Alzheimer's disease and HRT

The 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)) (1)

A case-control study has shown (2):

• use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer's disease (AD)
  • risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen-progestogen (1.17, 1.13 to 1.21)
  • risk increases in users of oestrogen-progestogen therapy were not related to different progestogens (norethisterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years
  • exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01).

NICE state with respect to HRT and dementia (3):

• Explain to menopausal women that the likelihood of HRT affecting their risk of dementia is unknown

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
• a greater penetrance of an APOE4 genotype occurs in females
• Saleh et al
  • undertook a multiple linear regression models to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes (comparing APOE4 carriers versus non-carriers)
  • showed that HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only (3)
    • may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup

A Danish registry study (5589 incident cases of dementia & 55,890 age matched controls) found use of oestrogen-progestogen therapy linked to higher rates of all cause dementia (HR 1.24, 95% CI 1.17-1.33) & Alzheimer's disease (1.22, 1.07-1.39) compared to non-use (4):

• increasing durations of use yielded higher hazard ratios, ranging from 1.21 (1.09 to 1.35) for <= 1year of use to 1.74 (1.45 to 2.10) for > 12 years of use. The increased rate of dementia was similar between continuous and cyclic regimens
• the researchers caution that these findings require confirmation in further studies as there is need to determine whether they represent an actual effect of HRT on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments
• an Editorial states (5):
  • "...Previous observational studies have reported conflicting findings on the risks and benefits of hormone therapy with respect to cognitive function and dementia. Although Pourhadi and colleagues’ study was done carefully using national registries, the observed associations could be artefactual and should not be used to infer a causal relationship between hormone therapy and dementia risk. These findings cannot inform shared decision making about use of hormone therapy for menopausal symptoms. Randomised clinical trials provide the strongest evidence on the effect of hormone therapy on dementia risk.."

Reference:

1. Saleh, R.N.M., Hornberger, M., Ritchie, C.W. et al. 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. Alz Res Therapy 15, 10 (2023). https://doi.org/10.1186/s13195-022-01121-5
2. Savolainen-Peltonen H et al. Use of postmenopausal hormone therapy and risk of Alzheimer's disease in Finland: nationwide case-control study. BMJ. 2019 Mar 6;364:l665
3. NICE (November 2015). Menopause: diagnosis and management
4. Pourhadi N et al. Menopausal hormone therapy and dementia: nationwide, nested case-control study BMJ 2023; 381 :e072770 doi:10.1136/bmj-2022-072770
5. Kantarci K, Manson J E. Menopausal hormone therapy and dementia BMJ 2023; 381 :p1404 doi:10.1136/bmj.p1404