who were more fit. No significant KL-VSxVO2peak 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-VSHET and CRF with pTau181, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VSHET and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.

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