# Presentation: 100429

## National Institute on Aging (NIA) Menopausal Hormonal Treatment:Alzheimer’s Disease and Cognition Studies

**Judith A. Salerno**
**Deputy Director **
**NIA/NIH/DHHS**

## Continuing NIA Studies UsingEstrogen /Progestin or Estrogen Alone 

**Alzheimer’s disease and related cognitive studies**
**Studies to alleviate menopausal symptoms**
**Studies to investigate cardiovascular risk factors**

## Alzheimer’s Disease and Cognition:Why Estrogen?

**Evidence from some epidemiology studies suggest a role for estrogen in prevention of AD**
**No definitive clinical trials**
**Basic biological studies suggest neuroprotective effect**

## Published Studies on Effect of Estrogen on Cognitive Function in Women (1976 – 2001)

| TYPE OF 
STUDY | No Effect on
Cognition | Equivocal Effect on  Cognition | Positive Effect on Cognition |
| --- | --- | --- | --- |
| Randomized, placebo-controlled trial | 
6 | 
3 | 
3 |
| Observational
study | 
1 | 
8 | 
3 |
| 
TOTAL | 
7 | 
11 | 
6 |

## Alzheimer’s Disease and Estrogen

**No Estrogen**

**AD risk with postmenopausal**
**estrogen use**

**46%**

**Estrogen**

**Less estrogen**

**More estrogen**

**Relative Risk**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0**

**Notes:**
Picture from: Toran-Allerand CD.  Mechanisms of estrogen action during neural development: mediation by interactions with the neurotrophins and their receptors?  Journal of Steroid Biochemistry & Molecular Biology  1996; 56:169-178.

Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Lingle DD, Metter E  A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: The Baltimore Longitudinal Study of Aging   NEUROLOGY 48 (6): 1517-1521 JUN 1997
Previous reports have suggested that estrogen replacement therapy (ERT) in women may exert a protective effect on their risk of developing Alzheimer's disease (AD). We investigated this relationship in the Baltimore Longitudinal Study of Aging (BLSA), a prospective multidisciplinary study of normal aging conducted by the National Institute on Aging. The sample consisted of 472 post- or perimenopausal women followed for up to 16 years in the BLSA. We documented ERT
prospectively at each BLSA visit, and we categorized women who had used oral or transdermal estrogens at anytime as ERT users. We used Cox proportional hazards models with time-dependent covariates to estimate the relative risk of developing AD after ERT as compared with women who had not used estrogen replacement. Approximately 45% of the women in the cohort had used ERT, and we diagnosed 34 incident cases of AD (NINCDS/ADRDA criteria) during
follow-up, including nine estrogen users. After adjusting for education, the relative risk for AD in ERT users as compared with nonusers was 0.46 (95% CI, 0.209-0.997), indicating a reduced risk of AD for women who had reported the use of estrogen. Our data did not show an effect for duration of ERT usage. Our finding offers additional support for a protective influence of estrogen in AD. Randomized clinical trials are necessary to confirm this association, which could have
significant public health impact. 

## Alzheimer’s Disease (AD) and Related Studies of Cognition

| S. Asthana
University of Wisconsin/ Madison | AD Treatment
Trial | 13 enrolled;
160 target 
 | Estradiol patch (50 or 100 mcg/day)  OR Patch + medroxyprogesterone (2.5 mg/day) in women with uterus |
| --- | --- | --- | --- |
| M. Sano
Columbia University Health Sciences Center | AD Prevention Trial | 408 enrolled;
900 target | Premarin (0.625mg/day)  OR Prempro (0.625 mg premarin + 2.5 mg medroxyprogesterone/ day) in women with uterus |
| S. Resnick
NIA Intramural Program
 | WHI Study of Cognitive Aging | 2298 enrolled | Premarin (0.625 mg/day) in women without uterus ORPrempro (0.625 mg + 2.5 mg medroxyprogersterone/day) in women with uterus |

## Recommendations for Continuation of Studies

*First Priority: protection of human subjects*
**Data Safety Monitoring Boards revisited risks vs. benefits**
**Notification of enrolled subjects**
**Initiation of re-consenting of  enrolled subjects **