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Cited by 110Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsGenetic Associations and Epidemiology

Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4

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Belloy, Michael E., Napolioni, Valerio, Han, Summer S., Le Guen, Yann, Greicius, Michael D., for the Alzheimer’s Disease Neuroimaging Initiative·2020·JAMA Neurology
DOI 10.1001/jamaneurol.2020.0414PMC PMC7154955
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Abstract

Importance: Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear. Objectives: To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4. Design, Setting, and Participants: This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019. Main Outcomes and Measures: The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling. Results: Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04). Conclusions and Relevance: The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.

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  • KLOTHO-VS heterozygosity has been reported to decrease Aβ plaque deposition, tau accumulation and tau-mediated cognitive impairment.

    “Of particular interest is the longevity-increasing KLOTHO-VS heterozygosity, which has been reported to operate by decreasing Aβ plaque deposition, tau accumulation and tau-mediated cognitive impairment23–26.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [24]

    The Results in the Abstract (page unavailable) associate KL-VS heterozygosity with lower brain Aβ on PET scans in cognitively normal APOE4 carriers aged 60–80, supporting the reduced-plaque-burden part of the claim. The paper does not establish that the variant operates by reducing Aβ, and the passages searched for tau accumulation and tau-mediated cognitive impairment do not support those parts. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Belloy, M. E., Napolioni, V., Han, S. S., Le Guen, Y., Greicius, M. D., & Initiative, F. T. A. D. N.
Affiliations
  • Department of Neurology and Neurological Sciences, Functional Imaging in Neuropsychiatric Disorders (FIND) Lab, Stanford University, Stanford, California
  • Stanford Medicine (US)
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2020-07-01
Volume
77
Issue
7
Pages
849
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2020.0414
PMC
PMC7154955
OpenAlex
W3016001416
Cited by
110
References
10
Citations by year
2026: 15 · 2025: 12 · 2024: 13 · 2023: 22 · 2022: 19 · 2021: 21 · 2020: 7
FWCI
12.29
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
Funders
  • Foundation for the National Institutes of Health (AG047366, AG060747)
  • Eli Lilly and Company
  • Pfizer
  • University of Southern California
  • Vanderbilt University
  • Oregon Health and Science University
  • University of Miami
  • F. Hoffmann-La Roche
  • Meso Scale Diagnostics
  • University of Washington
  • University of Pittsburgh
  • Rush University
  • Northern California Institute for Research and Education
  • Eisai
  • Servier
  • H. Lundbeck A/S
  • IXICO
  • National Institutes of Health (AGO5131, AG047366)
  • Genentech
  • Canadian Institutes of Health Research
  • Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
  • National Institute on Aging (AG047366, R01AG060747, AG-O5131, P50AG047366, AG060747, P30AG066515)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease risk, APOE ε4, genetic interactions, amyloid-beta, cerebrospinal fluid amyloid, amyloid PET, cognitive decline, aging, older adults, single nucleotide variants, competing risk regression, family-based association study, longitudinal cohort
MeSH terms
Klotho Proteins, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Genotype, Glucuronidase, Heterozygote, Humans, Male, Middle Aged, Mutation, Case-Control Studies, Amyloid beta-Peptides, Disease Progression, Genetic Predisposition to Disease, Apolipoprotein E4, Cognitive Dysfunction

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