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Menopause Matters

Alzheimer’s Disease and Dementia: New Insights

Cheryl Bushnell, MD, MHS

Age-related dementias represent a significant health problem in the postmenopausal population. The rising incidence of dementias expected to coincide with the continuous increase in life expectancy in most industrialized countries demands the exploration of causes, treatment, and prevention. Evidence suggests that Alzheimer’s disease (AD) has a vascular component; therefore, identification and treatment of vascular risk factors in patients in the preclinical phase have the potential to delay onset or slow progression of this devastating disease. In addition, cognitively stimulating activities may play a role in reducing the risk of dementia.

VASCULAR RISK FACTORS

Differentiating AD from vascular dementia has become more and more difficult, especially when patients have a combination of both strokes (clinical or silent) and cognitive decline. Research focusing on the similarities between AD and vascular dementia has provided clues to the possible underlying pathogenesis of both types of dementia. For example, epidemiologic studies have shown that multiple vascular risk factors, such as aging, stroke, diabetes, high cholesterol, hypertension, and high fat intake have been associated with an increased incidence of AD.¹ These risks are commonly associated with vascular dementia as well. This has led to the hypothesis that both AD and vascular dementia are caused by one or more vascular risk factors that ultimately lead to reduced cerebral blood flow. In support of the notion of hypoperfusion, single-photon emission computed tomography (SPECT) studies have shown patterns of regional cerebral perfusion deficits in AD patients, a finding that often precedes the development of cognitive deficits.² In addition, cholinesterase inhibitors currently used to slow cognitive decline, such as donepezil, rivastigmine, and galantamine, not only increase acetylcholine stores, but also lead to modest and transient improvements in cerebral blood flow.

STATINS AND DEMENTIA

The association between AD, elevated cholesterol, and the use of statins is also being actively studied. For instance, high cholesterol (> 6.5 mmol/L) in midlife has been associated recently with a nearly 2-fold risk in late-life mild cognitive impairment (MCI), a precursor to AD in which memory problems predominate and other cognitive domains are relatively preserved. The same study also found that the levels of cholesterol and systolic blood pressure were higher in demented subjects than those with MCI.³ To examine the role of cholesterol-lowering with statins and a potential for reducing the risk of dementia, a cohort study from the United Kingdom found that patients who used statins were almost 70% less likely to have a diagnosis of dementia than nonusers (odds ratio 0.29, 95% confidence interval 0.13-0.63, P=002).⁴ The actual mechanism of how statins may decrease the risk of dementia is unclear, but they have been shown to decrease cholesterol neogenesis in the brain⁵ and decrease production of Ab peptide,⁶ a precursor to amyloid plaque formation found commonly in the brains of AD patients. A recent randomized controlled trial of simvastatin vs placebo found no overall decrease in cerebrospinal fluid levels of Ab peptide in AD subjects, but those with milder dementia (Mini-mental Status Exam score of 21-26) had a significant reduction in one subtype of Ab.⁷ More clinical trials are either planned or in progress to further investigate the potential of statins for delaying onset or slowing progression of AD and/or vascular dementia.

HYPERHOMOCYSTEINEMIA

Hyperhomocysteinemia is an additional vascular risk factor implicated in vascular dementia and AD. This condition results from a disturbance in methionine metabolism, originating with enzyme and/or vitamin deficiency. Moderately elevated homocysteine levels have been shown in multiple studies to be an independent risk factor for cardiovascular disease, and the association between homocysteine and dementia may be related to its role in vascular disease. For example, one study found that AD and vascular disease together were associated with homocysteine levels greater than 12 mmol/L, but AD without vascular disease was not.⁸ However, a recent study from Northern Ireland reported a significant increase in plasma homocysteine levels in subjects with stroke, vascular dementia, and AD compared to controls, a finding that was independent of apolipoprotein E (APO E) genotype or nutritional status.⁹ In addition, the Framingham study reported a nearly 2-fold risk of developing AD in patients with a homocysteine level greater than 14 mmol/L.¹⁰ Based on evidence from these and other studies, homocysteine testing in patients at risk for vascular dementia and/or AD could be useful, especially because these levels can be lowered with a combination of folic acid, and vitamins B6 and B12. However, whether lowering homocysteine levels improves cognition in those with dementia is unknown.

SUPPORT FOR COGNITIVE EXERCISE

An intriguing new paper by Wilson et al describes a longitudinal cohort study following 724 older Catholic nuns, priests, and brothers who did not have dementia at enrollment, recruited from 40 churches across the United States.¹¹ At baseline, participants rated their frequency of participation in cognitive activities that require information processing (eg, reading); the investigators used these data to calculate a composite measure of cognitive activity. The analysis also included global and specific tests for cognitive function administered at baseline and at 1-year intervals during the study period (mean follow-up 4.5 years). A total of 111 participants developed AD during the study period. After accounting for age, sex, and education, a 1-point increase in cognitive activity score correlated with a 33% reduction in the risk for AD. In addition, there was up to a 60% reduction of specific types of memory loss. Although the subjects were highly selected in terms of lifestyle and education (mean 18.1 years), this study provides evidence that frequent cognitively stimulating activities are linked with a reduced risk of AD. The authors also speculate that if a high level of cognitive activity prevents AD, then a reduction in this cognitive activity may signal early development of the disease.¹¹ Further research in this area, including markers of transitions from normal cognition, to MCI, to AD, correlated with preclinical imaging studies (eg, SPECT) are necessary to determine whether cognitively stimulating activities would delay onset or slow progression of AD.

CONCLUSION

New research findings are clearly providing insights into the pathogenesis of AD and vascular dementia. Treatment and modification of common vascular risk factors in the primary care setting are essential since this could lead to a reduction in the risk of dementia in many elderly patients. This could include aggressive lowering of cholesterol with statins and treatment of hyperhomocysteinemia and elevated blood pressure, for example. In addition, encouraging patients to maintain cognitively stimulating activities in their daily routines may be a simple nonpharmacologic method of reducing their risk of dementia. Understanding of the pathogenesis of dementia ultimately will lead to the development of effective disease-altering therapies.

Cheryl Bushnell, MD, MPH, is associate in neurology, Duke University Medical Center, Durham, NC.

REFERENCES

1. de la Torre J. Alzheimer disease as a vascular disorder. Nosological evidence. Stroke. 2002;33:1152-1162.
2. Johnson K, Jones K, Holman B, Becker J, Spiers P, Satlin A, Albert M. Preclinical prediction of Alzheimer’s disease using SPECT. Neurology. 1998;50.
3. Kivipelto M, Helkala E-L, Tanninen T, et al. Midlife vascular risk factors and late-life mild cognitive impairment. A population-based study. Neurology.2001;56:1683-1689.
4. Jick h, Zornberg G, Jick S, Seshadri S, Drachman D. Statins and the risk of dementia. Lancet. 2000;356:1627-1631.
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6. Fassbender K, Simons M, Bergmann C. Simvistatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA. 2001;98:5856-5861.
7. Simons M, Schwarzler F, Lutjohann D, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002;52:346-350.
8. Miller J, Green R, Mungas D, Reed B, Jagust W. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology. 2002;58:1471-1475.
9. McIlroy S, Dynan K, Lawson J, Patterson C, Passmore A. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke. 2002;33.
10. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s Disease. N Engl J Med. 2002;346:476-483.
11. Wilson R, Mendes de Leon C, et al. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002;287: 742-748.

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