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. 2000 Feb;172(2):115–120. doi: 10.1136/ewjm.172.2.115

Update on Alzheimer's disease: recent findings and treatments

Ruth O'Hara 1, Martin S Mumenthaler 1, Jerome A Yesavage 1
PMCID: PMC1070770  PMID: 10693374

The United Nations estimates that the number of people with dementia in developed countries will increase from 13.5 million to 36.7 million between 2000 and 2050.1 Currently, about 4 million individuals with dementia live in the United States. Alzheimer's disease is the most common form of dementia, accounting for 50% to 70% of all cases and more than 100,000 deaths annually.2

The disease was first described by Alois Alzheimer in 1907; it is a progressive dementia characterized neuropathologically by widespread neuronal loss, β amyloid deposits in cerebral blood vessels, the development of neuritic plaques and the presence of neurofibrillary tangles. These deficits particularly affect the association areas of the cerebral cortex, the hippocampus, and the middle and temporal lobes. Decreased concentrations of the neurotransmitter acetylcholine are also a hallmark of Alzheimer's disease and are strongly associated with the severity of the dementia.

These neuropathologic changes result in the primary symptom of the disease: a decline in memory and cognition that leads to marked impairment in daily functioning. Changes in personality may be present as an early symptom of the illness, and behavioral disturbances including agitation, hallucinations, and delusions often occur as the disease progresses. The duration of the illness is approximately 7 to 10 years from the time of diagnosis; in the later stages of the disease, patients require total care. The overall economic and emotional burden of this illness is significant; the annual cost of caring for patients with Alzheimer's disease in the United States is estimated to be $119 billion.3

Although there has been important progress in describing and understanding Alzheimer's disease, there is no cure, and researchers are still trying to understand its etiology and pathophysiology. Currently, research is focused both on increasing our understanding of the pathophysiology of the illness to develop appropriate treatments and on identifying the risk factors for Alzheimer's disease to intervene in the preclinical stages of the illness. In this article we summarize the diagnostic criteria for Alzheimer's disease, describe the risk factors and current pharmacologic approaches, and discuss treating patients with the disease.

METHODS

This overview is based on findings from recent epidemiologic and experimental studies as well as randomized clinical trials. In addition to the data and literature available through Stanford's Aging Clinical Research Center, we conducted MEDLINE and PsychLit searches using the terms “Alzheimer's disease” and “dementia”, and searched the Cochrane Library database. This review also draws on additional literature reviews and the opinions of leaders in subspecialties of research into Alzheimer's disease.

Summary points

  • About 50% to 70% of all cases of dementia are Alzheimer's disease

  • Risk factors for Alzheimer's disease include being older than 60 years, having a family history of dementia, being female, and having lower levels of educational attainment

  • The apolipoprotein Eε4 allele has been identified as a genetic risk factor for Alzheimer's disease

  • The drugs tacrine and donepezil have been approved by the US Food and Drug Administration for use in treating Alzheimer's disease

  • In the United States, about 40% of patients with Alzheimer's disease take donepezil, the most commonly prescribed drug for this condition

  • Taking estrogen replacement therapy, anti-inflammatory drugs, and antioxidants may lower the risk and delay the onset of Alzheimer's disease

DIAGNOSTIC CRITERIA

The standard clinical criteria for the diagnosis of Alzheimer's disease were developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.4 Alzheimer's disease is classified as into one of three diagnostic categories: definite Alzheimer's disease, probable Alzheimer's disease, and possible Alzheimer's disease. The diagnosis of definite Alzheimer's disease requires histopathologic confirmation of clinical features by postmortem examination. Diagnoses made from the findings of the postmortem examination correspond to antemortem diagnoses about 90% of the time.5

In general, the criteria for the clinical diagnosis of probable Alzheimer's disease include onset between the ages of 40 and 90; no disturbance of consciousness; dementia established by clinical examination and a standardized assessment of mental status, which is supplemented by neuropsychologic tests; deficits in two or more areas of cognition (one of which is memory) that are characterized by gradual onset and progression; absence of systemic disorders or other brain diseases that could account for the progressive deficits in memory and cognition; and the deficits do not occur exclusively during an episode of delirium.

