Alzheimer's disease might be argued to be a lifestyle condition, but it is not as much of a lifestyle condition as type 2 diabetes - it is not as reliably connected to lifestyle choices. Not everyone who lets themselves go, becoming fat and sedentary, winds up with a diagnosis of Alzheimer's disease, despite it being clear from the data and what is known of the mechanisms involved that both of those environmental circumstances are contributing risk factors. So why do only some people with the risk factors suffer Alzheimer's disease? Why do some people without the risk factors suffer from Alzheimer's disease? Is there anything useful to be learned at this stage from comparing the biochemistry of various groups with and without the condition?
These are questions very focused on how exactly the condition progresses, which stands a little in opposition to the strategy of attacking all of the known root causes of disease - in other words striving to remove all of the accumulated protein aggregates thought to cause the condition. In the case of Alzheimer's disease, that strategy hasn't been doing so well to date; the amyloid clearance field is a graveyard of failed clinical trials. Does this mean there is vital information yet to be discovered, or does it mean that the research community hasn't been clearing enough molecular waste, and both tau and amyloid must be reduced in the aging brain in order to see benefits? Arguments can be made either way.
The two primary histopathological changes to the brain due to Alzheimer's disease (AD) are the deposition of amyloid and tau. These two AD-related brain changes are the primary underlying causes of neurodegeneration and cognitive dysfunction which ultimately leads to dementia. As human longevity increases, and AD dementia increasingly becomes a major societal burden, finding pathways that lead to brain aging without AD pathologies (ADP) are critical.
Currently, much of the research has been focused on resilience or cognitive reserve, wherein the focus has been on discovering how and why individuals are able to remain clinically unimpaired or cognitively normal despite ADP. However, it is important to investigate, using surrogates of amyloid and tau pathologies via cerebrospinal fluid (CSF) and positron emission tomography (PET), why majority of individuals develop ADP as they age and how some oldest old individuals are able to age without significant ADP. The latter individuals are called "exceptional agers" without ADP.
There are three testable hypotheses. First, discovering and quantifying links between risk factors and early ADP changes in midlife using longitudinal biomarker studies will be fundamental to understanding why the majority of individuals deviate from normal aging to the AD pathway. Second, a risk factor may have quantifiably greater impact as a trigger and/or accelerator on a specific component of the biomarker cascade (amyloid, tau, neurodegeneration). Finally, and most importantly, while each risk factor may have a different mechanism of action on AD biomarkers, "exceptional aging" and protection against AD dementia will come from "net sum" protection against all components of the biomarker cascade.
While important strides have been made in identifying risk factors for AD dementia incidence, further efforts are needed to translate these into effective preventive strategies. Using biomarker studies for understanding the mechanism of action, effect size estimation, selection of appropriate end-points, and better subject recruitment based on subpopulation effects are fundamental for better design and success of prevention trials.