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Dementia in Women: A Clinical Update

Vivian M. Dickerson, MD

The association between increasing age and dementia risk is indisputable, but data on possible protective/preventive measures remain tantalizingly ambiguous.

Physicians are all too aware of the fear that the word “Alzheimer’s” generates in patients. Alzheimer disease (AD), which is more prevalent in women, is the most common cause of dementia in the United States.1 In fact, the term is frequently misused to characterize a broad spectrum of cognitive disorders, from the cognitive decline of aging, through mild cognitive dysfunction, to severe dementia due to a number of different etiologies. Although it is realistic to expect some cognitive decline with aging, dementia is not a normal part of this process.

Cognitive decline with aging includes decreased memory, slowed learning, and/or impaired concentration. Minimizing or delaying these changes requires concerted effort. Data suggest that it is effort well spent, though, as use-related neuroplasticity of the corticolimbic regions of the brain appears to be a lifelong process.2 Nonetheless, there is no consensus on what sorts of activities most effectively retard cognitive decline.

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MILD COGNITIVE IMPAIRMENT

Mild cognitive impairment (MCI) is defined as a cognitive decline that is of a greater magnitude than would be expected with aging alone. It includes amnestic MCI, multiple domain MCI, and single, nonmemory domain MCI. The prevalence of MCI is unclear from epidemiologic studies, ranging from 3% to 19%.3 The condition is not necessarily progressive; indeed, some patients with MCI remain stable or return to baseline. However, there is a definite relationship with future dementia in more than 50% of cases.3

Dementia represents various forms of cognitive decline, but is more profound than MCI in terms of clinical implications and impact on lifestyle (Table 1). Not a disease entity per se, dementias are rather a collection of symptoms that tend to occur together, such as language deficits, memory loss, and behavioral changes. Dementia may occur at any time during the lifespan, but is more common in the elderly—age being a major risk factor. Other risk factors vary, depending on the type of dementia. Amnestic MCI appears to be a prognostic indicator for the development of AD. In addition to age, other risk factors for AD include lower educational level, hypercholesterolemia, and the apolipoprotein Eε4 allele.4 Risk factors for vascular dementia (VaD)—also referred to as multi-infarct dementia—include hypertension, stroke, and drug or alcohol abuse. Data suggest that smoking confers an increased risk of AD, but not VaD.5 Genetics and family history play a predominant role in the dementias associated with Parkinsonism, epilepsy, and Huntington disease, and to a lesser degree, AD. At one time it was thought that head trauma was associated with an increased risk for dementia, but this remains controversial.6 Women were thought to be at greater risk for AD than men, but a study of stratified, random samples of people aged 65 and older found that risk did not differ significantly between men and women, and that the excess number of women with AD simply reflects their longer life expectancy.7

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Table 1. Types Of Dementia

Given the higher prevalence of dementia in women, the clinician must be alert to changes that occur in patients over time. If such changes are suspected, involving family members in discussion and referral can be most helpful. Routine questioning during physical examination may elicit memory deficits or slowed cognitive functioning (Table 2). Patients may be referred to a neurologist for more formal mental status evaluation, laboratory testing, and imaging.

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Table 2. Mental Status Screening in the Office

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PREVENTION

In many cases, dementia cannot be prevented. Nonetheless, measures to reduce the risk and/or impact of diabetes, hypertension, and cerebrovascular disease—especially stroke—are essential. There are 4 additional areas of particular interest to women: hormones, statin drugs, caffeine intake, and physical activity.

Hormones

The most definitive review of the role of hormones in cognition and dementia was published in 2004 by ACOG.8 The review was prompted by conflicting findings regarding hormone therapy (HT) and dementia from several major studies, ranging from a protective effect to no effect to a deleterious effect.9-12 The analysis concluded that the data were insufficient to:

• Evaluate any positive or negative impact of estrogen, with or without progestin, on cognitive decline
• Conclude that HT provides long-term cognitive protection when used early in menopause
• Support HT use to prevent or treat cognitive decline.

Since the ACOG review, there has been only one significant trial of relevance. This study involved 180 women aged 45 to 55 years who had cognitive concerns and were randomized to either estrogen/progestin HT or placebo.13 The trial was truncated, but the limited data (powered to detect an effect size of 0.45 or more) found modest negative effects on short- and long-term verbal memory.

Notably, a study on premenopausal oophorectomy demonstrated an increased lifetime risk of cognitive impairment and dementia.15 The effect was age-dependent, with the greater risk in younger women, and was similar for both unilateral and bilateral cases. Data also show that women with dementia appear to have lower estrogen levels than women without dementia. It has been proposed that there may be an age-dependent “window” in which endogenous hormones are neuroprotective.16

Statins

Hyperlipidemia has been noted to be a risk factor for dementia,17 so it would seem that the ability of statin drugs to reduce lipid levels and vascular inflammation might help to prevent or slow the progress of dementia. One study found such a protective effect for individuals over the age of 50,18 concluding that statins conferred a substantially lower risk of dementia, independent of hyperlipidemia. The subtypes of dementia were not differentiated. A confirmatory study likewise noted that use of lipid-lowering agents (LLAs) in patients less than 80 years of age was associated with a decreased risk of dementia, particularly AD.19 An observational study found that LLAs slow cognitive decline in AD, and appear to have a neuroprotective effect.20 As with HT and dementia, though, data are conflicting, with other research identifying no such effect.21,22 Therefore, data remain insufficient to warrant a recommendation to prescribe statins to prevent or slow dementia.

