PROJECT SUMMARY/ABSTRACT:
Women have a higher prevalence of developing Alzheimer’s disease (AD) than men, which is believed to be
associated with the drop in neuroprotective female sex hormone estrogen (E2) at menopause. Although E2 is
well known for its neuroprotection, the underlying mechanisms are still largely unexplored, especially when it
comes to the impact of menopausal E2 levels on the pathophysiology of AD. Clearly, a reason for this is the
complexity of E2 signaling, which is mediated by brain area and cell-type specific estrogen receptor (ER)
isoforms interacting with many signaling pathways, of which brain cholesterol metabolism is of major relevance
to AD. Another reason is the controversies surrounding use of estrogenic compounds in menopausal hormone
therapies (HT). Observational studies put forward an inverse association between HT use and risk of AD.
However, several study limitations have raised important questions on the validity of these studies. To address
this gap in knowledge, multidisciplinary efforts are needed: Large epidemiological studies based on high quality
data on HT use, cardiometabolic disease history and other variables of pertinence including AD outcome are
needed in combination with experimental studies acquired in models relevant to human AD and menopause.
Our preliminary results suggest that the estrogen receptor beta (ERß) has significant neuroprotective effects in
an animal model relevant to human AD. Clear sex differences on AD pathology can be seen and the largest
neuroprotective effect of ERß is after induced menopause. In addition, our preliminary data supports ERß as a
node linking E2 signaling and brain cholesterol metabolism. In this 3-aim project, we will elaborate and expand
on these data. We will unambiguously determine the neuroprotective contribution of E2 and ERß in available
and novel innovative models of human AD and menopause. In parallel, we will utilize high quality epidemiological
data sets of over 88 000 postmenopausal women to study associations between HT use and AD outcome later
in life. Importantly, we will have access to detailed data on HT use (including timing of initiation in relation to
menopause), history of cardiovascular events, prevalence of cardiometabolic disease at baseline, genetic data
and data on multiple potential confounding factors. We will link our data to national patient registers to identify
AD as well as non-AD dementia diagnoses. In this way, we will accurately pinpoint the population-wide
contribution of E2 and HT to AD and non-AD dementia risk. By combining the epidemiologic data with
experimental studies we will also determine the effect of HT type, timing, genetic predispositions and contribution
of specific ER isoforms and brain cholesterol metabolism on markers of AD. We also have the possibility to
validate our data in postmortem AD brains. Overall, the combined expertise of our research team allows us to
compare data acquired across different epidemiologic and experimental data sets to accurately determine the
contribution of estrogenic neuroprotection to the sex differences observed in AD, which will contribute to better
informed recommendations for HT use and evaluation of ERß as a possible clinical target to combat AD.