Women and Alzheimer’s Disease1

Alan J. Lerner

Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44120

Address all correspondence and requests for reprint to: Dr. Alan J. Lerner, Alzheimer Center, 12200 Fairhill Road, Cleveland, Ohio 44120. E-mail: ajl3{at}po.cwru.edu

Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with aging. It can also be classified as a complex polygenetic disease, such as hypertension, coronary artery disease, or schizophrenia, because there are both genetic and environmental factors that result in the phenotypic expression of what is clinically called AD. Due to the demographic shifts and remarkable medical advances of the last century, aging populations are now the fastest growing portions of the population, and women constitute a majority of this population due to their increased life expectancy relative to males. Thus, women would appear to be at special risk for AD, although this review will also focus on gender differences in disease expression and opportunities for treatment using estrogen replacement therapy (ERT).

Alzheimer’s disease was first described by Alois Alzheimer in 1906, based on a single case of a 51-yr-old woman who developed severe behavioral disturbances, aphasia, and memory loss. Alzheimer followed the patient for several years and described the classic neuropathological findings of intracellular neurofibrillary tangles and neuritic amyloid plaques in her brain postmortem. Emil Kraeplin proposed the disease eponym several years after his initial description. Remarkably, Alzheimer’s original notes, and the original neuropathological specimens have been recovered within the past 2 yr, confirming that the patient did indeed have AD by modern diagnostic criteria (1, 2).

Epidemiology

Although AD was long believed to be a rare disease, awareness of AD prevalence was highlighted in the late 1960s and 1970s by Blessed and colleagues (3) and Katzman (4). Present epidemiological data suggest that dementia, defined as the clinical state of acquired cognitive loss in multiple domains, affects about 5–7% of individuals over age 65 yr. In the East Boston study of community-dwelling elderly, by age 85 yr up to 47% of individuals will suffer dementia (5). The vast majority of these cases will have AD. Translated into population statistics, these numbers imply a current U.S. prevalence of about 4 million cases. This has been estimated to cost between 70–100 billion dollars/yr, much of it due to the need for long term care facilities.

With women over 65 yr of age outnumbering men (20 million women vs. 13.9 million men in the U.S.), and with an American women who reaches age 65 yr having an average life expectancy of 19 yr (15.5 yr for men), women appear to be at particular risk for AD. Meta-analysis of population prevalence studies found no sex difference in overall dementia prevalence by gender, but showed that AD rates tend to be higher in females, and vascular dementia tends to be more common in males. A meta-analysis of incidence studies (6) across different nationalities showed little difference in overall gender-specific incidence. AD incidence for women showed a steeper age-incidence curve, indicating a higher incidence at older ages. East Asian countries had lower AD incidence than Europe or the U.S., but their incidence curve steepens with age, which may reflect environmental or genetic differences contributing to AD risk.

The issue of AD in the oldest old (over age 85 yr) has also been investigated, with particular reference to whether AD is an inevitable part of aging (7). Genetic marker studies involving apolipoprotein E (Apo E), whose e4 allele is a well established disease risk modifier (see below), have also suggested that the vast majority of Apo E e4 carriers will be demented by age 120 yr, although the incidence curves also become flatter after age 90 yr. Jorm and Jolly (6) found no evidence of incidence curve flattening after age 90 yr. These studies are beginning to provide scientific basis for anecdotes suggesting that great longevity need not be accompanied by inevitable deterioration of cognition.

Studies in developing nations have produced interesting results regarding gender issues and environmental and genetic risks for AD. In rural elderly in Northern India, Chandra et al. found no gender or literacy association, although prevalence increased with age (8). A low prevalence and incidence were been found in Ibadan, Nigeria compared to that in African-Americans in Indianapolis, IN (8.24% in Indianapolis vs. 2.3% in Ibadan) (9). A cross-cultural study of Japanese-American men living in Hawaii found that height correlated negatively with dementia prevalence, suggesting that early life dietary adequacy may play a role in late-onset brain disorders (10). Studies are currently underway in geographically or genetically isolated populations, such as Central Kenya, Brazil, and Israeli Arabs, and many others that may help determine whether genetic or environmental factors, such as toxins, literacy and education, physical activity, nicotine exposure, or other variables are important in determining AD development (11, 12, 13). One methodological issue in all of these studies, especially in developing nations, is the censuring effect of competing sources of mortality, which would tend to favor AD expression in women. More subtly, the life experiences of women, their educational and vocational opportunities, their access to health care, medications, and disease exposures may affect their risks of AD in ways that current research is only beginning to comprehend.

