Abstract
Background
Cardiovascular disease (CVD) risk factors including obesity, hypertension and sedentary behaviour are frequently investigated for their contribution to Alzheimer's Disease (AD) risk. In the current study, we examine AD risk by combining a newly developed CVD index with a targeted selection of ∼2000 single nucleotide polymorphisms (SNPs).
Methods
Cognitively normal (CN) and AD participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were given one point for each of the following nine CVD risk factors; 1) BMI ≥25; 2) systolic blood pressure ≥140mmHg, and/or diastolic ≥90mmHg, and/or a history of hypertension; a history of 3) angina; 4) heart attack; 5) stroke; 6) smoking; 7) diabetes; 8) low physical activity, and; 9) elevated homocysteine level (>10μmol/L). Points were summed to produce an index ranging from 0-9, with a higher score indicating higher CVD risk. Scores were then converted to a binary factor, with ≤2 assigned a ‘zero’, and ≥3 assigned a ‘one’. Data were then analysed in the presence/absence of at least one polymorphic allele for each of the ∼2000 SNPs to evaluate AD risk, I.e. CN-vs-AD.
Results
Assessing the interaction between SNP and CVD index for AD risk, we identified 18 SNPs from 10 genes (APP, ACO1, AKR1C3, COMT, CP, CYP11B2, FTH1, FTL, HSD11B2, PPAP2B) with a p-value <2.5*10−5. Of these associations, two SNPs in the CYP11B2 gene in combination with the binary CVD index had the strongest relationship with AD, with the presence of both minor allele and at least three CVD risk factors contributing to ∼5-fold increase in AD risk (rs6438- OR:5.26 [95%CI:2.76–10.1], p=4.90*10−7, rs4536- OR:4.99 [95%CI:2.55–9.77], p=2.63*10−6). Furthermore, a SNP in the PPAP2B gene in combination with the presence of at least 3 CVD risk factors was associated with ∼7-fold increase in AD risk (OR:7.22 [95%CI:3.15-16.52], p=2.90*10−6). The remaining SNPs in combination with at least three CVD risk factors yielded similar increases in AD risk.
Conclusions
Further work is needed to characterise the complex relationship between genetics and lifestyle and understand their combined contribution to AD risk.