The clinical diagnosis of possible Alzheimer's disease is made using the same criteria as probable Alzheimer's disease except that only a single, progressive, severe cognitive deficit is identified and other identifiable causes are absent. Because this deficit is often memory loss alone there is sometimes an overlap between this syndrome and what is referred to as “mild cognitive impairment.” However, mild cognitive impairment typically involves milder memory loss than would be observed in dementia and also requires the absence of functional impairment.6

RISK FACTORS

Many investigators emphasize that intervening during both the preclinical and the early stage of Alzheimer's disease may prolong the functioning of patients and extend the length of time before they are placed in institutional care. Identifying candidates in the preclinical stages of the illness requires knowledge of the risk factors for Alzheimer's disease, and a large amount of research aims to identify these factors.

Age

Both the prevalence and incidence of Alzheimer's disease increase with advancing age, seeming to double about every 5 years after the age of 60.2, 7 The strong association between age and Alzheimer's disease has led investigators to suggest that biologic processes associated with aging may play a part in the development of the disease but that genetic, psychosocial, and environmental risk factors alter the age-specific rates of the illness.8

Genetic vulnerability

In the past 10 years there has been an important increase in our understanding of the genetic etiology of Alzheimer's disease. Point mutations in genes on chromosomes 1, 14, and 21 are expressed as autosomal traits linked to the development of early-onset Alzheimer's disease in specific families; however, patients with these mutations account for less than 5% of all patients with Alzheimer's disease.5

Several susceptibility genes for Alzheimer's disease have been identified. In particular, the apolipoprotein E ε4 allele is a genetic risk factor for the development of Alzheimer's disease.9 Apolipoprotein E is a protein that is thought to be active in the transport of plasma cholesterol and the repair of neurons. Apolipoprotein E is encoded by a gene on chromosome 19, and there are three allelic variants (ε2, ε3, ε4), yielding six possible genotypes. The presence of the ε4 allele is associated with a dose-dependent increased risk of Alzheimer's disease. Individuals with one ε4 allele have twice the risk of developing the disease as people without the allele, and individuals who are homozygous for the allele are 10 times more likely to develop the disease.10 However, studies have not found a strong association between the allele and progression of the disease, although there may be an association between the presence of the ε4 allele and the behavioral symptoms of Alzheimer's disease.11

Although it has been suggested that apolipoprotein E affects the deposition of amyloid, the development of neurofibrillary tangles, and cholinergic function, the exact pathophysiologic link between the ε4 allele and Alzheimer's disease remains unclear. Individuals without any of these susceptibility genes may develop the disease, but those who have genetic risk factors may never develop it.7,12 The current recommendations of the National Institute of Aging and the Alzheimer's Disease and Related Disorders Association are that genotyping for the allele should not be used to predict the risk of developing Alzheimer's disease in people without symptoms and should not be used as the sole diagnostic test for the disease.13

Family history of dementia

Having a family history of dementia is a risk factor for Alzheimer's disease; this risk extends beyond those family members who have genetic markers for susceptibility. The risk seems to increase between two- and four-fold among people who have a first-degree relative with the disease.5

Other possible risk factors

Prevalence studies have identified higher rates of Alzheimer's disease in women.5 However, these studies have often included only a small number of men with the disease, thus rendering the estimate of prevalence unstable. Higher levels of educational attainment are associated with a delay in the onset of the disease and lower levels with an increased risk.7 Investigators have suggested that education may increase synaptic density and thus minimize or delay the effects of neuronal loss associated with the disease.14 However, having less education may be a proxy for other factors such as poor nutrition and test bias. The observation of an association between arteriosclerosis, the ε4 allele, and risk of Alzheimer's disease has led to consideration of vascular risk factors in the etiology of the illness.15 Other suggested risk factors include traumatic head injury, depression, low levels of occupational attainment, and engaging in fewer social activities.16, 17 Interactions among these individual risk factors can significantly affect the degree of risk. For example, the age of onset of Alzheimer's disease in women who have both the ε4 allele and a family history of dementia has been found to be significantly lower than that in women who have only one of these risk factors. Although the identification of risk factors can suggest that someone is at risk of developing Alzheimer's disease, some individuals who have a variety of risk factors may never develop the illness.18

CURRENT PHARMACOLOGIC APPROACHES

Pharmacologic treatments for Alzheimer's disease are generally recommended only for those patients who already have been diagnosed with mild to moderate disease. However, several studies are investigating pharmacologic treatments in people who do not yet have the disease but are at risk of developing it. For example, the National Institute of Aging is currently funding an investigation into the effectiveness of donepezil in individuals with mild cognitive impairment.

