Older more fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles
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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, APOE 4+ 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 (pTau 181 ), Aβ 42 /Aβ 40 , pTau 181 /Aβ 42 ]. 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), pTau 181 ( 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 Aβ 42 /Aβ 40 , pTau 181 /Aβ 42 , α-syn, NfL, GFAP, IL-6 or S100B (all P s>0.09).
CONCLUSIONS
We report a synergistic relationship between KL-VS HET and CRF with regard to pTau 181 , 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.
Research in Context
Systematic Review
PubMed literature review suggests that both KLOTHO KL-VS genotype and cardiorespiratory fitness (CRF) are associated with pathophysiological processes related to Alzheimer’s Disease (AD). Both KL-VS heterozygotes (KL-VS HET ) and those with higher CRF fare better when faced with age-related biomolecular changes of relevance to AD. The present study investigates whether the relationships between CRF and cerebrospinal fluid biomarkers (CSF) of core AD neuropathology, neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VS HET compared to non-carriers.
Interpretation
Our findings suggest a synergistic relationship between KL-VS HET and higher CRF against core AD pathology along a range of unfavorable biomolecular changes implicated in this multifactorial disease. This supports the idea that CRF may interact with genetic factors to confer resilience against a multitude of adverse AD-associated processes.
Future Directions
Future studies should examine longitudinal changes in CSF biomarkers to determine whether maintaining or improving CRF over time enhances AD resilience in KL-VS HET .
