Everest regression and the effect of age in Alzheimer’s disease

A new-to-me concept is the idea of an Everest regression — “controlling for altitude, Everest is room temperature” — wherein you use a regression model to remove a critical property of an entity, and then go on to make inappropriate/confusing/misleading inferences about that entity.330px-everest_kalapatthar

My immediate thought is that this is an excellent analogy for one of my concerns regarding regressing out the effect of age in studies of Alzheimer’s disease (AD). It’s such a tricky topic.

On the one hand, not everyone who reaches advanced age develops the amyloid beta plaques and other features that defines the cluster of AD pathology. Whereas there are potentially other changes in brain biology that you will see in advanced aging but not AD, such loss of dendritic spines, epigenetic changes, and accumulation of senescent cells.

On the other hand, advanced age is the most important risk factor for AD and explains most of the variance in disease status on a population basis. Arguably, a key part of why some “oldest old” folks do not have AD are protective factors. There have also been suggestions that accelerating aging is part of AD pathophysiology; although, as far as I can tell, the evidence for this remains preliminary. From this perspective, advanced age in AD is like the high altitude of Everest — it’s one of the key associated features.

So if you are trying to find the effects of AD pathophysiology, for example in a study of postmortem human brain samples, should you adjust for the effect of age or not? This is a practical and tricky question without a clear answer. It probably depends on your underlying model of how AD develops in the first place.

So I think it’s worthwhile to be cognizant of the potential hazards of adjusting for age — namely, that you risk inadvertently performing an Everest regression and removing an important chunk of the pathophysiology that you actually want to understand.