Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies

Abstract

Background:Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear.Objective:To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia.Methods:We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality.Results:We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer’s disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects.Conclusions:Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

“…In line with our results, studies have reported significant genetic overlap between AD and plasma lipids [13, 53]. However, others have found weak casual evidence for plasma lipids and AD using MR [54] or no association between these traits using LD score regression [55]. The methods used in these studies may help explain differences from our results to some extent.…”

Leukocyte Telomere Length Is Related to Brain Parenchymal Fraction and Attention/Speed in the Elderly: Results of the Austrian Stroke Prevention Study

“…In this model, we hypothesize that longer LTL plays a causal and protective role in the process of brain aging. Mendelian randomization studies suggested a causal role for telomeres for Alzheimer's Disease (22,23). Its effect on BPF might be mediated by two major pathways, one linked to the development of the brain up to puberty and the second related to aging.…”

Role of Vitamin D in Preventing and Treating Selected Extraskeletal Diseases—An Umbrella Review

“…We identified four publications that applied a Mendelian randomisation approach to address causal inference [157][158][159][160]. Kuzma et al [160] investigated the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Genetic evidence supported a causal association between telomere length and Alzheimer's disease, whereas limited evidence for other risk factors including vitamin D status was found.…”

“…Results 13 SRs (including eight MAs) [100,[145][146][147][148][149][150][151][152][153][154][155][156] on vitamin D and risk of dementia and/or cognitive decline were included in this analysis (Supplemental Tables S14-S17 and Figure S4). In addition, four Mendelian randomisation studies were considered [157][158][159][160]. The quality of the publications according to AMSTAR 2 is summarised in Supplemental Tables S14-S17.…”