Genetic risk factors

Beginning with the observation that individuals with Down’s syndrome almost universally develop neuropathological and frequently clinical evidence of AD by age 35 yr and the discovery of familial forms of AD, interest in the genetic risk factors for AD has been an active field of investigation. To date, three AD genes have been isolated: mutations of the amyloid precursor protein on chromosome 21 (21q21), of presenilin-1 on chromosome 14 (14q24.3), and of presenilin-2 on chromosome 1 (1q31.42). These rare mutations have generated new insights into the molecular biology of AD in terms of amyloid processing and differential processing of the APP, but are clinically very rare. The most important AD gene identified to date is the disease risk modifier, Apo E (19q13.2), particularly the presence of the e4 allele (14, 15). Apo E e4 status has been associated with both late-onset and early-onset familial forms of AD, as well as being a general risk factor for AD. Individuals carrying at least one e4 allele have between a 25–40% lifetime chance of developing AD. In a meta-analysis of Apo E and AD studies, women who have at least one e4 allele appear to be at greater risk for AD, with the strongest effects occurring between age 50–75 yr (16). Caucasian women with the e3/e4 genotype were 1.5 times more likely to develop AD than males with that genotype. Similar results were seen with women possessing an e2/e4 genotype, but due to sample size considerations they did not reach statistical significance. Apo E does not appear to be as strong an AD risk factor in African-American or Hispanic samples, but among Hispanic women, sex-related trends similar to those in Caucasian samples are detected. This gender effect was not seen in Japanese women in the meta-analysis study. The reason for this genetic sexual dimorphism is unclear, but it may represent an interaction with postmenopausal ERT or possibly a sex-specific susceptibility among e3/e4 heterozygotes (17). Women with a positive family history and an e4 allele may also have an earlier age at onset (18).

Environmental risk factors

Besides aging, a large number of environmental risk factors have been investigated. Particular interest has focused on whether certain exposures may be protective, such as the relationship of education to the concept of functional neuronal reserve, and the commonly held idea of "use it or lose it." The results of epidemiological studies are inconsistent, but protective risk factors may include postmenopausal ERT, smoking, more education, and chronic exposure to nonsteroidal antiinflammatory medications. Positive risk factors include history of depression, head injury (particularly in individuals with the Apo E e4 allele), and possibly thyroid disease.

ERT has been shown to be protective for developing AD in a number of studies and appears to be a dose-related phenomenon (19, 20, 21). Exposure of only 1 yr postmenopausally appears to provide some risk reduction in terms of both disease development and age of onset, even many years later. The crude odds ratio for ERT exposure in the New York, Cleveland, and Baltimore studies has been about 0.4. The relative risk reduction from ERT may interact with other risk factors, such as Apo E genotype, smoking, and history of AD in first degree relatives. The public health aspects of this have begun to be investigated, and more study is needed to determine whether agents such as selective estrogen receptor modulators will produce similar effects. Judging from the experience with ERT use in cardiovascular disease and osteoporosis, it may take many years to understand the full implications on a risk-benefit basis, but the impact of AD is often so catastrophic that further study is necessary. The role of ERT in acute treatment of established AD is discussed below.

The biology of how ERT can modify AD development is complex, with probably several components interacting. These include the importance of estrogen in normal brain development, the presence of estrogen receptors in brain areas important to memory systems such as hippocampus, estrogen-induced changes in Apo E messenger ribonucleic acid expression, increased cerebral blood flow, trophic effects on neuronal systems, and interactions with the basal forebrain cholinergic system, which degenerates in AD and is a major therapeutic target for treatment. Estrogens have been shown to be involved in axonal elongation, enhancing the outgrowth of nerve cell processes in vitro and promoting the formation of synapses and dendritic spines

Clinical features

The clinical expression of AD is quite variable, with diagnostic criteria requiring a mixture of memory deficits in addition to deficits in other aspects of cognition, such as language, praxis, agnosia, or executive function disturbance (e.g. planning, abstraction, and judgment). Behavioral manifestations are common and include depression, agitation, delusions, and hallucinations, or anxiety syndromes. Sleep disorders and purposeless behaviors such as pacing may also occur in individual patients. Few studies have addressed the gender specificity of clinical expression. Studies of gender difference in AD need to be interpreted cautiously in light of underlying gender differences in lateralization and visual-spatial and language abilities occurring in normal development.