Neurobiologic features, such as the accumulation of amyloid and the reduction in acetylcholine, and possible impairments in immune and inflammatory mechanisms have informed the development of current pharmacologic approaches. Clinicians must rule out any other potentially treatable causes of the symptoms of dementia such as thyroid disease, alcoholism, or drug toxicity before their patients begin drug treatment.16

Acetylcholinesterase inhibitors

The best developed approach to treatment aims at correcting the deficit of acetylcholine which is associated with Alzheimer's disease. Acetylcholinesterase inhibitors include first-generation compounds such as physostigmine and tacrine and second-generation compounds such as donepezil and metrifonate and rivastigmine. These compounds increase the concentration of acetylcholine and the duration of its action in synapses by inhibiting the acetylcholinesterase enzyme (which metabolizes acetylcholine). Acetylcholinesterase inhibitors are currently the most successful drugs used to enhance the transmission of acetylcholine, and they may be more beneficial than direct activation of cholinergic receptors.

In 1993, tacrine became the first cholinesterase inhibitor to receive approval from the Food and Drug Administration for use in patients with Alzheimer's disease; treatment with tacrine, however, resulted in only modest improvements in cognition.19 Tacrine has a lower bioavailability than second-generation cholinesterase inhibitors such as rivastigmine and donepezil, and it has a worse side-effect profile which includes hepatotoxicity.20,21

Donepezil is a highly selective, noncompetitive, reversible, second-generation acetylcholinesterase inhibitor that received approval from the Food and Drug Administration in 1996.22 In phase 2 and phase 3 clinical trials, treatment with donepezil significantly improved cognition, scores on the global assessment of change, and reduced the severity of the disease when compared with placebo.23,24,25 Donepezil has a better side-effect profile, is not hepatotoxic, and more patients are able to tolerate donepezil at therapeutic doses than can tolerate tacrine.19 Other second-generation cholinesterase inhibitors are either already on the market (for example, rivastigmine in the United States and Europe) or have been submitted for approval in the United States (metrifonate). Initial trials have found that the magnitude of improvement in patients treated with rivastigmine matches or exceeds that of other compounds.26 However, rivastigmine seems to require a longer period of titration than donepezil before a therapeutic dose is reached.27

Estrogen

Epidemiologic studies have suggested that in women estrogen replacement therapy may significantly delay the onset of Alzheimer's disease and lower the risk of developing it.28,29 Several small randomized clinical trials found that treatment with estrogen improved cognition in patients with the disease.30,31 Additionally, a clinical trial of tacrine found that women who also took estrogen exhibited significantly better cognitive performance than women taking only tacrine or placebo.32

The ability of estrogen to act both as an antioxidant and an anti-inflammatory agent may explain its association with a reduction in risk.33,34,35 Estrogen also increases acetylcholine concentrations and may promote the growth and survival of neurons in the regions of the brain that are most sensitive to degeneration in Alzheimer's disease.36 Additionally, it has been suggested that estrogen reduces neuronal injury by reducing the metabolism of β amyloid from its precursor protein.37 However, not all studies have found that estrogen reduces the risk of Alzheimer's disease.29 Because the decision to take estrogen replacement therapy may be affeted by differences in occupational, educational or socioeconomic status, the epidemiological evidence must be balanced by data from randomized, controlled clinical trials. Additionally, further studies assessing the safety of estrogen replacement therapy in treating Alzheimer's disease are required.

Anti-inflammatory drugs

The inverse relation between rheumatoid arthritis and Alzheimer's disease has led to the hypothesis that anti-inflammatory agents reduce the risk of developing the disease. Anti-inflammatory drugs may affect the inflammatory processes associated with the development of neuritic plaques. An association between the use of nonsteroidal anti-inflammatory drugs and a decreased risk of Alzheimer's disease has been identified in the literature but there have been few randomized clinical trials.38 The Alzheimer's disease cooperative study is looking at the possible effects of steroids and is conducting a multicenter, randomized, placebo-controlled trial of treatment with prednisone in patients with Alzheimer's disease. However, some investigators have suggested that prednisone can have adverse effects on memory,39 and adverse gastrointestinal effects have been observed in studies of anti-inflammatory drugs.40 Several clinical trials of the potential role of the nonsteroidal anti-inflammatory cyclooxygenase-2 inhibitors both in patients with Alzheimer's disease and people at risk for the disease are under way. These inhibitors are less toxic than other nonsteroidal anti-inflammatory drugs, which is important in the treatment of elderly adults.

