•Females have approximately twice the lifetime risk of Alzheimer disease (AD) compared to males¹.

•APOE ε4 is a major genetic risk factor for AD².

•Menopause-related estradiol (E2) decline and shorter lifetime exposure to endogenous E2 (LEE2) may contribute to AD pathology^3,4.

•Supplementation of E2 with menopause hormone therapy (MHT) is inconsistently associated with AD risk⁵.

1.Circulating E2: Plasma E2 quantified using SiMOA.

2.LEE2: Menopause age – menarche age.

3.AD biomarkers: Aβ42/40, p-tau181, p-tau181/Aβ42, and glial fibrillary acidic protein (GFAP).

4.APOE status: ε4 carriers (ε2/ε4, ε3/ε4, ε4/ε4) vs non-carriers (ε2/ε2, ε2/ε3, ε3/ε3).

•Adjusted linear regression models.

•Covariates: age, education, race, menopause type, and MHT use.

 

Result: 

Relationship between Aβ42/40 and circulating estradiol levels significantly moderated by APOE ε4 status:  b_interaction=-0.11, 95%CI [-0.19, -0.04], p=0.003

Relationship between p-tau181 and circulating estradiol levels not moderated by APOE ε4 status: b_interaction=-0.18, 95%CI [-0.37, 0.02], p=0.073

Relationship between p-tau181/Aβ42 and circulating estradiol levels not moderated by APOE ε4 status: b_interaction=-0.07, 95%CI [-0.29, 0.16], p=0.555

Relationship between glial fibrillary acidic protein and circulating estradiol levels not moderated by APOE ε4 status: b_interaction=0.00, 95%CI [-0.16, 0.17], p=0.968

Relationship between Aβ42/40 and LEE2 not moderated by APOE ε4 status: b_interaction=0.00, 95%CI [-0.01, 0.01], p=0.764

Relationship between p-tau181 and LEE2 significantly moderated by APOE ε4 status: b_interaction=0.02, 95%CI [0.00, 0.03], p=0.036

Relationship between p-tau181/Aβ42 and LEE2 not moderated by APOE ε4 status: b_interaction=0.02, 95%CI [0.00, 0.04], p=0.059

Relationship between glial fibrillary acidic protein and LEE2 not moderated by APOE ε4 status: b_interaction=0.02, 95%CI [0.01, 0.03], p=0.004

Conclusion:

Estradiol-biomarker associations in postmenopausal females varied by APOE ε4 status, with patterns among ε4 carriers consistent with greater AD-related pathology.

 •Higher circulating E2 associated with lower plasma Aβ42/40 ratios among ε4 carriers (b=-0.07, 95% CI [-0.13, -0.02], p=0.012).

•Longer LEE2 duration associated with higher p-tau181 and GFAP levels among ε4 carriers (p-tau181: b=0.02, 95%CI [0.00, 0.03], p=0.008; GFAP: b=0.02, 95%CI [0.01, 0.03], p=0.005).

•Relationships between E2 exposures and AD biomarkers did not reach significance among non-carriers.

 

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