Belloy, ME;
Eger, SJ;
Le Guen, Y;
Napolioni, V;
Deters, KD;
Yang, H-S;
Scelsi, MA;
... Alzheimer's Disease Neuroimaging Initiative; + view all
(2021)
KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers.
Neurobiology of Aging
, 101
pp. 123-129.
10.1016/j.neurobiolaging.2021.01.008.
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Abstract
KLOTHO∗VS heterozygosity (KL∗VSHET+) was recently shown to be associated with reduced risk of Alzheimer’s disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VSHET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across 5 independent studies, comprising 3581 pre-clinical participants ages 60–80, to investigate whether KL∗VSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VSHET+ reduced the risk of amyloid positivity in APOE∗4 carriers (odds ratio = 0.67 [0.52–0.88]; p = 3.5 × 10−3), but not in APOE∗4 non-carriers (odds ratio = 0.94 [0.73–1.21]; p = 0.63). The combination of APOE∗4 and KL∗VS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE∗4 and AD are warranted.
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