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Klotho‐VS decreases probability of amyloid pet positivity in APOE4+ controls
Author(s) -
Eger Sarah J.,
Belloy Michael E.,
Guen Yann Le,
Napolioni Valerio,
Deters Kacie D.,
Mormino Elizabeth C.,
Greicius Michael D.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.045360
Subject(s) - apolipoprotein e , medicine , odds ratio , cohort , demography , logistic regression , population , oncology , endocrinology , psychology , disease , sociology
Background Klotho‐ VS heterozygosity ( KL ‐VS HET ) has been linked to increased longevity and decreased rate of cognitive decline. In Alzheimer’s disease (AD), KL ‐VS HET was recently shown to decrease both AD risk and amyloid burden, specifically, in APOE 4+ controls of Northwestern European descent within the age range of 60 to 80 years (Belloy et al., 2020). We investigated whether this protective effect of KL ‐VS HET could be replicated in a larger, independent cohort of cognitively normal subjects. Method The A4 study provides genotypic data and cross‐sectional amyloid PET cortical composite standard uptake value ratios (SUVr) of a large group of cognitively healthy older controls (CDR = 0 and MMSE 25‐30). We performed identity‐by‐decent analysis and SNPweights ancestry determination to select only unrelated individuals of Northwestern European ancestry (n = 2453) (Figure 1). With this sample, we examined the association between KL ‐VS HET and amyloid positivity (SUVr equal to or greater than 1.17, as determined by a Gaussian Mixture Modeling approach with a 2‐cluster solution), for each of the age strata (60‐80, 80+, full sample) and within the APOE 4+ and APOE 4‐ groups. A logistic regression model was implemented using the amyloid positive phenotype as the target outcome variable, KL ‐VS HET as the covariate of interest, adjusting for age, sex, and the first three genetic principal components to account for population structure. Result As predicted, KL ‐VS HET significantly reduced the odds of being amyloid positive for APOE 4+ controls within the age range of 60 to 80 years (OR = 0.72 [0.53, 0.98]; p = 0.041) (Table 1). This was not the case in APOE 4‐ controls in the same age range (OR = 0.93 [CI = 0.65, 0.13]; p = 0.703), nor in either of the 80+ age‐stratified analyses (Table 1). Figure 2 shows the logistic model for amyloid positivity and demonstrates the difference in probabilities of amyloid positivity between the APOE 4+ KL‐VS HET carriers and non‐heterozygotes (wild type homozygotes and minor allele homozygotes combined). Conclusion These findings provide additional evidence that for APOE 4+ controls KL ‐VS HET is associated with decreased amyloid burden. Elucidating the molecular mechanisms underlying this protective effect may lead to novel drug targets for AD.