KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD

Claire M Erickson; Stephanie A Schultz; Jennifer M Oh; Burcu F Darst; Yue Ma; Derek Norton; Tobey Betthauser; Catherine L Gallagher; Cynthia M Carlsson; Barbara B Bendlin; Sanjay Asthana; Bruce P Hermann; Mark A Sager; Kaj Blennow; Henrik Zetterberg; Corinne D Engelman; Bradley T Christian; Sterling C Johnson; Dena B Dubal; Ozioma C Okonkwo

doi:10.1212/WNL.0000000000007323

KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD

Neurology. 2019 Apr 16;92(16):e1878-e1889. doi: 10.1212/WNL.0000000000007323. Epub 2019 Mar 13.

Authors

Claire M Erickson¹, Stephanie A Schultz¹, Jennifer M Oh¹, Burcu F Darst¹, Yue Ma¹, Derek Norton¹, Tobey Betthauser¹, Catherine L Gallagher¹, Cynthia M Carlsson¹, Barbara B Bendlin¹, Sanjay Asthana¹, Bruce P Hermann¹, Mark A Sager¹, Kaj Blennow¹, Henrik Zetterberg¹, Corinne D Engelman¹, Bradley T Christian¹, Sterling C Johnson¹, Dena B Dubal¹, Ozioma C Okonkwo²

Affiliations

¹ From the Geriatric Research Education and Clinical Center (C.L.G., C.M.C., S.A., S.C.J., O.C.O.), William S. Middleton Memorial VA Hospital; Wisconsin Alzheimer's Disease Research Center (C.M.E., J.M.O., Y.M., C.M.C., B.B.B., S.A., B.P.H., M.A.S., C.D.E., B.T.C., S.C.J., O.C.O.); Departments of Population Health Sciences (B.F.D., C.D.E.), Neurology (C.L.G., B.P.H.), Radiology (M.A.S.), Medical Physics (T.B., B.T.C.), and Biostatistics & Medical Informatics (D.N.), University of Wisconsin School of Medicine and Public Health, Madison; Division of Biology and Biomedical Sciences (S.A.S.), Washington University in St. Louis, MO; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institute of Neurology (C.L.G., H.Z.), University College London, Queen Square; UK Dementia Research Institute (H.Z.), London; Wisconsin Alzheimer's Institute (C.M.C., B.B.B., S.A., B.P.H., M.A.S., C.D.E., S.C.J., O.C.O.), Madison; and Department of Neurology and Weill Institute for Neurosciences (D.B.D.), University of California, San Francisco.
² From the Geriatric Research Education and Clinical Center (C.L.G., C.M.C., S.A., S.C.J., O.C.O.), William S. Middleton Memorial VA Hospital; Wisconsin Alzheimer's Disease Research Center (C.M.E., J.M.O., Y.M., C.M.C., B.B.B., S.A., B.P.H., M.A.S., C.D.E., B.T.C., S.C.J., O.C.O.); Departments of Population Health Sciences (B.F.D., C.D.E.), Neurology (C.L.G., B.P.H.), Radiology (M.A.S.), Medical Physics (T.B., B.T.C.), and Biostatistics & Medical Informatics (D.N.), University of Wisconsin School of Medicine and Public Health, Madison; Division of Biology and Biomedical Sciences (S.A.S.), Washington University in St. Louis, MO; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institute of Neurology (C.L.G., H.Z.), University College London, Queen Square; UK Dementia Research Institute (H.Z.), London; Wisconsin Alzheimer's Institute (C.M.C., B.B.B., S.A., B.P.H., M.A.S., C.D.E., S.C.J., O.C.O.), Madison; and Department of Neurology and Weill Institute for Neurosciences (D.B.D.), University of California, San Francisco. ozioma@medicine.wisc.edu.

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 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 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.

MeSH terms

Adult
Alzheimer Disease / genetics*
Amyloid beta-Peptides / genetics
Apolipoprotein E4 / genetics*
Heterozygote
Humans
Longevity
Middle Aged
Positron-Emission Tomography
Wisconsin

Substances

Amyloid beta-Peptides
Apolipoprotein E4

Abstract

MeSH terms

Substances

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