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KLOTHO heterozygosi...
KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD
- Article/chapterEnglish2019
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2019-03-13
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Ovid Technologies (Wolters Kluwer Health),2019
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LIBRIS-ID:oai:gup.ub.gu.se/283343
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https://gup.ub.gu.se/publication/283343URI
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https://doi.org/10.1212/wnl.0000000000007323DOI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Objective To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated beta-amyloid (A beta) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's 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 A beta 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 A beta was different among KL-VS heterozygotes compared to noncarriers. APOE4 carriers exhibited greater A beta 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 A beta 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 A beta 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. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated A beta aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.
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Schultz, S. A.
(author)
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Oh, J. M.
(author)
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Darst, B. F.
(author)
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Ma, Y.
(author)
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Norton, D.
(author)
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Betthauser, T.
(author)
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Gallagher, C. L.
(author)
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Carlsson, C. M.
(author)
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Bendlin, B. B.
(author)
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Asthana, S.
(author)
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Hermann, B. P.
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Sager, M. A.
(author)
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Blennow, Kaj,1958Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xbleka
(author)
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Zetterberg, Henrik,1973Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xzethe
(author)
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Engelman, C. D.
(author)
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Christian, B. T.
(author)
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Johnson, S. C.
(author)
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Dubal, D. B.
(author)
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Okonkwo, O. C.
(author)
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Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
(creator_code:org_t)
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In:Neurology: Ovid Technologies (Wolters Kluwer Health)92:160028-38781526-632X
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Neurology
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Erickson, C. M.
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Schultz, S. A.
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Oh, J. M.
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Darst, B. F.
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Ma, Y.
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Norton, D.
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Betthauser, T.
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Gallagher, C. L.
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Carlsson, C. M.
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Bendlin, B. B.
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Asthana, S.
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Hermann, B. P.
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Sager, M. A.
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Blennow, Kaj, 19 ...
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Zetterberg, Henr ...
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Engelman, C. D.
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Christian, B. T.
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Johnson, S. C.
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Dubal, D. B.
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Okonkwo, O. C.
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- MEDICAL AND HEALTH SCIENCES
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Neurology
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University of Gothenburg