Gender Differences in Alzheimer's Disease
by Brian R. Ott, M.D., and Deborah A. Cahn-Weiner, Ph.D.
| Geriatric Times |
 |
November/December 2001 |
|
Vol. II |
|
Issue 6 |
Clinicians who diagnose and treat patients with Alzheimer's disease (AD)
recognize that there is heterogeneity in its cognitive and behavioral
manifestations. Recent research suggests that gender may be an important
modifying factor in AD's development and expression.
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.
Neuropsychological Differences
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.
Differences in Behavioral Disturbances
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).
Structural Brain Differences
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.
Conclusion
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.
References
Bayles KA, Azuma T, Cruz RF et al. (1999), Gender differences in language of
Alzheimer disease patients revisited. Alzheimer Dis Assoc Disord
13(3):138-146.
Buckwalter JG, Rizzo AA, McCleary R et al. (1996), Gender comparisons of
cognitive performances among vascular dementia, Alzheimer disease, and older
adults without dementia. Arch Neurol 53(5):436-439.
Buckwalter JG, Sobel E, Dunn ME et al. (1993), Gender differences on a brief
measure of cognitive functioning in Alzheimer's disease. Arch Neurol
50(7):757-760.
Coffey CE, Lucke JF, Saxton JA et al. (1998), Sex differences in brain
aging: a quantitative magnetic resonance imaging study. [Published erratum Arch
Neurol 55(5):627.] Arch Neurol 55(2):169-179.
Cohen D, Eisdorfer C, Gorelick P et al. (1993), Sex differences in the
psychiatric manifestations of Alzheimer's disease. J Am Geriatr Soc
41(3):229-232.
Devanand DP, Brockington CD, Moody BJ et al. (1992), Behavioral syndromes in
Alzheimer's disease. Int Psychogeriatr 4(suppl 2):161-184.
Drachman DA, Swearer JM, O'Donnell BF et al. (1992), The Caretaker
Obstreperous-Behavior Rating Assessment (COBRA) Scale. J Am Geriatr Soc
40(5):463-470.
Hauser WA, Amatniek JC (1998), Gender differences in diseases of the nervous
system. In: Neurologic Disease in Women, Kaplan PW, ed. New York: Demos Medical
Publishing Inc., pp433-442.
Hebert LE, Wilson RS, Gilley DW et al. (2000), Decline of language among
women and men with Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci
55(6):354-360.
Henderson VW, Buckwalter JG (1994), Cognitive deficits of men and women with
Alzheimer's disease. Neurology 44(1):90-96.
Jack CR Jr, Petersen RC, Xu YC et al. (1997), Medial temporal atrophy on MRI
in normal aging and very mild Alzheimer's disease. Neurology 49(3):786-794 [see
comment].
Jagust WJ, Haan MN, Eberling JL et al. (1996), Functional imaging predicts
cognitive decline in Alzheimer's disease. J Neuroimaging 6(3):156-160.
Jorm AF, Jolley D (1998), The incidence of dementia: a meta-analysis.
Neurology 51(3):728-733.
Lyketsos CG, Steele C, Galik E et al. (1999), Physical aggression in
dementia patients and its relationship to depression. Am J Psychiatry
156(1):66-71.
Nitrini R, Buchpiguel CA, Caramelli P et al. (2000), SPECT in Alzheimer's
disease: features associated with bilateral parietotemporal hypoperfusion. Acta
Neurol Scand 101(3):172-176.
Ott BR, Heindel WC, Tan Z, Noto RB (2000a), Lateralized cortical perfusion
in women with Alzheimer's disease. J Gend Specif Med 3(6):29-35.
Ott BR, Lapane KL, Gambassi G (2000b), Gender differences in the treatment
of behavior problems in Alzheimer's disease. SAGE Study Group. Systemic
Assessment of Geriatric drug use via Epidemiology. Neurology 54(2):427-432.
Ott BR, Tate CA, Gordon NM, Heindel WC (1996), Gender differences in the
behavioral manifestations of Alzheimer's disease. J Am Geriatr Soc
44(5):583-587.
Paulsen JS, Salmon DP, Thal LJ et al. (2000), Incidence of and risk factors
for hallucinations and delusions in patients with probable AD. Neurology
54(10):1965-1971.
Ripich DN, Petrill SA, Whitehouse PJ, Ziol EW (1995), Gender differences in
language of AD patients: a longitudinal study. Neurology 45(2):299-302.
Sherwin BB (1997), Estrogen effects on cognition in menopausal women.
Neurology 48(5 suppl 7):S21-S26.
Small GW, Kuhl DE, Riege WH et al. (1989), Cerebral glucose metabolic
patterns in Alzheimer's disease. Effect of gender and age at dementia onset.
Arch Gen Psychiatry 46(6):527-532.
Smith CD, Pettigrew LC, Avison MJ et al. (1995), Frontal lobe phosphorus
metabolism and neuropsychological function in aging and in Alzheimer's disease.
Ann Neurol 38(2):194-201.