Could HRT Be an AD-Preventative Strategy for Older Women With the APOE4 Gene?

The use of HRT was associated with improved delayed memory and larger entorhinal and amygdala brain volumes in women who are APOE4 carriers.

Among women who are carriers of apolipoprotein E (APOE) allele 4 (APOE4), hormone replacement therapy (HRT) associated with improved delayed memory and larger entorhinal and amygdala volumes, according to study findings published in the journal Alzheimer’s Research & Therapy.

The majority of patients with Alzheimer disease (AD) are older women, suggesting the decline in estrogen with age may contribute to AD. Previously published data from the United Kingdom (UK) Biobank suggested that women who were APOE4 carriers and started HRT earlier had fewer signs of brain aging compared with women who started HRT later. As such, use of HRT during the transition to menopause has been considered a potential AD-preventative strategy.

Researchers from the University of East Anglia in the UK designed this study to test the hypothesis that HRT may delay AD onset among women carrying the APOE4 gene. Data for this study were sourced from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. The effect of APOE status and HRT use on brain volumes and cognitive test outcomes were evaluated among 1074 women.

The women were mean age, 65.1 (standard deviation [SD], 7.3) years, 67.5% were married or cohabitating, they had obtained 14.1 (SD, 3.7) years of education, 83 used HRT, and 399 were APOE4 carriers. At baseline, the APOE4 carriers obtained significantly fewer years of education than noncarriers (mean, 13.8 vs 14.4 years; P =.014), respectively.

The findings highlight the heterogeneous 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.

Among the APOE4 carriers, HRT users had higher Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total (mean, 106.68 vs 100.52 points; P =.045) and delayed memory (mean, 109.37 vs 98.29 points; P =.002) scores compared with nonusers, respectively. Among nonusers of HRT, the APOE4 carriers had significantly lower delayed memory scores compared with noncarriers (mean, 102.09 points; P <.001), indicating a significant interaction between APOE status and HRT (P =.009) on delayed memory.

At magnetic resonance imaging (MRI), in individuals in the APOE4 carrier cohort, the HRT users had significantly greater left (P <.001) and right (P =.04) entorhinal volumes and left amygdala volume (P =.03). Whereas among the noncarriers, the HRT users were found to have significantly reduced right (P =.03) and left (P =.04) amygdala volumes, indicating significant APOE-by-HRT interactions for left entorhinal (P =.002) and left (P =.003) and right (P =.005) amygdala volumes.

In addition, a significant negative relationship with age at HRT initiation among the APOE4 carriers was observed in the left (b, -0.577; P =.028) and right (b, -0.555; P =.035) hippocampal volumes but was not observed among the noncarriers (b range, 0.268-0.310; both P ³.271).

This study was limited by its cross-sectional design, in which causal relationships could not be evaluated.

HRT may have cognitive benefits for women who are APOE4 carriers and justified conducting a randomized controlled trial to evaluate HRT as an AD prevention strategy, according to the researchers.

“The findings highlight the heterogeneous 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,” they concluded.

References:

Saleh RNM, Hornberger M, Ritchie CW, Minihane M. 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. Alzheimers Res Ther. Published online January 9, 2023. doi:10.1186/s13195-022-01121-5