KLOTHO KL‐VS genotype modifies the relationship between cardiorespiratory fitness and CSF biomarkers of neurodegeneration, synaptic dysfunction, and inflammation

Abstract Background Less adequate cardiorespiratory fitness (CRF) is associated with several aspects of Alzheimer’s disease (AD) pathology, including neuroinflammation, neurodegeneration and synaptic dysfunction, all of which are known contributors to the clinical outcome – progressive cognitive decline [1]. AD‐associated biomolecular changes also seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL‐VS HET ) [2]. While KL‐VS HET and CRF both appear to mitigate aspects of AD pathology, they have been exclusively studied in isolation. Here we investigate whether the relationships between CRF (VO 2 max) and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, synaptic dysfunction, and inflammation differ for KL‐VS HET compared to non‐carriers (KL‐VS NC ). Method The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (N=132; Mean AGE =62.7) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center. Covariate‐adjusted (age, sex, parental AD history, APOE, and age difference between CSF sampling and exercise test) linear models examined the relationship between VO 2 max and CSF biomarkers of neurodegeneration [α‐synuclein (α‐syn), neurofilament light polypeptide (NfL), total tau (tTau)], 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)] as a function of KLOTHO KL‐VS. Result The interaction between VO 2 max and KL‐VS HET was significant for tTau (P=0.05), Ng (P=0.02), sTREM2 (P=0.02), and YKL‐40 (P=0.03) (Table 1; Figure 1), such that KL‐VS HET who were more fit had significantly lower levels of tTau, Ng, sTREM2, and YKL‐40 but not α‐syn, NfL, GFAP, IL‐6, or S100B (all Ps>0.63). Conclusion We report a synergistic relationship between KL‐VS HET and CRF with regard to neurodegeneration (tTau), synaptic dysfunction (Ng) and inflammation (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. References [1] Huuha, A.M., et al., Can exercise training teach us how to treat Alzheimer's disease? Ageing Res Rev, 2022. 75: p. 101559. [2] Driscoll, I., et al., AD‐associated CSF biomolecular changes are attenuated in KL‐VS heterozygotes. Alzheimers Dement (Amst), 2022. 14(1): p. e12383.