In a longitudinal study of AD patients compared to normal elderly, female AD patients performed worse than male AD patients on tests of naming, vocabulary, and word recognition skills, but not on syntactic measures (22). These deficits persisted during longitudinal follow-up and contrast with no gender differences in these measures in normal elderly. Henderson and Buckwalter (23, 24) also found gender differences on the Mini-Mental status examination score related to language dysfunction. No gender differences were found using the Blessed test (a cognitive screening instrument), and the rate of deterioration was similar in both sexes (25).

The biological basis for this difference in language abilities in AD may be due to several factors. AD women have a much stronger correlation of disease state with postdexamethasone cortisol levels than men (26). Regional cerebral blood flows measured by positron emission tomography in AD have been described, with women having higher mean nonweighted metabolic rates than men (27). The explanations for these phenomena include differences in the regional pattern of cell loss and ß-amyloid deposition, which is coupled to regional cerebral blood flow. Dexamethasone resistance has been associated with damage to the hippocampal formation, which is intimately involved in short term memory processing (28). Baseline differences in neural organization, such as increased lateralization in males, may influence patterns of language breakdown, becoming magnified with disease progression.

The Nun study also showed the importance of early life experiences and possible interactions with genetic background. Linguistic abilities, as measured by an analysis of idea density and grammatical complexity in an autobiographical essay written on entrance to a convent, predicted late life cognitive outcome. Among 14 sisters who died, AD was present in all with low linguistic ability but in none of those with a high degree of linguistic complexity (29).

Noncognitive symptoms may also show gender differences. Males tend to have more problems with verbal aggressiveness, preoccupation with bodily function, and apathy. In multiple regression model analysis of the Dementia Behavior Disturbance Scale, there were no gender differences in behavior severity. However, males scored higher on scales of apathy and vegetative signs, whereas females showed more reclusive behavior and emotional lability, with behaviors such as hoarding, refusing help, and inappropriate laughter and crying (30). Differences in baseline behavior may contribute to these findings, and differences in levels of androgens and estrogens may play a role in behavioral expression.

The identification of Apo E, its role in cholesterol transport, and its risk factor status for cardiovascular disease have led to a reappraisal of the role of vascular factors in AD. Although ß-amyloid is found in meningeal vessels, no consistent evidence of a systemic amyloidosis has been identified in AD. Cerebral ischemia may complicate AD, leading to decrements in neuropsychological performance and faster clinical progression, as suggested by the findings in the Nun study (31).

Overall disease survival from onset and diagnosis is variable, but averages between 8–10 yr. Many investigators have used age at onset or particular clinical features to investigate the possibility of AD subgroups, but these have not been shown to have consistent biological validity. Factors associated with quicker progression include the presence of family history, onset at an early age, extrapyramidal symptoms, psychosis, and comorbid medical conditions. In our study of two large cohorts, smoking did not affect disease survival (32). Moritz et al. (33) found men had shorter survival times than women, with shorter male survival associated with more psychiatric symptomatology. Among women, but not men, a history of cardiovascular disease was associated with poorer survival.

Treatment

The major basis for current pharmacological treatment of AD is based on the cholinergic hypothesis. The cholinergic system radiates from basal forebrain nuclei and degenerates early in AD, and cholinergic markers correlate with disease course. Enhancement of cholinergic function by acetylcholinesterase inhibitors has been demonstrated to improve cognitive functioning compared to the effect of placebo and may have effects on noncognitive symptoms and vegetative symptoms as well (34, 35). A retrospective review of data from the 30-week tacrine trial (36) showed that the most robust improvements in neuropsychological testing occurred in women with concurrent ERT or recent treatment (within 3 months of trial enrollment) (37).

The cognitive effects of ERT have been investigated in a number of human models since the 1950s. In surgically or naturally menopausal women, ERT has been associated with enhanced short and long term memory and increased capacity for learning paired associations. Visual memory, however, does not improve with ERT (38). In women aged 32–36 yr old with uterine myomas given a GnRH agonist (GnRH-a) for 12 weeks, verbal memory scores declined significantly. This was followed by GnRH-a with estrogen or placebo, with the former group showing improvements to baseline verbal scores but continued poorer performance in the GnRH-a and placebo cohort. These results suggest that estrogen deprivation effects are reversible with replacement, at least in the short term (39).

