Overview and Risk Factors
Alzheimer's disease is a slowly progressive dementia characterized by memory loss and behavioral changes. Pathological changes in the brain include atrophy of the cerebral cortex (particularly in the temporal and parietal lobes), the presence of neurofibrillary tangles and senile (amyloid) plaques, a loss of cholinergic neurons in the brain, and reduced activity of choline acetyltransferase (the enzyme responsible for acetylcholine production) in the cerebral cortex and hippocampus. The presence of the allele ApoE epsilon 4 (e4) is a major risk factor for Alzheimer's disease, as it is associated with increased amyloid plaque accumulation.
The disease progresses from mild memory impairment to severe cognitive loss with personality/behavioral changes, sometimes including irritability, delusions and hallucinations. Often there are language problems (particularly with generation of nouns (dysnomia)), and spatial disorientation is common. Alzheimer's disease reduces life expectancy by as much as 50% following initial diagnosis.1
Alzheimer's disproportionately affects women and African Americans. Evidence suggests that Alzheimer's disease is associated with the following:
- Older age. Results of a U.S. community study (n=3,623) estimated prevalence at 3.0% for ages 65 to 74, 18.7% for ages 75 to 84, and 47.2% for those over 85.2 In 2000, 4.5 million people in the United States had Alzheimer's, and that number will nearly triple by 2050 with the aging of the population.3
- Family history. Risk is inversely proportional to the age of onset in a first-degree relative.
- Genetics. Presence of the ApoE e4 allele and other genetic factors such as trisomy 21.4
- Insulin resistance.5
- Hypercholesterolemia.4 Of the 1,037 postmenopausal women enrolled in the Heart and Estrogen/Progestin Replacement Study, those with LDL cholesterol levels in the top 25 percent had 76% greater odds of developing cognitive impairment, compared with women who had lower LDL levels.6
- Overweight. Women over the age of 70 had a 36% increased risk for Alzheimer's disease for every one point increase in body mass index.7 This finding has not been replicated in men.
- Hypertension,4 declining blood pressure over time, cerebro/cardiovascular disease, diabetes, smoking, and persistently elevated alcohol use. All of these factors are associated with cerebral atrophy. Being overweight may exacerbate these factors or lead to cerebral atrophy directly.8
- Elevated homocysteine.9,10
Diagnosis and Treatment
Since the pathologic findings cannot be demonstrated except by autopsy (or, rarely, by brain biopsy), evaluation of the patient with suspected Alzheimer's disease is generally focused on identifying potentially treatable disorders that produce cognitive deficits.
Neuroimaging, particularly magnetic resonance imaging, can help rule out potentially treatable causes of dementia such as vascular dementia, hydrocephaly, and brain tumors, even in the absence of focal findings. Tests of potential metabolic abnormalities (eg, hypothyroidism, vitamin B12 deficiency, electrolyte abnormalities) should be included in the workup.
Severe sleep disorders, disorders of liver and renal function, and various medications can produce cognitive effects. Strong consideration should be given to possible depression (pseudodementia). Neurospychiatric testing may be useful to aid in the diagnosis of Alzheimer's disease or to evaluate its course. Such testing may be particularly helpful if the presentation is atypical.
Overlap with other causes of dementia does occur; eg, Lewy body dementia and Pick's disease. However, because treatment is based on symptoms, biopsy is not commonly performed.
People who exercise, participate in intellectually stimulating activities, and remain active in social networks appear to be at lower risk for Alzheimer's,11 and those affected may slow its progression through these activities.
Drugs may have a modest effect.
- Memantine, an N-methyl-D-aspartate receptor antagonist, along with galantamine, may slow the loss of mental and physical function. Memantine has modest effects in patients with moderate-to-advanced disease.
- Preliminary evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may provide some protection against Alzheimer's disease.12 This finding requires further study.
- The benefits of acetylcholinesterase inhibitors, such as donepezil, have been questioned, are small and may not be greater than placebo.13
- Ginkgo biloba may provide a modest benefit. A ginkgo biloba extract known as EGb761 appears to act by a mechanism similar to that of cholinesterase inhibitors for mild-to-moderate Alzheimer's disease,14 and showed a small benefit over a placebo in clinical trials.15-17
Several epidemiological studies have examined associations between diet and Alzheimer's disease risk.18 The following factors are under study for a possible role in reducing risk:
Low Plasma Cholesterol
Elevated cholesterol levels are associated with increased risk for Alzheimer's disease, even after controlling for the presence of the apo E e4 allele.19 Use of lipid-lowering agents has been found in several epidemiological studies to be associated with a lower risk of dementia,20,21 although clinical trials have not yet supported this conclusion. It is not clear whether the lipid-lowering effect of statin drugs or some other neuroprotective effect of these medications may be responsible.