Caffeine

Although there are no extensive studies regarding caffeine and dementia, some interesting data on women have emerged. One modest case-control study of 54 patients with probable AD and 54 cognitively normal, matched controls found that the patients with AD had a daily caffeine intake that was more than 50% lower than that of the controls.23 Indeed, caffeine exposure was found to be inversely associated with AD. Many other factors were assessed, including the use of NSAIDs, which appear to confer protection in some studies. However, none of these other factors reached statistical significance in association with AD risk. Another, much larger, cohort study confirmed that women with high rates of caffeine consumption (defined as 3 or more cups per day) showed less cognitive decline when compared with women consuming one cup or less.24 Furthermore, the protective effect of caffeine increased with age. No such relationship between caffeine and cognitive decline has been found in men. Caffeine seems to have no impact on the dementia risk for either gender.

Physical Activity

Perhaps the sine qua non of modifiable lifestyle elements related to overall health is physical activity. Patients should be encouraged to engage in regular exercise for 30 minutes, at least 5 times per week. Reasons for this recommendation include cardiovascular benefit, stamina, overall fitness, and weight control/maintenance. Physical activity has been positively correlated with reductions in blood pressure, low-density lipoprotein levels, and breast cancer risk, and an increase in high-density lipoprotein levels. With so many reasons to encourage exercise in women, it is not surprising that physical activity has been evaluated as a possible protective mechanism against cognitive decline and dementia. The major studies to date all seem to indicate some benefit. A prospective study of 5925 women over age 65 demonstrated that those with a higher level of baseline physical activity were less likely to experience cognitive decline.25 Another trial of subjects over age 65 found that VaD was significantly lower for the upper tertiles of walking and total physical activity compared with the corresponding lowest tertiles. The risk of AD was not found to be associated with measures of physical activity.26 By contrast, a prospective cohort study of 1740 patients over the age of 65 demonstrated that regular exercise was associated with a delay in the onset of both AD and incident dementia.27 Indeed, a meta-analysis of patients with dementia or cognitive impairment demonstrated increased cognitive function with exercise.28

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CONCLUSION

Alzheimer disease and other dementias represent a major health problem among elderly women. While risk factors are known, the data remain unclear with regard to protection and risk reduction. At present, neither HT nor statins can be prescribed for this purpose alone. The data on caffeine and NSAIDs seem to be more promising. Physical activity—always a good idea—may have some protective benefit, and should be encouraged not only in healthy elderly women, but also in those with existing cognitive impairment or dementia.

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Vivian M. Dickerson, MD, is Clinical Professor of Obstetrics and Gynecology, University of California, Irvine; Director of Women’s Health Care and Programs, Hoag Memorial Hospital, Newport Beach, CA; and Editor-in-Chief, The Female Patient.

References

1. Naftolin F. Cognitive function and menopause. The Female Patient. 2002;27(2):46-47.
2. Verghese J, Lipton R, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003;348(25):2508-2516.
3. Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet. 2006;367(9518): 1262-1270.
4. Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156(5):445-453.
5. Anstey KJ, von Sanden C, Salim A, O’Kearney R. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol. 2007;166(4):367-378.
6. Jellinger KA. Head injury and dementia: trauma and rehabilitation. Curr Opin Neurol. 2004;17(6): 719-723.
7. Hebert LE, Scherr PA, McCann JJ, Beckett LA, Evans DA. Is the risk of developing Alzheimer’s disease greater for women than for men? Am J Epidemiol. 2001;153(2):132-136.
8. American College of Obstetricians and Gynecologists Women’s Health Care Physicians. Cognition and dementia. Obstet Gynecol. 2004;104(4 Suppl):25S-40S.
9. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. JAMA. 2002;113(7):543-548.
10. Pan H-A, Wang S-T, Pai M-C, Chen C-H, Wu M-H, Huang K-E. Cognitive function variations in postmenopausal women treated with continuous combined HRT or tibolone: a comparison. J Reprod Med. 2003;48(5):375-380.
11. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20): 2651-2662.
12. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women. Women’s Health Initiative Memory Study. JAMA. 2004; 291(24):2959-2968.
13. Maki PM, Gast MJ, Vieweg AJ, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology. 2007;69(13):1322-1330.
14. Pozzi S, Benedusi V, Maggi A, Vegeto E. Estrogen action in neuroprotection and brain inflammation. Ann NY Acad Sci. 2006;1089:302-323.
15. Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007; 69(11):1074-1083.
16. Manly JJ, Merchant CA, Jacobs DM, et al. Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neurology. 2000;54(4):833-837.
17. Kivipelto M, Helkala E-L, Laakso MP, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ. 2001;322(7300):1447-1451.
18. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356(9242):1627-1631.
19. Rockwood K, Kirkland S, Hogan DB, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002;59(2): 223-227.
20. Masse I, Bordet R, Deplanque D, et al. Lipid lowering agents are associated with a slower cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2005;76(12): 1624-1629.
21. Zandi PP, Sparks DL, Khachaturian AS, et al. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005;62(2):217-224.
22. Li G, Higdon R, Kukull WA, et al. Statin therapy and risk of dementia in the elderly: a community based prospective cohort study. Neurology. 2004;63(9): 1624-1628.
23. Maia L, de Mendonca A. Does caffeine intake protect from Alzheimer’s disease? Eur J Neurol. 2002;9(4):377-382.
24. Ritchie K, Carriere I, de Mendonca A, et al. The neuroprotective effects of caffeine: a prospective population study (the Three City Study). Neurology. 2007; 69(6):536-545.
25. Yaffe K, Barnes D, Nevitt M, Lui L-Y, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med. 2001;161(14): 1703-1708.
26. Ravaglia G, Forti P, Lucicesare A, et al. Physical activity and dementia risk in the elderly. Findings from a prospective Italian study. Neurology. 2007 Dec 19 [epub ahead of print].
27. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144(2):73-81.
28. Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil. 2004;85(10): 1694-1704.

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