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Cited by 70Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

KLOTHO heterozygosity attenuates APOE4 -related amyloid burden in preclinical AD

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Erickson, Claire M., Schultz, Stephanie A., Oh, Jennifer M., Darst, Burcu F., Ma, Yue, Norton, Derek, Betthauser, Tobey, Gallagher, Catherine L. +12 more·2019·Neurology
DOI 10.1212/wnl.0000000000007323PMC PMC6550504
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Abstract

Objective To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Methods Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer9s Prevention and the Wisconsin Alzheimer9s Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aβ was different among KL-VS heterozygotes compared to noncarriers. Results APOE4 carriers exhibited greater Aβ burden than APOE4-negative participants. This effect was stronger in CSF (t = −5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: t = −5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aβ burden than APOE4-negative individuals (CSF: t = −1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. Conclusion In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

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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 [23]

    The Discussion reports that KL-VS heterozygosity attenuated APOE4-related Aβ burden in cognitively normal, late-middle-aged adults at risk for Alzheimer’s disease. The paper does not establish that heterozygosity decreases Aβ deposition generally or that it operates by this mechanism; its participants were cognitively normal, and the passages do not report reduced tau accumulation or tau-mediated cognitive impairment. (LLM, conf=0.90)

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Authors
Erickson, C. M., Schultz, S. A., Oh, J. M., Darst, B. F., Ma, Y., Norton, D., Betthauser, T., Gallagher, C. L., Carlsson, C. M., Bendlin, B. B., Asthana, S., Hermann, B. P., Sager, M. A., Blennow, K., Zetterberg, H., Engelman, C. D., Christian, B. T., Johnson, S. C., Dubal, D. B., & Okonkwo, O. C.
Affiliations
University of California, San Francisco (US)
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-04-16
Volume
92
Issue
16
Pages
e1878-e1889
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000007323
PMC
PMC6550504
OpenAlex
W2922355275
Cited by
70
References
5
Citations by year
2026: 6 · 2025: 12 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 15 · 2020: 12 · 2019: 1
FWCI
6.35
Type
journal article
Language
en
Open access
Locations
  • Neurology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs (#I01CX000555)
  • Göteborgs Universitet
  • Sahlgrenska Akademin
  • National Institute on Aging (R01AG037639, R01AG054047, P50AG033514, R01AG062285, R01AG027161, P30AG062715)
  • National Institute of Neurological Disorders and Stroke (R01NS092918)
  • U.S. National Library of Medicine (T15LM007359)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090256)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Klotho, APOE ε4, amyloid burden, preclinical Alzheimer's disease, heterozygosity, amyloid PET, cerebrospinal fluid biomarkers, late middle-aged adults, Alzheimer's disease risk
MeSH terms
Adult, Alzheimer Disease, Heterozygote, Humans, Longevity, Middle Aged, Wisconsin, Amyloid beta-Peptides, Positron-Emission Tomography, Apolipoprotein E4

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