Causal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome

Abstract

Objective The purpose of this study was to infer causal relationships between 22 previously reported risk factors for Alzheimer's disease (AD) and the “AD phenome”: AD, AD age of onset (AAOS), hippocampal volume, cortical surface area and thickness, cerebrospinal fluid (CSF) levels of amyloid‐β (Aβ42), tau, and ptau181, and the neuropathological burden of neuritic plaques, neurofibrillary tangles (NFTs), and vascular brain injury (VBI). Methods Polygenic risk scores (PRS) for the 22 risk factors were computed in 26,431 AD cases/controls and the association with AD was evaluated using logistic regression. Two‐sample Mendelian randomization (MR) was used to infer the causal effect of risk factors on the AD phenome. Results PRS for increased education and diastolic blood pressure were associated with reduced risk for AD. MR indicated that only education was causally associated with reduced risk of AD, delayed AAOS, and increased cortical surface area and thickness. Total‐ and LDL‐cholesterol levels were causally associated with increased neuritic plaque burden, although the effects were driven by single nucleotide polymorphisms (SNPs) within the APOE locus. Diastolic blood pressure and pulse pressure are causally associated with increased risk of VBI. Furthermore, total cholesterol was associated with decreased hippocampal volume; smoking initiation with decreased cortical thickness; type 2 diabetes with an earlier AAOS; and sleep duration with increased cortical thickness. Interpretation Our comprehensive examination of the genetic evidence for the causal relationships between previously reported risk factors in AD using PRS and MR supports a causal role for education, blood pressure, cholesterol levels, smoking, and diabetes with the AD phenome. ANN NEUROL 2021;89:54–65

The Genetic Architecture of Alzheimer’s Disease Risk: A Genomic Structural Equation Modelling Study

“…Our findings here support previous work that found AD to have a greater amount of unique genetic variance compared to psychiatric, behavioural or cardiometabolic traits [11,12]. The strongest bivariate correlation for AD was with less education, which is consistent with previous Mendelian randomisation results, suggesting a causal effect of less education on risk of AD [27][28][29]. Our study goes beyond such bivariate approaches by identifying clusters of shared variance between traits that might not meet the stringent power requirements of Mendelian randomisation [30,31], and highlighting smaller, yet potentially meaningful, overlap in genetic pathways.…”

“…For example, since having less education is not only significantly genetically correlated with AD, but also all other risk factors (except for hearing difficulty), and it is one of the highest loading traits for the Common Factor, it seems probable that the common liability between less education may be a mediating or moderating driver of the shared relationship with AD and its other risk factors via extensive shared pleiotropy. Previous studies measuring bivariate associations have highlighted a causal genetic link between less education and AD [27][28][29] and its early life occurrence makes it a stronger candidate for being on the causal pathway to AD than other proposed risk factors that seem to exert risk later in life so are more likely to be linked by reverse causation [5]. Loneliness may also have a direct shared component with AD, but further work to identify the underlying SNPs in this model are needed to establish this.…”

Genetically Determined Blood Pressure, Antihypertensive Medications, and Risk of Alzheimer’s Disease: A Mendelian Randomization Study

“…However, Larsson and colleagues exploited more SNPs, nding no signi cant association between SBP level and AD. [9] Andrews and colleagues also found a null association between polygenic risk scores (PRS) for increased SBP and AD risk [23].…”

“…Alternatively, this nding might be mediated by increased arterial stiffness, which is associated with decreased DBP, although we did not nd a direct association between PP, a proxy marker of arterial stiffness, and AD risk. One recent MR analysis observed association between high BP and vascular brain injury (VBI), which suggests that while reducing BP in late life may have limited utility in the prevention of AD, it may reduce the risk of vascular dementia by reducing the risk of VBI, but not speci cally affect the risk of AD [23].…”

Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer’s disease: a Mendelian randomization study

“…However, another study exploited more SNPs (N= 93), nding no signi cant association between SBP level and AD [9]. Andrews et al also found a null association between polygenic risk score (PRS, prioritizing putative causal risk factor score) for increased SBP and AD risk [10]. The differences among the research results may lie in the differences in the number of SNPs included, the statistical power and analytical bias, thus higher-quality studies with larger sample size are urgently needed to corroborate this question.…”