Reduced Saturated and Trans Fatty Acids
High intake of saturated fats and trans fats, which come mainly from animal products, are associated with risk of Alzheimer's disease.22-24 In contrast, limited evidence suggests that diets high in omega-3 fatty acids may reduce Alzheimer's disease risk.25
Adherence to a Mediterranean diet is associated with reduced Alzheimer's risk.26 Some have suggested that the regular consumption of fatty fish intake (ie, more than twice per week) may be associated with lower risk for AD in individuals without the e4 allele.27 However a systematic review by the Agency for Healthcare Research and Quality (AHRQ) concluded that data are inadequate to justify conclusions.28
Maintaining Healthy Weight
Avoidance of overeating and maintenance of ideal weight may lower risk for Alzheimer's. Reduced energy intake may reduce the risk for Alzheimer's, especially in people carrying the apo E e4 allele.29 An 18-year follow-up study found that women diagnosed with dementia had higher average body mass index than non-demented individuals.7
Antioxidant supplements and nutrients may offer a measure of protection against Alzheimer's disease. Some evidence indicates that a combination of vitamins C and E is associated with an 80% lower risk for Alzheimer's disease,30 and two prospective studies found that greater intakes of foods high in either vitamin E31 or vitamin C32 may lower the risk for Alzheimer's disease. One study suggested benefits from pharmacologic dosages of vitamin E in treating Alzheimer's disease that were similar to those from selegiline.33 Recent studies have suggested that the specific, diet-derived forms of vitamin E may be important to any protective effect.34 Not all studies have supported these findings, however, andcontrolled clinical studies are required to assess the possible benefits of vitamin E and vitamin C.
Good sources of vitamin C include citrus fruits, kiwi, melons, and many vegetables. Good sources of vitamin E include wheat germ, peanuts, and sunflower seeds.
An adequate intake of folate, B6, and B12 may reduce risk of Alzheimer's disease. Inadequate intakes of these B vitamins can cause a rise in plasma homocysteine, which in turn is a strong and independent risk factor for the development of Alzheimer's disease.9,35 Findings suggest that low folate or B12 status may precede the onset of Alzheimer's disease.18,36
Some evidence suggests that avoiding dietary or environmental exposure to aluminum may reduce the risk for Alzheimer's disease. Although aluminum is not yet established as a direct cause of Alzheimer's disease in humans,37,38 epidemiological studies have found statistically significant relationships between aluminum in drinking water and Alzheimer's disease,39 and some evidence exists that patients with Alzheimer's disease have increased absorption of aluminum even when they are on normal diets.40 Aluminum has caused neurotoxic effects in individuals who have been exposed to the metal occupationally, by dialysis, or through the use of aluminum-containing medications.37,41
Avoiding Excess Iron
Excess iron intake may contribute to Alzheimer's risk. Iron accumulates in the brain with aging, and evidence suggests that iron contributes to the beta-amyloid deposition, amyloid precursor protein, free radicals, and neurofibrillary tangles that characterize this disease. In addition, the brains of Alzheimer's patients appear to exhibit numerous defects in iron storage, binding, and mobilization not seen in the brains of healthy control participants.42 Evidence of the role of these ions in Alzheimer's disease is partly confirmed by previous studies43,44 and more recent investigations45 revealed improvement in Alzheimer's patients treated with chelating agents that remove excess aluminum, iron, and copper.
Moderate Alcohol Consumption
Although alcohol intake as low as 20 grams per day (1.25 servings) is a known risk factor for certain cancers, hypertension, and several other diseases,46 recent studies show that people who consume 1 to 3 drinks per day have a lower risk for Alzheimer's disease, compared with teetotalers.47 In most of these studies, risk reduction was associated with wine and not alcohol per se,18 and a cause-and-effect relationship has not been established. Benefits of moderate alcohol consumption, if any, are thought to derive from alterations in blood lipids, platelet aggregation, and antioxidant flavonoids present in red wine.
Physical and occupational therapy consultation for home safety evaluation and needs assessment.
What to Tell the Family
Although no cure for Alzheimer's disease is known, drug treatment may slow progression. Additionally, behavioral changes that include mental and physical exercise may help slow the disease process. A diet low in saturated fat, cholesterol, and trans fatty acids will help prevent other age-related debilitating diseases in the patient. This diet is also ideal for the general health of the whole family, and may help prevent the occurrence of Alzheimer's in family members. Safety precautions for Alzheimer's patients are important at all times. Connection with social services or a support group may also help ease the burden of care for a person with Alzheimer's disease. Family members may desire to be tested for the presence of the apo E e4 allele; at minimum, they should be encouraged to mitigate their future risk of Alzheimer's by noting the above recommendations.
1. Larson EB, Shadlen MF, Wang L, et al. Survival after initial diagnosis of Alzheimer's disease. Ann Int Med. 2004;140:501-509.
2. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported. JAMA. 1989;262:2551-2556.
3. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer's disease in the US population: prevalence estimates using the 2000 census. Arch
4. Kivipelto M, Helkala EL, Laakso MP, et al. Apoliprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer's disease. Ann Intern Med. 2002;137:149-155.
5. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3:169-178.
6. Yaffe K, Barrett-Connor E, Lin F, Grady D. Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol. 2002;59:378-384.
7. Gustafson D. An 18-year follow-up of overweight and risk of Alzheimer's disease. Arch Intern Med. 2003;163:1524-1528.
8. Gustafson D, Lissner L, Bengtsson C, BjÃƒÂ¶rkelund C, Skoog I. A 24-year follow-up of body mass index and cerebral atrophy. Neurology. 2004;63:1876-1881.
9. den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of nondemented elderly. Brain. 2003;126(pt 1):170-175.
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. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 2004; 3:343-353.
12. In't Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001;345:1515-1521.
13. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet. 2004;363:2105-2115.
14. Wettstein A. Cholinesterase inhibitors and Gingko extracts--are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration. Phytomedicine. 2000;6:393-401.
15. Le Bars PL, Kieser M, Itil KZ. A 26-week analysis of a double-blind, placebo-controlled trial of the ginkgo biloba extract EGb 761 in dementia. Dement Geriatr Cogn Disord. 2000;11:230-237.
16. Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multicenter, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry. 2003;36:297-303.
17. Birks J, Grimley EV, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2002;(4):CD003120.
18. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. Lancet Neurol. 2004;3:579-587.
19. Notkola IL, Sulkava R, Pekkanen J, et al. Serum total cholesterol, apoliprotein E e4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;17:14-20.
20. 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;59:223-227.
21. Simons M, Keller P, Dichgans J, Schulz JB. Cholesterol and Alzheimer's disease. Neurology. 2001;57:1089-1093.
22. Morris MC, Evans DA, Bienias JL, et al. Dietary fats and the risk of incident Alzheimer's disease. Arch Neurol. 2003;60:194-200.
23. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997;42:776-782.
24. Giem P, Beeson WL, Fraser GE. The incidence of dementia and intake of animal products: preliminary findings from the Adventist Health Study. Neuroepidemiology. 1993;12:28-36.
25. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer's disease. Arch Neurol. 2003;60:940-946.
27. Huang TL, Zandi PP, Tucker KL, et al. Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology. 2005;65:1409-1414.
28. MacLean CH, Issa AM, Newberry SJ, et al. Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Rockville, MD: Agency for Healthcare Research and Quality; February 2005. AHRQ publication 05-E011-2.
29. Luchsinger JA, Tang M-X, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer's disease. Arch Neurol. 2002;59:1258-1263.
31. Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer's disease in a biracial community study. JAMA. 2002;287:3230-3237.
32. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer's disease. JAMA. 2002;287:3223-3229.
33. Sano M, Ernesto C, Thomas RG. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med. 1997;336:1216-1222.
34. Morris MC, Evans DA, Tangney CC, et al. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. American Journal of Clinical Nutrition. 2005;81:508-514.
35. Mattson MP. Will caloric restriction and folate protect against AD and PD? Neurology. 2003;60:690-695.
36. Quadri P, Fragiacomo C, Pezzati R, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer's disease, and vascular dementia. Am J Clin Nutr. 2004;80:114-122.
37. Campbell A. The potential role of aluminum in Alzheimer's disease. Nephrol Dial Transplant. 2002;17(suppl 2):17-20.
38. Yokel RA. The toxicology of aluminum in the brain: a review. Neurotoxicology. 2000;21:813-828.
39. Flaten TP. Aluminum as a risk factor in Alzheimer's disease, with emphasis on drinking water. Brain Res Bull. 2001;55:187-196.
40. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm. 2003;110:95-110.
41. Soni MG, White SM, Flamm WG, Burdock GA. Safety evaluation of dietary aluminum. Regul Toxicol Pharmacol. 2001;33:66-79.
42. Thompson KJ, Shoham S, Connor JR. Iron and neurodegenerative disorders. Brain Res Bull. 2001;55:155-164.
43. McLachlan DR, Smith WL, Kruck TP. Desferrioxamine and Alzheimer's disease: video home behavior assessment of clinical course and measures of brain aluminum. Ther Drug Monit. 1993;15:602-607.
44. Crapper-McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet. 1991;337:1304-1308.
45. Ritchie CW, Bush AI, Mackinnon A, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60:1685-1691.
46. Rehm J, Gmel G, Sempos CT, Trevisan M. Alcohol-related morbidity and mortality. Alcohol Res Health. 2003;27:39-51.
47. Letenneur L, Larrieu S, Barberger-Gateau P. Alcohol and tobacco consumption as risk factors of dementia: a review of epidemiological studies. Biomed Pharmacother. 2004;58:95-99.