Interactions between oestrogen and the renin angiotensin system - potential mechanisms for gender differences in Alzheimer's disease.

Interactions between oestrogen and the renin angiotensin system (RAS) are reviewed and explored from the perspective where these interactions may modulate risk of developing Alzheimer's disease (AD). AD is more prevalent in women than men, partly attributed to women's increased life expectancy; however underlying vascular differences may also contribute to AD risk. The RAS is a key regulator of blood pressure (BP). Pharmacological inhibition of angiotensin converting enzyme (ACE) and blockade of angiotensin II type 1 receptors (AT1R) are widely used to treat hypertension. Variation in components of the RAS such as ACE, neprilysin (NEP) and AT1R have been reported in AD, some of which may also directly alter AD neuropathology with changes in amyloid beta (Aβ) levels, cognitive decline and neuroinflammation. Recently, RAS inhibiting drugs have been shown to attenuate the incidence, progression and pathology of AD. Oestrogen is also thought to prevent hypertension by reducing the vasoconstrictive actions of the RAS. Reduced oestrogen levels in women during the menopausal transition may therefore increase their risk of hypertension and/or RAS-mediated changes to cerebrovascular or AD pathology. Specifically, oestrogen prevents the production and action of angiotensin II (Ang II), thought to exert harmful effects of the RAS in both hypertension and AD, while also potentially facilitating RAS-mediated Aβ degradation. These oestrogen-RAS interactions may partly explain current conflicting findings regarding oestrogen depletion and hormone therapy with respect to AD risk. Clinical trials targeting either the RAS or oestrogen systems for AD prevention and treatment should perhaps give closer attention to key biochemical components of these pathways as potential confounders to primary and secondary outcome measures.