HRT and dementia risk

Last edited 01/2023 and last reviewed 01/2023

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
  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).
  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