Antioxidants

The products of oxidative metabolism, such as free radicals, may be neurotoxic.41 β amyloid neurotoxicity may be mediated through the formation of free radicals. Agents that protect against this oxidative damage, such as vitamin E and Ginkgo biloga extract, are thought to reduce neuronal damage and potentially slow the onset and progression of Alzheimer's disease. Initially, clinical trials found that treatment with Ginkgo biloba was associated with significant but modest improvements in cognition in patients with Alzheimer's disease.42,43 The ability to generalize from these findings is limited because the diagnostic criteria and the outcome measures used were variable.44 A controlled trial found that the antioxidants selegiline and vitamin E, alone or in combination, delayed progression to a mixed endpoint defined as severe functional decline, nursing home placement, or death.45,46

TREATING PATIENTS WITH ALZHEIMER'S DISEASE

A consensus statement on the diagnosis and treatment of dementia, produced by the American Association for Geriatric Psychiatry and the American Geriatrics Society, emphasized that cholinesterase inhibitors are the mainstay of pharmacologic treatment of patients with Alzheimer's disease.47 In the Unites States, about 40% of patients with the disease take donepezil.22

Donepezil is generally prescribed to patients with mild to moderate dementia at a starting dose of 5 mg per day. Many clinicians increase the dose to 10 mg per day after 10 weeks. Side effects seem to be better tolerated if the dose is increased over this time instead of starting patients on a 10 mg dose. Since donepezil has only recently become more widely used in clinical practice data on long-term benefits are limited, and it is unclear how long patients should remain on the drug. Similarly, there are limited data available to indicate which patients respond best to cholinesterase inhibitors, although preliminary finding suggest that patients with the apolipoprotein E ε4 allele do not respond as well to these agents as patients without this allele.48 Longitudinal follow up of patients treated with cholinesterase inhibitors will likely yield important information regarding how long treatment should be provided for and for whom it should be provided.

Although estrogen, anti-inflammatory drugs, and antioxidants seem to offer promise in treating and preventing Alzheimer's disease, their use is limited by the fact that their efficacy has yet to be established. Additionally, they are associated with a broad range of adverse side effects and physicians may be unwilling to expose their patients to these side effects without sufficient evidence of their efficacy. When information is available from the larger trials that are currently in progress their benefits will be able to be assessed more fully.

The consensus statement on the diagnosis and treatment of dementia suggested that antipsychotic agents could be helpful in controlling the behavioral problems that may occur, such as agitation and aggression. The statement cautions that such agents can have adverse side effects ranging from parkinsonian symptoms to delirium and sedation. Recent studies with atypical antipsychotics suggest that low doses of drugs such as risperidone may be effective in treating agitation and psychosis in these patients.49,50

Several investigators have emphasized the importance of nonpharmacologic approaches to treating both the cognitive and behavioral problems associated with Alzheimer's disease,16,51 and the necessity of providing adequate information to both the patient and the caregiver on community resources and social services.52

NEW DEVELOPMENTS AND DIRECTIONS FOR RESEARCH

Cholinesterase inhibitors continue to be developed and refined. Other pharmacologic developments are based on different approaches. Muscarinic agonists are being developed to enhance the effect of acetylcholine on nerve cell receptors. The depletions of other neurotransmitters, including serotonin and norepinephrine, that occur in Alzheimer's disease are also being considered as possible targets for treatment.

Reducing β amyloid is an approach also being targeted as a pharmacologic intervention. One strategy aims to develop compounds that will decrease deposits of β amyloid by inhibiting the enzymes that form amyloid but such treatments are still in the initial phases of development and safety testing.53 Another preliminary study observed that beta-amyloid deposits were reduced in laboratory mice after treatment with a vaccine that combined amyloid with substances that stimulate the immune system.54

In addition to the assessment of new pharmacologic treatments for Alzheimer's disease, there is a developing emphasis on investigating which patients derive the most benefit from which treatments.

Our understanding of the genetic etiology of Alzheimer's disease continues to increase. Studies are in progress to confirm the preliminary observations of associations between Alzheimer's disease and polymorphisms in several genes, some of which may interact with apolipoprotein E to alter the risk of Alzheimer's disease (for example, the α2-macroglobulin gene). In addition to enhancing our knowledge of the genetic etiology of the disease, future research will likely focus on increasing our understanding of the interactions between genetic vulnerabilities and psychosocial risk factors for the disease.

Figure 1.

Figure 1

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Many patients with Alzheimer's disease need total care

Funding: We would like to thank the Brookdale Foundation; the Institute for Research on Women and Gender; the Stanford Aging Clinical Research Center; the VA Sierra-Pacific Mental Illness Research, Education, and Clinical Center; and the Medical Research Service of the VA Palo Alto Health Care System for their support of this work.

Competing interests: None declared

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