It is generally recognized that the prevalence of AD is higher in women, but whether incidence is increased remains a controversial issue. In their review of gender differences in the incidence of neurologic disease, Hauser and Amatniek (1998) reported that age-adjusted incidence was higher in women, particularly with advancing age. In a meta-analysis of AD incidence studies, Jorm and Jolley (1998) found no significant sex difference overall; however, there was a trend toward higher incidence among women in the oldest age groups.

Such epidemiologic observations, as well as evidence of gender-related differences in cognition and behavior, suggest that there may be important genetic or other biological factors related to gender that are operative in the pathogenesis of AD.

Many studies of gender differences in cognition have pointed to greater language deficits in women with AD as compared to men. Naming and word-recognition skills have been reported to be more adversely affected in female patients with AD than in male patients, and the differences have been shown to be sustained over time (Ripich et al., 1995). One series of studies demonstrated differences between men and women with AD, with language skills being particularly affected (Buckwalter et al., 1993; Henderson and Buckwalter, 1994). Findings have suggested that male patients with AD retain verbal skills better than female patients in the early to middle stages. In a more recent study, researchers found that women with vascular dementia (VD) performed worse than men with VD on semantic memory, while women with AD showed a trend to perform worse than men with AD on the semantic memory test (Buckwalter et al., 1996).

Bayles and colleagues (1999) recently performed a critical analysis of these previous studies and revealed several statistical limitations, including unreliable methods of determining and insufficient control of dementia severity, failure to correct for multiple comparisons, and inappropriate statistical comparisons. In the Bayles et al. analysis, 63 patients with AD were administered a battery of tests designed to assess language comprehension and production. In a cross-sectional analysis of the data, no significant differences between men and women were found on any of the language measures when controlling for dementia severity. Similarly, in a longitudinal analysis of 26 of these subjects who were administered the same battery two years later, no significant gender effects were found. The authors interpreted their findings as suggesting that there was no evidence that AD adversely affected the language performance of women more than men. Moreover, the finding of an absence of gender-related language differences in AD was also reported by Hebert et al. (2000); no significant difference between the female and male patients with AD in decline of either language functioning or other measures of cognition, including memory and perception, was found in a follow-up study of 410 patients with AD.

Proponents of the gender difference in language functioning in AD have pointed to differing patterns of neural organization that may influence patterns of language breakdown in the course of the disease (Ripich et al., 1995) or to the influence of sex hormones on the brain (Sherwin, 1997). Bayles and colleagues (1999), however, argued that there is no theoretical basis for predicting such a discrepancy in language function. Additional work is needed to adequately address the issue of cognitive differences between male and female patients with AD.

While changes in cognition are typically the first and most pervasive change noted in patients with AD, behavioral disturbances also frequently occur. Many reports have suggested that increased behavioral disturbance in AD is related to dementia severity across gender, but qualitative differences between men and women in the manifestation of the disturbances also have been reported.

In one study from our laboratory, we reported that female patients with AD exhibited tendencies to be more reclusive and emotionally labile, often hoarded, refused help, and had inappropriate laughter or crying. In comparison, men with AD showed more psychomotor and vegetative changes (Ott et al., 1996). In addition, there was an association noted between aggressive behaviors and male gender in this study.

In a more recent study by our group, we examined gender differences in non-cognitive behavioral problems using a cross-section of nursing home residents in five U.S. states (Ott et al., 2000b). Behavior problems documented at the first assessment of 28,367 residents with AD were evaluated. Male patients exhibited greater problems than female patients in wandering, abusiveness and social impropriety, particularly in the more advanced stages of the disorder. Major tranquilizers and behavior management programs were used more frequently on male patients with AD, while there was no difference between genders in the use of physical restraints.

Other studies of patients with AD have reported increased physical, verbal and sexual aggression in men as compared to women (Drachman et al., 1992; Lyketsos et al., 1999). Psychiatric symptoms have also been reported in patients with AD, but the relationship between gender and psychiatric disturbance is equivocal. Depression does appear to be more prevalent in female than in male patients with AD (Cohen et al., 1993). Some studies have reported that delusions also occur more frequently in women with AD (Cohen et al., 1993; Devanand et al., 1992).

No gender differences were found in prevalence of hallucinations and delusions among demented nursing home residents (Ott et al., 2000b) or in psychotic features such as hallucinations and delusions (Paulsen et al., 2000).

There have been many observations of gender differences in normal brain structure and function. Quantitative sex differences in brain aging of normal males and females have been reported in a number of magnetic resonance imaging (MRI) studies. Recently, Coffey and colleagues (1998) reported that, in men, reduction in brain volume was greater in the parieto-occipital regions. No hemispheric asymmetries were noted between sexes. In their review of 19 prior studies examining radiologic changes of brain aging, there were inconsistent observations on gender differences.

There are few studies of the morphological and physiological differences between men and women with AD. Jack et al. (1997) reported that medial temporal atrophy was similar between men and women in normal aging. Furthermore, no gender effect was found for decline in medial temporal lobe volumes for those with early AD. In a magnetic resonance spectroscopy study, phosphorus metabolism was reduced in the frontal lobes of women with AD as compared to men. A similar, though non-significant, effect was seen among normal elders (Smith et al., 1995).

Functional brain imaging using positron emission tomography (PET) and single photon emission computed tomography (SPECT) may provide more sensitive measures of physiological and pathological changes in the brain than does MRI, particularly in AD where abnormalities have been demonstrated even in the pre-dementia phase of the illness. Small et al. (1989) studied metabolic rates in 13 subjects with early-onset AD and 11 subjects with late-onset AD. Women had higher metabolic rates in all regions studied compared to men; however, the differences did not approach statistical significance. Hemispheric sex differences were 9% on the right and 7% on the left. Jagust et al. (1996), in contrast, found that among 18 patients with AD, women showed lower metabolic rates in all regions evaluated, particularly in the visual cortex. Such inconsistent gender effects may be related to the small sample sizes employed in earlier studies.

Based on two studies of 220 patients (Nitrini et al., 2000) and 300 patients (Ott et al., 2000a), unilateral temporo-parietal defects are seen more commonly on SPECT images of women compared to men with AD, indicating a potential gender effect on diagnostic utility. This is a finding of practical importance, since bilateral defects are regarded as the characteristic pattern in AD. Furthermore, we have found that unilateral left hemisphere perfusion defects were more common in women compared to men, particularly for those with probable AD (26% versus 8%,

²=9.3, p=0.01). In a multiple regression study, female gender and shorter duration of disease were independent predictors of the unilateral left hemisphere pattern in those with AD (Ott et al., 2000a). This evidence suggests that the left hemisphere of the female brain may be more vulnerable to AD, or that the right hemisphere may be relatively protected in some women by factors yet to be determined.

It remains controversial whether men and women differ in the incidence of AD and whether there are clearly recognizable sex differences in cognition and behavior among those afflicted. A thorough defining of these differences is important for the sake of understanding the behavioral problems of AD and for developing a more refined approach to their treatment. More research into the biological underpinnings as well as the social influences on these differences is needed.

Dr. Ott is associate professor of clinical neurosciences at Brown University. He serves as associate chief of neurology and director of the Alzheimer's Disease and Memory Disorders Center at Memorial Hospital of Rhode Island.

Dr. Cahn-Weiner is clinical assistant professor in the department of psychiatry and human behavior at Brown University. She serves as staff neuropsychologist for the Alzheimer's Disease and Memory Disorders Center at Memorial Hospital of Rhode Island.

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Gender Differences in Alzheimer's Disease