Implications of the APOE gene in vascular dementia

By: Jade Côté

You may have heard about the APOE gene’s implication in Alzheimer's disease. The APOE-ε4 variation is considered to be the strongest genetic risk factor for sporadic Alzheimer’s disease. However, in recent years, compelling evidence has demonstrated an involvement of the APOE-ε4 gene in vascular dementia.

So, how does having the APOE-ε4 gene increase your risk of developing vascular dementia? First and foremost, let’s delve into its function and what is already known in Alzheimer's disease research.

What is the APOE gene?

The APOE gene encodes a protein called the apolipoprotein E (APOE) which plays a role in the transportation of cholesterol and other types of fat (i.e., lipids) through the bloodstream. This lipid regulation is necessary for the function, maintenance and repair of the central nervous system thus a crucial process for a healthy brain (Husain et al.).

APOE alleles and Alzheimer's disease

Three forms (i.e., alleles) of this gene exist which are the ε2, ε3, and ε4. An individual who inherits the ε4 allele is at an increased risk of developing Alzheimer’s disease. This is because this variation can reduce an individual’s ability to clear away the toxic form of the beta-amyloid protein (i.e., Amyloid-β42). Abnormal levels of this protein clump together and form amyloid plaques – a hallmark of Alzheimer’s disease (Wildsmith et al.). Research on the APOE-ε3 has mainly put forth its neutrality with regards to this disease, whilst evidence on the APOE-ε2 has consistently demonstrated its protective role against Alzheimer’s disease (Li et al., Martins et al.).

Now, you may be asking, do we all express APOE? What are my chances of getting either of the variants?

Everyone has two alleles of the APOE passed down from their biological mother and father. The allele combination determines your genotype. The ε3 allele and the ε3/ε3 genotype are the most common amongst individuals, whilst the ε2 allele is the rarest form with a prevalence of 8.4% globally. Expression of the APOE-ε4 is represented in 13.7% of individuals worldwide and the prevalence ranges from 39% to 65% in persons with Alzheimer's disease. (Farrer et al.)

As a further matter, it is important to note that the APOE gene works in a ‘’dose-dependent manner’’, meaning that individuals inheriting both ε4 alleles from their parents (i.e., ε4/ε4 genotype) have an increased risk of developing Alzheimer’s disease compared to individuals with only one ε4 allele (i.e., ε4/ε3 or ε4/ε2).

The APOE-ε4 gene and vascular dementia

In recent years, more evidence has supported an implication of the APOE-ε4 gene in vascular dementia (Skrobot et al.). Cognitive impairment can occur when there is insufficient/reduced blood flow to the brain (I.e., hypoperfusion), thus termed vascular dementia.

Notably, positive carriership is related to poorer outcome following a vascular event such as a stroke thereby increasing your risk for vascular dementia (Biffi et al.), but to a lesser extent than Alzheimer’s disease (Rohn et al.).

Recent studies demonstrated that the APOE-ε4 gene was associated with increased inflammation, which can cause damage to the vasculature in the brain, thus influencing blood circulation. Furthermore, the APOE-ε4 gene has been directly linked to the breakdown of the blood brain barrier. This, in turn, alters its permeability and causes reduced blood flow to the brain, therefore resulting in cognitive impairment. (Montagne et al.)(Civeira-Marín et al.)   

The APOE-ε4 gene runs in my family, what should I do?

Although having the gene confers an increased risk for Alzheimer’s disease and vascular dementia, it does not guarantee onset. In fact, some individuals with the APOE-ε4 gene will never go on to develop Alzheimer’s disease or vascular dementia. See more on this here.

Both diseases are complex, and causality is determined by a myriad of factors such as lifestyle, genetics and environment. Therefore, an individual adopting a healthy and active lifestyle can reduce the impact of genetics in this highly complex equation.

To learn more about vascular dementia risk factors, visit the Alzheimer Society of Canada’s website.

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About the author

Jade Côté is a research assistant at the Montreal Heart Institute- she completed her master's in psychology with specialization in Neuropsychology at Maastricht University and studied the APOE-ε4 gene.

Specifically, her work aimed to evaluate the combined effect of the APOE-ε4 gene and diabetes mellitus on Alzheimer's disease biomarkers and cognition using data from the PRIME study. Given the literature showing a mediator effect of the APOE-ε4 gene and conflicting results on the influence of diabetes on Alzheimer's disease biomarker, it was hypothesized that diabetes would be associated with Alzheimer’s disease biomarkers only in APOE-ε4 carriers, and that participants with both diabetes and the APOE-ε4 gene would have worse cognitive performance on delayed memory and executive function measures compared to participants without diabetes or the APOE-ε4 gene.

Her findings add to a large body of research that aims to elucidate the mechanism behind the relationship between diabetes and Alzheimer's disease, with the objective to create valid prevention strategies and improve medical care by personalizing treatment plans using genetic profiling.

Jade hopes to continue her research in cognitive decline prevention by assessing the impacts of physical and cognitive interventions in the elderly.