Lag time: Alzheimer’s disease dementia begins in the brain decades before clinical detection. At what point(s) in the Alzheimer’s disease process are vascular risk factors important?
Window of susceptibility: The influence of vascular risk factors on dementia risk changes over the lifespan. At what age(s) is a vascular risk factor important?
Gene environment interactions: Certain vascular risk factors may confer different risks in people with difference genetic susceptibility. For example, many studies report that the association of vascular risk factors with dementia is dependent on the APOE e4 allele.62, 63
Cumulative impact: Certain risk factors may only be important or may have greater impact in the presence of other risk factors. Clusters of risk factors may be more important than individual risk factors.
Causal or concurrent: Some risk factors may predispose to Alzheimer’s disease decades before onset (i.e. APOE e4 allele) whereas others may accelerate cognitive dysfunction through entirely non-neurodegenerative mechanisms.
Measurement error: Certain risk factors can be difficult to measure or may vary with physiologic state or time of day. Measuring one vascular risk factor at one point in time (i.e. systolic blood pressure) may not accurately reflect long-term exposure. Measures reflecting cumulative burden, such as white matter injury burden or left ventricular mass, may be better markers of cumulative burden.
Give and take: Declining trends in some vascular risk factors (i.e. blood pressure levels) may be offset by increasing trends in others (i.e. diabetes).
