Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Abstract

ImportanceAn estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.ObjectiveTo comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.Design, Setting, and ParticipantsThis genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.ExposuresGenetically determined modifiable risk factors.Main Outcomes and MeasuresOdds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.ResultsThe EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.23 [95% CI, 1.01-1.50]).Conclusions and RelevanceThis genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Low- and High-Density Lipoprotein Cholesterol and Dementia Risk Over 17 Years of Follow-up Among Members of a Large Health Care Plan

“…6,9,12,17,20,36-38 Our finding of a U-shaped association between HDL-C and dementia is consistent with a recent study reporting an association between genetically determined high HDL-C and risk of AD using Mendelian randomization (OR per 1 SD increase = 1.10, 95% CI 1.05–1.16). 39 Together, our results additionally support recent literature suggesting complex effects of HDL-C on many diseases and mortality. 14,40 Because HDL-C is nonlinearly associated with risk of cardiovascular disease, 14 HDL-C may be nonlinearly associated with dementia through this increased risk of cardiovascular disease.…”

Association of genetically predicted 486 blood metabolites on the risk of Alzheimer’s disease: a Mendelian randomization study

“…To address this, we carefully scrutinized the IVs for metabolites using the Phenoscanner V2 website, 3 to determine whether each SNP was linked to established risk factors of AD. According to the study conducted by Luo et al (2023), the following risk factors for AD were considered, including educational attainment (Stern et al, 1994), HDL cholesterol (Reitz et al, 2010), smoking (Barnes and Yaffe, 2011), body mass index (Buchman et al, 2005), diastolic blood pressure (Qiu et al, 2003), and systolic blood pressure (Kivipelto et al, 2005). If SNPs exhibited a relationship with the potential confounders at a significance level of p < 1 × 10 −5 , we conducted an additional IVW analysis after excluding these SNPs to affirm the stability and accuracy of our results.…”

Artificial intelligence for dementia prevention

“…89 However, recent MR evidence has provided limited and inconclusive evidence of causal relationships of the modifiable risk factors presented by the Lancet Commission with dementia. 90,91 This may be in part due to effects of survival bias, particularly for risk factors that are significantly associated with earlier mortality, as well as loss of power due to heterogeneity in both the dementia outcome measure and riskfactor exposures. A description of these issues relating to MR and the potential for ML to help alleviate some of these problems in dementia prevention research is discussed in detail in the genetics and omics article also included in this special issue.…”

“…Other MR studies have also shown causal relationships between cognitive ability, education, and dementia 89 . However, recent MR evidence has provided limited and inconclusive evidence of causal relationships of the modifiable risk factors presented by the Lancet Commission with dementia 90,91 . This may be in part due to effects of survival bias, particularly for risk factors that are significantly associated with earlier mortality, as well as loss of power due to heterogeneity in both the dementia outcome measure and risk‐factor exposures.…”