Antihypertensives for combating dementia? A perspective on candidate molecular mechanisms and population-based prevention

Abstract

Age-related increases in prevalent dementia over the next 30-40 years risk collapsing medical resources or radically altering the way we treat patients. Better prevention of dementia therefore needs to be one of our highest medical priorities. We propose a perspective on the pathological basis of dementia based on a cerebrovascular-Alzheimer disease spectrum that provides a more powerful explanatory framework when considering the impact of possible public health interventions. With this in mind, a synthesis of evidence from basic, clinical and epidemiological studies indeed suggests that the enhanced treatment of hypertension could be effective for the primary prevention of dementia of either Alzheimer or vascular etiology. In particular, we focus on candidate preventative mechanisms, including reduced cerebrovascular disease, disruption of hypoxia-dependent amyloidogenesis and the potential neuroprotective properties of calcium channel blockers. Following the successful translation of large, long-term and resource-intense trials in cardiology into improved vascular health outcomes in many countries, new multinational prevention trials with dementia-related primary outcomes are now urgently required.

Figure 1

Conceptual diagram depicting the most common type of dementia being of mixed pathology—a combination of AD and CVD. Reducing vascular risk factors not only will have an impact on the CVD end of the spectrum but also will reduce dementia risk in general.

Figure 2

Fluid-attenuated inversion recovery-weighted magnetic resonance imaging of an elderly cognitively impaired individual with severe white matter disease (hyperintense lesions around ventricles, arrow) as well as severe hippocampal atrophy (highlighted boxed area).

Figure 3

A 5-year hazard risk for incident dementia as a function of number of cardiovascular risk factors (adapted from text of Luchsinger et al.).

Figure 4

The hypothetical disease pathway for development of mixed dementia. AHT medication may have three hypothetical preventative actions: direct antipressor effects, neuroprotection and disease modification.