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Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort
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In conclusion, we show that HRT had more cognitive benefits in APOE4 carriers. APOE4 women on HRT performed better in delayed memory tasks and had large entorhinal and amygdala volumes than non-HRT users. Earlier HRT initiation was associated with larger hippocampus volume, an effect only seen in APOE4 carriers. These results highlight the importance of personalized medicine in the prevention of AD. This work provides the rationale for the conduct of an RCT which examines the impact of early (perimenopause or early post-menopause) HRT introduction on cognition and brain atrophy according to APOE4 carrier status to confirm the observed associations. Finally, the findings highlight the heterogenous nature of AD with the effectiveness of HRT in APOE4 carriers only, indicating differences in the mechanistic basis of cognitive decline and pathology relative to non-carriers.
The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.
The analysis used baseline data from participants in the European Prevention of Alzheimer's Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.
APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6-10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= -0.555, p=0.035) and left hippocampal volumes (standardized β= -0.577, p=0.028) only in APOE4 carriers.
HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.
More than two-thirds of Alzheimer's disease (AD) patients are women [1, 2]. The recent 2022 Global Burden of Disease (GBD) report shows that the age-standardized dementia prevalence is higher in women (female-to-male ratio= 1.69 (1.64-1.73)) [3]. Thus, higher incident cases in women cannot simply be explained by greater life expectancy [2, 4, 5]. The neurophysiological impact of estrogen decline during menopause is emerging as the main aetiological basis for the higher prevalence of AD in females [6, 7]. Estrogen receptors are expressed throughout the brain, with estrogen regulating multiple physiological processes including neuronal synaptic plasticity, neuroinflammation, brain macronutrient utilization, DHA metabolism, and blood brain barrier (BBB) integrity [8,9,10]. Consequently, the use of hormone replacement therapy (HRT) during the menopausal transition and post-menopausal period is being considered as a strategy to mitigate cognitive decline. Early observation studies showed that oral estrogen may be protective against dementia [11], with a risk reduction of 34% in an early meta-analysis [12]. However, results of clinical trials have been inconsistent [13, 14] or even shown harmful effects [15]. For example, the Women's Health Initiative Memory study (WHIMS), in women over the age of 65 years, showed that the use of oral estrogen alone (conjugated Equine Estrogen, CEE) or CEE plus medroxyprogesterone acetate (MPA) resulted in a 49% or 76% increased risk of dementia respectively [16]. A recent meta-analysis showed that the negative effect of HRT on global cognition has been predominately tested in those >60years. In this meta-analysis, only two studies recruited participants <60years, with one showing no impact of oral estrogen on global cognition and the second showing a positive impact of CEE plus MPA on global cognition [17]. Limited recent, mainly preclinical, data has identified APOE genotype and age of HRT initiation as potential modulators of the HRT cognitive response [7, 18, 19].
APOE genotype is the most important common genetic determinant of cognitive decline and AD risk. In Caucasians, a 3-4-fold and 12-15-fold increased risk of AD is evident in APOE3/E4 and APOE4/E4 relative to the wild-type APOE3/E3 genotype with several years earlier age of onset [20]. A greater penetrance of an APOE4 genotype in females, first reported in the early 90s [6, 21], is likely to be an important contributor to the higher AD rates in women [6]. This somewhat understudied association has been reiterated over the years [22,23,24]. More decline in MMSE, immediate and delayed memory scores was observed with an increasing number of APOE4 alleles in women compared to men [25].
The other possible contributor of inconsistencies to the impact of HRT on AD risk is the timing of its initiation [26]. For cognition and AD risk, HRT intervention may be most beneficial if introduced before a certain threshold of neuronal damage accumulates [7], with potentially a 'critical window' where HRT can be neuroprotective [27, 28]. This critical window is likely to be during the transition to menopause, where gradual estrogen decline increases the brain liability to AD-related pathologies. In a UK BIOBANK analysis, despite showing that cumulative life-time estrogen exposure was associated with increased brain aging (measured by cortical thickness, and cortical and subcortical volumes), a subgroup analysis revealed that women who started HRT earlier had less apparent brain aging compared to later starters. Importantly, this effect of HRT timing was only evident in APOE4 carriers [29], raising the notion that the interaction of APOE and HRT initiation might have a significant effect on brain health later in life. However, to date, there are no comprehensive analyses investigating APOE genotype and HRT interactions on multiple cognitive and MRI outcomes in humans, which the current study addresses.
Therefore, we hypothesize that HRT will have more cognitive benefits in APOE4 compared to non-APOE4 women, in particular when introduced early during menopausal transition. The independent and interactive effect of APOE genotype and HRT use on select cognitive function tests and medial temporal lobe-related MRI brain volumes was tested cross-sectionally in the European Prevention of Alzheimer's Dementia (EPAD) cohort.

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