Sex and APOE genotype differences related to statin use in the aging population

Abstract

Background: Significant evidence suggests that the cholesterol-lowering statins can affect cognitive function and reduce the risk for Alzheimer's disease (AD) and dementia. These potential effects may be constrained by specific combinations of an individual's sex and apolipoprotein E (APOE) genotype.

Methods: Here we examine data from 252,327 UK Biobank participants, aged 55 or over, and compare the effects of statin use in males and females. We assessed difference in statin treatments taking a matched cohort approach, and identified key stratifiers using regression models and conditional inference trees. Using statistical modeling, we further evaluated the effect of statins on survival, cognitive decline over time, and on AD prevalence.

Results: We identified that in the selected population, males were older, had a higher level of education, better cognitive scores, higher incidence of cardiovascular and metabolic diseases, and a higher rate of statin use. We observed that males and those participants with an APOE ε4-positive genotype had higher probabilities of being treated with statins; while participants with an AD diagnosis had slightly lower probabilities. We found that use of statins was not significantly associated with overall higher rates of survival. However, when considering the interaction of statin use with sex, the results suggest higher survival rates in males treated with statins. Finally, examination of cognitive function indicates a potential beneficial effect of statins that is selective for APOE ε4-positive genotypes.

Discussion: Our evaluation of the aging population in a large cohort from the UK Biobank confirms sex and APOE genotype as fundamental risk stratifiers for AD and cognitive function, furthermore it extends them to the specific area of statin use, clarifying their specific interactions with treatments.

Keywords: APOE genotype; Alzheimer's disease; UK Biobank; aging population; statins.

FIGURE 1

Study aims and analysis flow chart. The main aims are illustrated in the top boxes, subaims and their implementation in the bottom. Aim I (orange) is to assess differences in treatments in the aging population and identify potential stratifiers for greater beneficial effects of statins, to achieve the aim we determined drug exposure and assess their differences, focusing on statins treatments. Aim II (green) is to evaluate the potential beneficial effects of statin use in the aging population on survival, Alzheimer's disease (AD) incidence and cognitive decline; to achieve the aim we used the matched cohort and the identified stratifiers, derived from Aim I

FIGURE 2

Drug exposure propensity scores in females (red) and males (blue) in the matched data sets

FIGURE 3

Results of the tree model. Each node shows the predicted class (Yes = treated or No = not treated). Color legend indicates the fitted value. Each tree node reports the predicted class, the predicted probability of the class (i.e., of being treated), and the actual percentage of observations in the node belonging to the class. Branches indicate the value of the variable for which the node was split. For example, the first node includes the whole population, split on the basis of sex; node two indicates the female population, where the probability of being treated is 0.45, the predicted class in “No”; node three indicates the male population, where the probability of being treated is 0.63, the predicted class in “Yes”

FIGURE 4

Comparison of statin users (red) and non‐users (gray) in the different population strata. For each of the four strata, the figure reports Reaction Time (RT) log‐transformed scores in time, and the RT Slope.yrs in the observation period