Alzheimer’s disease is the most common form of dementia, and the prodromal phases of Alzheimer’s disease can last for decades. Vascular dementia is the second most common form of dementia and is distinguished from Alzheimer’s disease by evidence of previous stroke or hemorrhage and current cerebrovascular disease. A compiled group of vascular-related dementias (vascular dementia and unspecified dementia) is often referred to as non-Alzheimer dementia. Recent evidence indicates that preventing dementia by lifestyle interventions early in life with a focus on reducing cardiovascular risk factors is a promising strategy for reducing future risk. Approximately 40% of dementia cases is estimated to be preventable by targeting modifiable, primarily cardiovascular risk factors. The aim of this review is to describe the association between risk factors for atherosclerotic cardiovascular disease and the risk of Alzheimer’s disease and non-Alzheimer dementia by providing an overview of the current evidence and to shed light on possible shared pathogenic pathways between dementia and cardiovascular disease. The included risk factors are body mass index (BMI); plasma triglyceride-, high-density lipoprotein (HDL) cholesterol-, low-density lipoprotein (LDL) cholesterol-, and total cholesterol concentrations; hypertension; diabetes; non-alcoholic fatty liver disease (NAFLD); physical inactivity; smoking; diet; the gut microbiome; and genetics. Furthermore, we aim to disentangle the difference between associations of risk factors in midlife as compared with in late life.

Left panel: results of three recent randomized trials of triglyceride-lowering drugs on lipids, lipoproteins, apolipoprotein B (apoB), and C-reactive protein (CRP), and on major adverse cardiovascular events (MACE) in patients at high cardiovascular risk with mild to moderately elevated triglycerides, low LDL cholesterol (LDL-C), and on statin therapy. REDUCE-IT randomized 8179 patients to 2 g of icosapent ethyl (EPA) twice daily vs. mineral oil.¹ STRENGTH randomized 13 078 patients to 4 g per day of a carboxylic acid formulation of EPA and docosahexanoic acid (DHA) vs. corn oil.² PROMINENT randomized 10 497 patients with type 2 diabetes to pemafibrate (a selective PPARα modulator) 0.2 mg twice daily vs. placebo.³ Although all active treatments were associated with reductions in triglycerides, the effects on other lipids, lipoproteins, apoB, and CRP differed between studies. Only REDUCE-IT was associated with a robust 25% reduction in cardiovascular risk; however, this might be partially driven by a 10% increase in LDL-C and a 32% increase in CRP caused by the comparator mineral oil.⁴ Right panel: results of the present study by Björnson et al.⁵ The study included individual participant data from the UK Biobank (n = 502 460) with available genetic data and standard lipid profiles including apoB to identify all single nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (remnant-C) and LDL-C in GWAS analyses. To investigate the per-particle atherogenicity (change in CHD risk per unit change in particle number, i.e. per unit change in apoB) of TRL/remnants and LDL, the effect size (β coefficient) of each SNP on TRL/remnant-C and LDL-C (markers of the abundance of particles) was plotted against its effect size on apoB (a marker of particle number). These SNPs fell into two groups, one with a much greater effect on TRL/remnant-C per unit difference in apoB than the other. Accordingly, SNPs were divided into two clusters. Cluster 1 contained SNPs involved in receptor-mediated clearance that affected LDL-C more than TRL/remnant-C (median ratio = 0.19), whereas cluster 2 contained SNPs with effects on triglyceride lipolysis and had a much greater effect on TRL/remnant-C (median ratio = 0.59). The CHD risk per standard deviation (SD) higher apoB was considerably higher for cluster 2 vs. cluster 1 SNPs, implying that TRL/remnant particles have a substantially greater per particle atherogenicity than LDL. RCT, randomized clinical trial; TG, triglyceride; non-HDL-C, non-HDL cholesterol (total cholesterol minus HDL cholesterol); HR, hazard ratio; TRL, triglyceride-rich lipoprotein; remnant-C, remnant cholesterol; OR, odds ratio; CHD, coronary heart disease; ND, no data; GWAS, genome-wide association study.