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

METHODS

The cohort, enriched for AD risk, consisted of cognitively unimpaired adults ( = 136; Mean(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 ( 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO and genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau], Aβ/Aβ, pTau/Aβ). 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 and KL-VS was significant for tTau ( = 0.05), pTau ( = 0.03), Ng ( = 0.02), sTREM2 ( = 0.03), and YKL-40 ( = 0.03), such that lower levels of each biomarker were observed for KL-VS who were more fit. No significant KL-VSxVO interactions were observed for Aβ/Aβ, pTau/Aβ, α-syn, NfL, GFAP, IL-6 or S100B (all s>0.09).

CONCLUSIONS

We report a synergistic relationship between KL-VS and CRF with pTau, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VS and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.

HIGHLIGHTS

KL-VS 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.More fit KL-VS also has lower levels of pTau and less neuroinflammation.