Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis

Abstract

ObjectiveTo determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer’s disease.DesignMendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables.SettingInternational Genomics of Alzheimer’s Project.Participants17 008 cases of Alzheimer’s disease and 37 154 controls.Main outcome measuresOdds ratio of Alzheimer’s per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis.ResultsThis study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer’s. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10−6) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10−5) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer’s (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer’s and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer’s. Genetically predicted alcohol consumption, serum folate, serum vitamin B12, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer’s disease.ConclusionThese results provide support that higher educational attainment is associated with a reduced risk of Alzheimer’s disease.

Lipid lowering and Alzheimer disease risk: A mendelian randomization study

“…The only major RCT to have addressed the effect of therapeutic LDL-C reduction on dementia risk to date found equal incidence (0.3%) in both simvastatin and placebo-allocated arms after 5 years of follow-up (albeit in a sample aged 40-80 years at baseline, thus including many individuals too young to be at risk of late onset AD). 33 Taking this finding alongside no prominent genetic associations observed for general LDL-C lowering (as others have observed previously), 34,35 and unclear or null results for HMGCR and 2 other drug targets, suggests that previous prospective observational associations of hyperlipidemia with AD, and of higher LDL-C with AD-related neuropathology, may have been overstated due to residual confounding. Associations of lipid-lowering drug use with AD risk would also be prone to bias via confounding by indication.…”

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

“…Although we did not evaluate causal associations using a Mendelian Randomization (MR) framework, our results have implications for the relationship between common genetic variants, CV-associated RFs and AD as an outcome. To date, MR studies have typically evaluated a single CV risk factor at a time, which is valid only if the genetic variants used for the MR influence AD exclusively via the selected CV-associated risk factor [25, 33]. For some variants, we found pleiotropy challenging the conventional MR approach for genes such as ABCA1 [17].…”

Preventing Alzheimer’s dementia

“…Larsson and colleagues found that more education was associated with a reduced risk of Alzheimer’s disease 4. A previous study linked the reduction in dementia prevalence over 12 years in the US to rising levels of education 8.…”

“…Larsson and colleagues found suggestive evidence that completing university and higher intelligence also predicted lower dementia risk 4. Few young people will prolong their education to avoid dementia decades later, but people in mid-to-late life may want to take steps to reduce their risk.…”

“…4 The authors examined 24 socioeconomic, dietary, lifestyle, health, and inflammatory factors for which genetic association data were available. They found that genes which predisposed to increased time in education were clearly associated with reduced risk of Alzheimer’s disease.…”