Estrogen and cognitive aging in women

Barbara B. Sherwin

Trends in Pharmacological Sciences 2002, 23:527-534

The steady increase in female life expectancy has attracted attention to the importance of preventing cognitive aging and Alzheimer's disease (AD) in women. Evidence from randomized, controlled trials and from cross-sectional and longitudinal studies shows that estrogen-replacement therapy preferentially protects against a decline in verbal memory in healthy postmenopausal women and decreases the risk of AD. Although results are not consistent across studies, they indicate that treatment with estrogen during the postmenopausal years might protect against cognitive aging in women during the latter part of their life.

The fact that female life expectancy has nearly doubled in industrialized countries during the past century means that more and more women are living into old age. In an attempt to preserve the quality of life for elderly women, research efforts have focused on preventing degenerative diseases, such as osteoporosis and coronary heart disease, that might compromise their daily functioning. There is increasing recognition that aspects of cognition also decline with normal aging in women and that this might impact negatively on their quality of life. Moreover, the epidemiological statistic of an ~1.6:1.0 female:male ratio in the incidence of Alzheimer's disease (AD) remains, even when controlling for greater female longevity [1]. The age-related decline in aspects of cognition observed in women has led some researchers to investigate whether changes in the levels of sex hormone in aging women might be influential. Here, I review the most recent evidence on the relationship between estrogen and cognition. This is preceded by a brief exposition of some of the neuroendocrine and neuropsychological effects of estrogen on brain structures and functions that are thought to be involved in cognitive functioning.

Changes in brain structure and cognition with aging

Not all cognitive functions decline with increasing age. Recent studies indicate that the system that underlies explicit, or declarative, memory is specifically and adversely affected with aging, whereas implicit, or nondeclarative, memory remains relatively intact [2]. Explicit memory refers to the conscious recollection of facts and events whereas implicit memory involves the performance of non-conscious habits, such as tying shoelaces, and repetition priming. Evidence from studies in rodents, non-human primates and humans indicates that structures in the medial temporal lobe, including the hippocampus, the dentate gyrus and the entorhinal cortex, are important at the time of learning and for some time thereafter, whereas the neocortical association areas are the permanent repository of memory [3]. The ability to retrieve previously learned material (long-term memory) is dependent on the prefrontal cortices [4].

Numerous mechanisms have been identified whereby estrogen affects structures and functions in the brain that are implicated in explicit memory [5]. Perhaps the most important of these is the promotion of acetylcholine synthesis in the hippocampus [6] and synaptogenesis in the CA1 area of the hippocampus [7]. Two subtypes of estrogen receptors, ER

and ER

, have been characterized thus far. ER

mRNA is predominant in the hypothalamus and amygdala, whereas ER

protein occurs mostly in the hippocampal formation, entorhinal cortex and thalamus [8], areas that are crucially involved in explicit memory. In rodents, treatment with estrogen protects against the neuronal cell death that results from brain injuries such as cerebrovascular stroke and neurotrauma [9]. These and other effects of estrogen on the neuroanatomy and neurophysiology of pathways that underlie memory processes provide the biological basis for the hypothesis that estrogen protects aspects of memory in women.

Accumulating evidence from human neuroimaging studies indicates that estrogen also influences regional cerebral blood flow (rCBF) in women. For example, resting rCBF in non-demented postmenopausal women was shown to be higher during estrogen treatment than before drug treatment [10]. Estrogen therapy is also associated with changes in brain-activation patterns in middle-aged, postmenopausal women during the performance of verbal and figural memory tasks [11]. Therefore, the administration of estrogen to postmenopausal women affects blood flow in a variety of brain areas that subserve memory.

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