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Alzheimer disease: Time to improve its diagnosis and treatment

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Amyloid-lowering drugs are being tested

The cholinesterase inhibitors and memantine are symptomatic therapies that help maintain neuronal function but do not have a significant impact on the underlying disease process. Their benefits are mild, and treatments that modify the disease course are urgently needed.54,55

New disease-modifying agents are being tested to see if they delay disability, promote independence, and improve quality of life. Chief among these are compounds that reduce brain amyloid.

The amyloid cascade hypothesis is the current prevailing view of the pathogenesis of Alzheimer disease.56 Small molecules of extracellular amyloid are deposited in the brain early in the course of the disease. These oligomers of beta-amyloid gradually coalesce into fibrillar sheets that form the core of amyloid plaques. Amyloid invokes an immune response and stimulates the hyperphosphorylation of tau into intraneuronal neurofibrillary tangles. The accumulation of these tangles contributes to neuronal and synaptic loss, which correlates with dementia and disability.

The current disease-modifying strategies are designed to decrease the production of amyloid, inhibit fibrillogenesis, and promote clearance of the toxic amyloid beta 1–42 fragment. We should note, however, that the correlation between amyloid burden and clinical decline is not strong, and that lowering brain amyloid may not produce a measurable clinical benefit.57

Large-scale trials are being conducted with agents that modulate and inhibit gamma secretase, an enzyme involved in cleaving the amyloid precursor protein into the toxic fragment of beta amyloid.58 Early results show improvement in cognition and decreased amyloid levels in transgenic animals treated with these agents.

A recently completed phase III trial of tramiprosate, a glycosaminoglycan receptor inhibitor that interferes with fibrillization of amyloid, did not show positive results, but other antifibrillization agents are currently being tested.59,60

Exciting immunotherapeutic approaches that target the toxic fragment of beta amyloid have been developed. In the active vaccine approach, a small fragment of beta amyloid is injected to stimulate the production of beta amyloid antibodies to lower brain amyloid levels. However, although active vaccines are designed primarily to stimulate a B-cell response, they can cause adverse effects through unplanned stimulation of T cells.

Passive immunization with a monoclonal antibody against beta amyloid may be a safer strategy, and a number of compounds are undergoing clinical trials.61–63 Intravenous immune globulin contains antiamyloid antibodies and other immunomodulatory factors that may be useful in treating Alzheimer disease, and a phase III trial is being planned in view of positive results from earlier-phase studies.64

Future disease-modifying treatments

Treatments designed to prevent hyperphosphorylation of tau are also being pursued. Currently approved compounds such as lithium (Eskalith) and valproic acid (Depakene) have been shown to decrease the formation of neurofibrillary tangles in laboratory models. There is some retrospective epidemiologic evidence that statin treatment is associated with a lower incidence of Alzheimer disease and decreased amyloid deposition in in vitro preparations, and two large phase III trials of statins in addition to cholinesterase inhibitors are nearing completion.65,66

Aging is the strongest risk factor for Alzheimer disease, and future treatment targets will be derived from new insights into the biology of neuronal aging and senescence. Two recent phase III trials of xaliproden, a neurotrophin enhancer, were negative in patients with mild to moderate Alzheimer disease.67

Future mechanism-based treatments will be directed at reducing oxidative stress, promoting neurorestoration, and genetic modification. A summary of the disease-modifying strategies now being tested has recently been published (Table 3).

SOME RISK FACTORS ARE MODIFIABLE

Evidence is growing that nutritional factors (eg, dietary restriction, antioxidant intake, and the Mediterranean diet) and lifestyle factors (eg, social and mental activity and exercise) can promote healthy brain aging and delay the onset of Alzheimer disease.69,70

Animals on low-calorie diets live longer, and some epidemiologic studies have shown that people who consume fewer calories have a lower incidence of Alzheimer disease.69

Consuming fish two to three times per week appears to lower the incidence of Alzheimer disease, and a recent report in 2,254 elderly people followed for 4 years found that a Mediterranean diet of fish, olive oil, vegetables, and fruit had a protective effect.71

Resveratrol, a chemical found in red wine, is associated with longevity. A clinical trial of resveratrol to prevent Alzheimer disease is being planned.72–74 Compounds such as docosahexaenoic acid (an omega-3 fatty acid), a flavanoid found in green tea, and curcumin (a component of many curry dishes) are also associated with lowering levels of amyloid.75–77

Foods high in antioxidants may reduce the risk of Alzheimer disease.69,78 Daily folate supplements may have a protective effect, but antioxidants such as vitamin E and anti-inflammatory medications have shown disappointing results in preventing or treating Alzheimer disease and may have significant adverse effects.44,59,79,80

Evidence is also increasing that education, learning new skills, frequent socializing, and regularly engaging in physical exercise and mentally stimulating activities delay the onset of Alzheimer disease, and these pursuits should be encouraged.81–83 Also, treatment of cardiovascular risk factors such as hypertension and hyperlipidemia in mid-life and in older age may lower the rate of cognitive impairment in the elderly.84–86

ACKNOWLEDGMENT

The authors would like to thank Caroline O’Connor and Martha Dunlap for their assistance in preparing this manuscript.

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