Year: 2020
Type: article
Abstract: Background Klotho‐VS heterozygosity (KL‐VSHET) has been linked to increased longevity and decreased rate of cognitive decline. In Alzheimer’s disease (AD), KL‐VSHET was recently shown to decrease both AD risk and amyloid burden, specifically, in APOE4+ 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‐VSHET 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‐VSHET 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 APOE4+ and APOE4‐ groups. A logistic regression model was implemented using the amyloid positive phenotype as the target outcome variable, KL‐VSHET 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‐VSHET significantly reduced the odds of being amyloid positive for APOE4+ 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 APOE4‐ 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 APOE4+ KL‐VSHET carriers and non‐heterozygotes (wild type homozygotes and minor allele homozygotes combined). Conclusion These findings provide additional evidence that for APOE4+ controls KL‐VSHET is associated with decreased amyloid burden. Elucidating the molecular mechanisms underlying this protective effect may lead to novel drug targets for AD.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.045360
Institution: Stanford University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3112919793