AJND Copyright © Since 2012-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711, USA
Am J Neurodegener Dis 2012;1(3):266-279

Original Article
Interactions between oestrogen and the renin angiotensin system -
potential mechanisms for gender differences in Alzheimer’s disease

Thomas Simon O’Hagan, Whitney Wharton, Patrick G Kehoe

Dementia Research Group, John James Laboratories, School of Clinical Sciences, University of Bristol, Frenchay
Hospital, Bristol, BS16 1LE; University of Wisconsin, School of Medicine and Public Health, Madison, WI 53792, USA;
Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI
53705 USA; Wisconsin Alzheimer’s Disease Research Center Madison, WI 53792 USA

Received October 12, 2012; Accepted November 9, 2012; Epub November 18, 2012; Published November 30, 2012

Abstract: 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 attenuating the vasoconstrictive actions of the
RAS. Reduced oestrogen levels in women during the menopausal transition may therefore increased their risk
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. (AJND1210005).

Keywords: Oestrogen, renin angiotensin system (RAS), gender difference, Alzheimer’s disease

Address all correspondence to:
Dr. Patrick G Kehoe
Dementia Research Group, John James Laboratories
School of Clinical Sciences, University of Bristol
Frenchay Hospital, Bristol, BS16 1LE, United Kingdom.
Tel: +44-117-340-6607
E-mail: Patrick.Kehoe@bristol.ac.uk