Serum levels of endogenous estrogens are not consistently correlated with cognitive performance in older women (40). Animal studies using paradigms such as ovariectomized animals and standardized behavioral tests have shown a wide variety of interactions of estrogens with cholinergic, dopaminergic, and serotoninergic neurotransmitter systems important for modulating memory, mood, and affect (41, 42, 43, 44, 45). Estrogens also facilitate hippocampal neuronal long term potentiation, a model for memory formation (46); protect against memory-impairing compounds, such as anticholinergics and benzodiazepines (44, 47, 48); and reduce neuronal responses to oxidative stress (49). Human studies have shown conflicting results in longitudinal and cross-sectional studies, with most studies showing only a modest effect on selected neuropsychological variables such as explicit memory or visual-spatial skills, but not immediate memory (50, 51, 52, 53). It is likely that the memory-promoting effects of acute estrogen replacement derive from its pleiotropic action in the central nervous system, including interactions with estrogen receptors with changes in gene expression, as well as up-regulation of other neurotransmitter systems, as indicated by extensive data from animal models.

In patients with established cognitive impairment, early open label studies and more recent randomized studies using current AD diagnostic criteria have showed trends toward improvements in several neuropsychological and behavioral ratings. However, many of these studies have been quite small and of relatively short duration (<6 months) (54). A larger, longer, multicenter, randomized, placebo-controlled study in established AD women is underway, and results will be available shortly.

Care-giving and AD

Implicit in the progressive deterioration of cognitive and self-care abilities in AD is the reality that care will be rendered to assist the patient with activities of daily living. Even in the United States, with its well developed system of long term care facilities for dementia patients, it is estimated that 80% of care occurs in the informal home setting. The most consistent finding in care-giving research is that the majority of family care-givers are women, providing approximately two thirds of care for AD patients. This compares to 80–90% of care provided by women among adult child care-givers. In studying the content of care-giving, women are more likely than men to carry out personal care activities, such as bathing, dressing, or personal hygiene. Women are more likely to attend to household chores and are equally likely to deal with money management compared to men (55).

Long term care in nursing facilities may be necessary in the later stages of AD. Major determinants of institutionalization include incontinence, behavioral disturbance, strength of the care-giving bond (spouses are most likely to continue home care), as well as underlying social and cultural values. Besides the moral and cultural issues, the cost to society for long term care has led to programs to enhance the home care system, reducing care-giver burden and attempting to forestall spousal and family impoverishment frequently imposed by the tremendous costs of long term care. Attempts to change this at the level of national health care programs, such as Medicare, have not been instituted to date.

Studies focusing on the burdens of care-giving have generally identified that women experience more distress as a result of this role, which may relate to the content of the role as well as the long term stress-coping mechanisms. Although the acute effects of care-giving, such as anger, guilt, and depression, are well known and can clearly affect the quality of care, long term health effects of care-giving in AD are less documented (56).

Two endocrine aspects are relevant to care-giving. A voluminous literature exists on biological measures of stress, such as hypothalamic-pituitary-adrenal axis responsivity, but relatively little is known about ways to quantify the actions of care-giving and to correlate with stress markers. Chronic glucocorticoid exposure from hypothalamic-pituitary-adrenal axis stimulation may damage hippocampal neurons, (28) possibly lending a biological basis to the neuropsychiatric hazards associated with care-giving. The effects of ERT as an adjunct to mood maintenance via interactions with serotoninergic and adrenergic systems suggest that ERT may augment the antidepressant drug response (57).

Summary and conclusion

AD is a major public health problem, and demographic trends have led to its being called the epidemic of the century. Because of increased longevity and the special challenges of ERT, women are well placed to both be at risk for and the beneficiaries of advances in AD therapy. Overall increases in health consciousness may impact future AD risk, and it is encouraging that women frequently outnumber men in clinical trials of new therapeutic agents in AD. The risk of AD from environmental exposures in the overall life experiences of women is unclear. To the extent that education and work promote the development of brain areas such as the association cortex that are preferentially affected in AD, creating a neuronal reserve, advances in women’s overall place in society may further help protect them from the ravages of AD.

Footnotes

1 Supported by a grant from the National Institutes of Health P50-AG08012. Back

Received December 4, 1998.

Revised February 23, 1999.

Accepted February 23, 1999.

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