Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

Abstract

This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of preventive strategies.

Keywords: Alzheimer's disease; biomarkers; cardiovascular risk; cerebrovascular dysfunction; dementia; hyperhomocysteinemia; hypertension; prevention; therapeutic strategies.

Figure 1.. Graphical hypothesis:

Hypertension and HHcy cause BBB permeability, endothelial cell stress, microhemorrhages, ROS production, inflammation, and cerebrovascular dysfunction, resulting in hypoperfusion, synaptic and neuronal loss, and cognitive impairment.