Most of the risk factors associated with Alzheimer’s disease from observational studies are likely wrong

Interesting article from Korologou-Linden et al 2022, “The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization”.

In this study, the authors used a Mendelian randomization approach to examine the causal relationships between various risk factors and Alzheimer’s disease. They used the UK Biobank, which has a massive sample size of >300,000 participants.

They found that genetic variation at one gene — APOE — is far and away the main mediator of Alzheimer’s disease genetic risk. This replicates why Alzheimer’s has been called a quasi-monogenic disease — APOE has that large of an effect.

They don’t hold anything back in the discussion, basically arguing that their study disagrees with observational studies because their methodology is better and observational studies are wrong, because observational studies can’t identify causality.

Instead, they suggest that associations with Alzheimer’s disease in observational studies are due to reverse causation (i.e. they are symptoms of early/prodromal Alzheimer’s disease, rather than causes) or simply due to selection bias.

This means that the things often associated with Alzheimer’s disease in observational studies — body mass index, blood pressure, and physical activity — might not actually increase the risk of disease. Interestingly, Alzheimer’s genetic risk in this study is actually associated with a lower body mass index and body fat in people 53-72 years old.

They also found that Alzheimer’s disease risk is associated with a lower fluid intelligence score, with no causal effect on educational attainment.

One caveat I have with the study is that I’d like to learn about the associations of these risk factors with other forms of cognitive impairment. Laypeople often use the term “Alzheimer’s” to refer to dementia or age-related cognitive impairment in general.

For example, does a higher genetic risk for elevated blood pressure or body mass index causally affect the risk for vascular-associated cognitive impairment? My guess is that they might, which might cause this study to be a bit misleading if the results were taken in the wrong way.

That said, there seems to be a real effect of APOE on the risk of cognitive impairment that is independent of classical risk factors body mass index, blood pressure, and physical activity. And this study helps to parse out how that might be occurring, which will hopefully help to develop better preventive approaches and treatments.