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. 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.
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.
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