High plasma estradiol interacts with diabetes on risk of dementia in older postmenopausal women.
OBJECTIVE
We aimed to investigate the impact of endogenous estradiol (E2) on dementia and to evaluate the contribution of vascular risk factors and inflammatory and blood coagulation markers to this association.


METHODS
Using data from a French population-based prospective study (the Three-City Study) including 5,644 postmenopausal women aged 65 years or older, we investigated the association of endogenous total-E2 and bioavailable-E2 and total-testosterone with the 4-year incidence of all-cause dementia. We further focused on the role of dementia and cardiovascular risk factors as well as inflammation (C-reactive protein, fibrinogen) and hypercoagulability (fibrin d-dimers, thrombin generation) in these associations. We used a case-cohort design consisting of a random subcohort of 562 women not using hormone therapy and 132 incident dementia cases.


RESULTS
Adjusted Cox proportional hazards models showed a J-shaped relationship between total-E2 and risk of dementia (p = 0.001). Total-E2 values in the lower and upper quartiles were associated with an increased dementia risk (adjusted hazard ratio [HR] [95% confidence interval] = 2.2 [1.1-4.5] and HR = 2.4 [1.2-5.2], respectively). Importantly, the risk associated with higher E2 levels was dramatically increased in women with diabetes compared with nondiabetic women (adjusted HR associated with the upper E2 quartile = 14.2 [1.60-123] and HR = 3.4 [0.1-147], respectively, p interaction <0.05). Similar results were found for bioavailable-E2. Adjustment for inflammatory and blood coagulation markers did not modify our results. No significant association was found for total-testosterone.


CONCLUSIONS
High E2 level is an independent predictor of incident dementia, particularly in postmenopausal women with diabetes.
From Inserm (L.C., P.-Y.S.), CESP Centre for Research in Epidemiology and Population Health, UMR-S1018, Hormones and Cardiovascular Disease, University Paris Sud, Villejuif; Hôpital Bicêtre (S.B.-T., A.G.-M.), APHP, Service de Génétique moléculaire, Pharmacogénétique et Hormonologie Kremlin-Bicêtre; Inserm UMR-S693 (S.B.-T., A.G.-M.), Université Paris Sud 11, Kremlin-Bicêtre; Inserm U1061 (M.-L.A.), Université Montpellier 1, Montpellier; CMMR CHU Dijon (O.R.), Dijon; Université Victor Segalen Bordeaux 2 (J.-F.-D.), Bordeaux; and Inserm U897 (J.-F.D.), Epidemiology and Neuropsychology of Brain Aging, Bordeaux, France.
Laure
L
Carcaillon
Sylvie
S
Brailly-Tabard
Marie-Laure
ML
Ancelin
Olivier
O
Rouaud
Jean-François
JF
Dartigues
Anne
A
Guiochon-Mantel
Pierre-Yves
PY
Scarabin
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D003704:Dementia / Q000453:epidemiology*; D003920:Diabetes Mellitus / Q000453:epidemiology*; D004958:Estradiol / Q000097:blood*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005602:France / Q000453:epidemiology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000453:epidemiology*; D015999:Multivariate Analysis; D017698:Postmenopause / Q000097:blood* / Q000276:immunology; D016016:Proportional Hazards Models; D012306:Risk; D012307:Risk Factors; D013739:Testosterone / Q000097:blood; D013917:Thrombin / Q000096:biosynthesis; D019851:Thrombophilia / Q000097:blood / Q000453:epidemiology*
D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D013739:Testosterone; D004958:Estradiol; D005340:Fibrinogen; D002097:C-Reactive Protein; D013917:Thrombin