It has not yet been convincingly shown in a therapeutic trial that controlling vascular factors reduces the risk of AD. The main reason is that, to date, no trial has been specifically designed with the prevention of dementia as the primary endpoint. Several trials using blood pressure lowering drugs in hypertensive subjects50-52
or in patients with a history of stroke53
have included dementia as a secondary endpoint. Their results remain inconclusive but they usually have poorly addressed the central issues of type of cognitive testing, duration of follow-up, calculation of study power based on cognitive events, type of patients included, and inclusion of neuroimaging criteria. The Syst-Eur study, the only trial to date that has shown that a blood pressure lowering treatment reduces the risk of AD, was based on only 32 cases of dementia in a cohort of 2,418 patients.51
An open extension of the follow-up of patients enrolled in that trial confirmed the results of the main study with a doubling of the number of cases but with the limitations of open studies.54
One of the most important questions in designing a prevention trial is the role of age on the relationship between vascular factors and the risk of dementia. Observational studies suggest that the relative risk of dementia associated with elevated blood pressure diminishes with age,55
a pattern that is also seen for stroke. Although this observed risk attenuation does not have an unequivocal explanation, it raises the issue of the efficacy of lowering blood pressure on the risk of dementia in older subjects. An alternative strategy would be to conduct a therapeutic trial on slightly younger subjects, between ages 65 and 75, for example. The major limitation of this type of trial is that the risk of dementia is relatively low in this age group. Thus, to demonstrate a clinically significant effect of blood pressure lowering, one would have to increase the number of subjects or the duration of follow-up (perhaps 10 years or more), which could be challenging in terms of the infrastructural and financial resources required to conduct such a trial.
The question of optimal age range is part of broader reflections on the definition of the optimal target population for therapeutic intervention. Cardiovascular studies published to date have recruited patients with certain vascular risk factors, such as hypertension or previous vascular event. A therapeutic prevention study of dementia should be done in patients with cognitive deterioration at risk for but who do not meet the criteria for dementia. The identification of this group of patients is more complicated than identifying subjects with vascular risk factors—this could be done by recruiting patients with cognitive complaints and a confirmed deficit on validated neuropsychological tests. As vascular pathologies may have greater impact on non-memory cognitive domains such as executive dysfunction and processing speed,56
inclusion criteria should not be restricted to only those with memory impairment but be broadened to individuals with deficits in any defined cognitive domain. The possibility of selecting subjects at high vascular risk within this group (patients with clinical risk factors or lesions due to small-vessel disease on neuroimaging) also becomes an important consideration.
Another major question concerns the type of workup required and the endpoint to be measured. MR imaging seems essential for selecting patients for the trial, for validating the impact of vascular factor reduction on the brain, and for understanding the variability of this effect across categories of patients. However, this type of evaluation may be difficult to achieve for large numbers of patients due to logistic considerations and the inherent high costs. Furthermore, the clinical endpoint in such a study also needs to be carefully defined. Using a continuous measure of cognitive function in addition to a specific threshold (which may only represent an arbitrary cutpoint) would provide a clinically meaningful and complementary quantitative measure of the effect of treatment.
Even a fundamental question such as the type of therapeutic intervention remains open. In the literature, there is no definitive argument to choose one type of intervention over another or to prefer one type of drug. Should one treat only one risk factor, or should a trial attempt an intervention on multiple risk factors? Should one treat subjects based on a threshold of risk, or should the intervention be given to all patients regardless of their estimated vascular risk? In subjects with high vascular risk, should the intervention replace or be added to their current treatment? Should one limit interventions to medication therapies or should non-medication intervention also be considered (e.g., exercise or diet)?
These set of questions, by no means exhaustive, demonstrate the complexities of designing such a trial. Options should be considered after careful reflection among experts as definitive scientific evidence for these options is lacking. However, one cannot be certain these choices will necessarily avoid reaching an inconclusive result, even in a carefully designed trial. Before launching a large therapeutic trial of long duration, it may be a reasonable option to conduct several smaller proof of concept studies on a limited number of precisely defined subjects such as those individuals at highest risk for dementia associated with vascular risk factors. This was done, for example, in a recently published trial of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a model of subcortical vascular dementia.41
Similar trials could potentially be designed in high risk populations such as these which then could be then tested in broader populations if initial results provide promise. Such potential approaches represent the important initial steps that must be taken in order to prevent the common forms of dementia in years to come.