Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2025 Mar 3:2025.02.27.25323056.
doi: 10.1101/2025.02.27.25323056.

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

Mackenzie Jarchow  1 , Ira Driscoll  1   2 , Brianne M Breidenbach  1   2 , Noah Cook  1   3 , Catherine L Gallagher  4   5 , Sterling C Johnson  1   2 , Sanjay Asthana  1   2   4 , Bruce P Hermann  1   2   5 , Mark A Sager  1   2 , Kaj Blennow  6   7   8   9 , Henrik Zetterberg  1   6   7   10   11   12   13 , Cynthia M Carlsson  1   2   5 , Gwendlyn Kollmorgen  13 , Clara Quijano-Rubio  14 , Dane B Cook  15   16 , Dena B Dubal  17 , Ozioma C Okonkwo  1   2
Affiliations

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

Mackenzie Jarchow et al. medRxiv. .

Update in

  • More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles.
    Jarchow M, Driscoll I, Breidenbach BM, Cook N, Gallagher CL, Johnson SC, Asthana S, Hermann BP, Sager MA, Blennow K, Zetterberg H, Carlsson CM, Kollmorgen G, Quijano-Rubio C, Cook DB, Dubal DB, Okonkwo OC. Jarchow M, et al. Alzheimers Dement (N Y). 2025 Aug 8;11(3):e70133. doi: 10.1002/trc2.70133. eCollection 2025 Jul-Sep. Alzheimers Dement (N Y). 2025. PMID: 40787159 Free PMC article.

Abstract

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-VSHET). 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 (VO2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VSHET compared to non-carriers (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, APOE4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO2peak and KLOTHO genotype on core AD biomarker levels in CSF [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 regard to pTau181, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VSHET and better cardiovascular fitness against unfavorable AD-related changes. Their potentially shared biological mechanisms will require future investigations.

Keywords: AD risk; Alzheimer’s disease; cerebrospinal fluid biomarkers; exercise; protective factors; resilience.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Statement All authors have no conflict of interest directly related to this study. S.C.J. has served on advisory boards for ALZPath and Enigma Biosciences. K.B. has served as a consultant, on advisory boards, or on data-monitoring committees for Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program (outside submitted work). H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). G.K. is a full-time employee of Roche Diagnostics GmbH. C. Q.-R. is a full-time employee of Roche Diagnostics International Ltd. D.B.D. has consulted for Unity Biotechnology and S.V. Health Investors. All other authors have no relevant disclosures to report.

Figures

Figure 1.
Figure 1.. KL-VS genotype differences in CSF pTau181 based on CRF (VO2peak).
KL-VSHET with high CRF had lower levels of pTau181. Abbreviations: AD = Alzheimer’s Disease; kg = kilogram; KL-VSHET = KLOTHO KL-VS heterozygote; KL-VSNC =KLOTHO KL-VS non-carrier; min = minute; mL = milliliter; pg = picograms; pTau181 = phosphorylated tau 181; VO2peak = peak oxygen consumption.
Figure 2.
Figure 2.. KL-VS differences in CSF A) tTau, B) Ng, C) YKL-40, and D) sTREM2 based on CRF (VO2peak).
KL-VSHET with high CRF had lower levels of neurodegeneration (tTau), synaptic dysfunction (Neurogranin) and neuroinflammation (sTREM2 and YKL-40). Abbreviations: KL-VSHET = KLOTHO KL-VS heterozygote; KL-VSNC =KLOTHO KL-VS non-carrier; kg = kilogram; min = minute ; mL = milliliter; ng = nanogram; pg = picogram; sTREM2 = soluble triggering receptor expressed on myeloid cells 2; tTau = total tau; VO2peak = peak oxygen consumption; YKL-40 = chitinase-3-like protein 1.
See this image and copyright information in PMC

References

    1. 2024 Alzheimer’s disease facts and figures. Alzheimers Dement, 2024. 20(5): p. 3708–3821. - PMC - PubMed
    1. Van Cauwenberghe C., Van Broeckhoven C., and Sleegers K., The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med, 2016. 18(5): p. 421–30. - PMC - PubMed
    1. Driscoll I., et al. AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes. Alzheimers Dement (Amst), 2022. 14(1): p. e12383. - PMC - PubMed
    1. Driscoll I., et al. Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes. J Alzheimers Dis, 2021. 79(3): p. 1297–1305. - PMC - PubMed
    1. Boots E.A., et al. Cardiorespiratory fitness is associated with brain structure, cognition, and mood in a middle-aged cohort at risk for Alzheimer’s disease. Brain Imaging Behav, 2015. 9(3): p. 639–49. - PMC - PubMed

Publication types