Erickson, CM; Schultz, SA; Oh, JM; Darst, BF; Ma, Y; Norton, D; Betthauser, T; ... Okonkwo, OC; + view all Erickson, CM; Schultz, SA; Oh, JM; Darst, BF; Ma, Y; Norton, D; Betthauser, T; Gallagher, CL; Carlsson, CM; Bendlin, BB; Asthana, S; Hermann, BP; Sager, MA; Blennow, K; Zetterberg, H; Engelman, CD; Christian, BT; Johnson, SC; Dubal, DB; Okonkwo, OC; - view fewer (2019) KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology 10.1212/WNL.0000000000007323. (In press).

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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 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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