HYPERTENSIVE CEREBRAL MICROANGIOPATHY AND ALZHEIMER PATHOLOGY: SMALL VESSELS, BIG TOLLS

Abstract

Hypertension is a major cause of cognitive impairment on vascular bases, resulting in alterations in decisional and executive abilities, e.g., executive dysfunction, and impairment in multiple cognitive domains impacting negatively on the activities of daily living (dementia). However, hypertension has also emerged as a significant contributor in Alzheimer's dementia (AD), and as many as 50% of patients with clinically diagnosed AD also have evidence of vascular brain lesions, in which hypertension plays a key pathogenic role. This presentation will provide an overview of the basic mechanisms by which hypertension overlaps with AD pathology. N/A. Hypertension disrupts the link between neural activity and cerebral blood flow (neurovascular coupling) resulting in a state of chronic vascular insufficiency. Cerebral hypoperfusion, in concert with damage to the structure of cerebral blood vessels (arteriolosclerosis, lipohyalinosis), leads to lesions in susceptible regions of the white matter, e.g., periventricular white matter. The mechanisms include the synergistic interaction among vascular oxidative stress, inflammation, and dysfunction of the blood-brain barrier. Remarkably, the major source of oxidative stress are not vascular cells, but perivascular macrophages, innate immune cells nestled around penetrating arterioles and venules. As for the link with AD, hypertension has a profound impact on the production of amyloid-beta. Thus, hypertension leads to activation of beta-secretase and suppression of the vascular clearance of amyloid-beta, promoting amyloid accumulation in plaques and blood vessels (amyloid angiopathy). In agreement withe these preclinical observations, clinical-pathological studies indicate that midlife hypertension promotes accumulation of amyloid into the brain and neurofibrillary tangle formation. In addition, amyloid imaging studies have revealed that hypertension promotes amyloid accumulation, an effect that is reversible with hypertension treatment. Hypertension has a profound impact on the brain and has emerged as a key contributor to both vascular cognitive impairment and AD. The responsible mechanisms involve the synergistic/additive interactions between harmful effects on neurovascular structure and function, as well as increased production and retention of amyloid-beta. Therefore, maintaining vascular health by controlling hypertension may also stave off the deleterious effects of AD pathology on the brain and limit the devastating socioeconomic impact of age-related cognitive impairment.