Family Practice Issues in Neurology

Fall 1999
Volume 10, Number 2

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Recently, our understanding and treatment of Alzheimer’s disease and other dementias have improved. Studies have identified new risk factors and possible pathologic processes involved in Alzheimer’s disease. In addition, therapy is available that may improve cognition and slow disease progression in patients with Alzheimer’s disease. This article reviews the current understanding of Alzheimer’s disease and other dementias and emphasizes the importance of early diagnosis and early treatment.

Introduction. Alzheimer’s disease (AD) is the most common of more than 70 diseases that may produce dementia.1 Alzheimer’s disease was first clearly described by Alois Alzheimer, a German neuropathologist. In 1907, he wrote an article in which he described a disease process affecting a 51-year-old woman.2 This article is remarkably concise; on the basis of one patient, Alzheimer clearly recognized and described the primary clinical and pathologic features of the disease that now bears his name.

Epidemiology. Dementia occurs primarily in older individuals, and the prevalence of dementia increases with age.3 Alzheimer’s disease represents approximately two-thirds of all dementias and is estimated to affect approximately 4 million Americans. The annual direct and indirect costs of AD are enormous and are estimated to be 50 to 100 billion dollars.5 As our population ages, the prevalence and costs are likely to increase significantly.

Clinical Manifestations. Alzheimer’s disease is characterized by the gradual onset and progression of cognitive dysfunction. A prominent early feature of the disease is memory impairment. Other early clinical manifestations include difficulties with problem solving, concentration, and word finding. Psychiatric features of AD, including social withdrawal, depression, and irritability, may also be seen early and are often under-recognized. As the disease progresses, the memory disorder becomes more apparent, cognitive dysfunction occurs in other areas, more prominent behavioral problems may develop, and patient supervision is often required. In the later stages of AD there is a severe decline of intellectual function and much supervision and care usually needs to be provided.4

Diagnostic Evaluation. A detailed history is critical in establishing a diagnosis of AD. The history should focus on the onset, progression, and characteristics of the memory disorder, as well as medications, other medical problems, current level of functioning, and mood. A physical exam, neurologic exam, and tests of cognitive function, such as Mini-Mental Status Exam, should be performed. Laboratory studies should include chemistry screen, complete blood count, thyroid function tests, vitamin B12 level, and syphilis serology. Imaging with head computed tomography (CT) or magnetic resonance imaging (MRI) should be strongly considered in all cases. Lumbar puncture and electroencephalography are not routinely indicated.6 Several commercially available blood and cerebrospinal fluid tests have recently been developed, including tests for apolipoprotein E genotype, tau protein, and amyloid protein. At this time, there is not a strong indication for any of these tests in routine clinical practice.7

Differential Diagnosis. Recent studies have clarified the relative importance of other neurodegenerative diseases that may produce dementia. Dementia with Lewy bodies (DLB)8 is now believed to be the second most common form of dementia in the elderly. It is characterized by a combination of cognitive dysfunction and parkinsonism. Episodic delirium, visual hallucinations, and depression may also be present relatively early in the disease course. Recent investigations indicate that frontotemporal dementia (FTD) is the third most common cause of dementia.9 Patients with FTD typically exhibit frontal lobe behavioral disorders and language dysfunction.

Depression is important to consider in the differential diagnosis of dementia since it may be under-recognized and may mimic AD by producing a “pseudodementia.” Depression and AD may also be present together. While depression may be under-diagnosed, multi-infarct dementia may be over-diagnosed.10 Patients who lack convincing clinical histories or neuroimaging evidence of strokes are sometimes diagnosed with multi-infarct dementia; many of these patients actually have AD, and diagnostic inaccuracy may prevent them from receiving appropriate therapy.

Risk Factors. Several different risk factors have been identified for developing AD. One of the most important risk factors is age.3 Alzheimer’s disease is rare under the age of 50. The prevalence of dementia is 2% to 3% in 65 to 74-year-olds, approximately 10% in 75 to 84-year-olds, and may be as high as 30% in those 85 and older.

Apolipoprotein E genotype has been identified recently as another important risk factor.11 There are 3 forms of apolipoprotein E: E2, E3, and E4. Individuals who possess one copy of the E4 allele have a 2- to 5-fold increased risk of developing AD, while those with 2 copies have a 5- to 18-fold increased risk. It is important to recognize that apolipoprotein E is a risk factor, and, as a result, it is possible for an individual to possess 2 copies of E4 and still not develop AD. Mutations in 3 other genes (amyloid precursor protein, presenilin-1, presenilin-2) have been associated with very rare forms of familial AD.12 Other risk factors for AD include Down’s syndrome, and possibly head trauma and low educational level.

Treatment. Significant advances have been made in the treatment of AD. It has been known for more than 20 years that acetylcholine levels are decreased in the brains of AD patients. Only recently has this observation led to the development of FDA-approved medications. The 2 medications currently available, tacrine (Cognex) and donepezil (Aricept), presumably increase acetylcholine levels by inhibiting acetylcholinesterase, the enzyme that hydrolyzes acetylcholine.13 Donepezil has less frequent dosing and fewer side effects than tacrine. These medications produce mild cognitive benefits and may also improve behavioral dysfunction. When initiating treatment with these medications, it is important to be realistic with patients and their families. It should be explained that improvement may occur, but that the improvement is likely to be mild.

On the basis of scientific studies, it has been hypothesized that free radical-induced oxidative damage may play a role in AD. As a result, a clinical study examined the effects of 2 antioxidant compounds, vitamin E (2000 mg daily) and selegiline, and concluded that both compounds delayed the progression of AD.14 For reasons of cost and tolerability, vitamin E, and not selegiline, is usually used in clinical practice. The optimal vitamin E dosage is not known. Lower doses of vitamin E, such as 400 mg or 800 mg twice daily, are sometimes used.

A recent well-publicized study demonstrated a beneficial effect of ginkgo biloba extract in dementia.15 There were some flaws with this study. Other past studies have found improvement with ginkgo biloba, and a recent meta-analysis of these studies suggests that this herbal medicine may have beneficial effects.16 The exact role of ginkgo biloba extract in AD treatment awaits further study. If patients choose to take ginkgo biloba, they should be made aware that efficacy and toxicity information is incomplete, as is true for most herbal medicines. Patients should also be told of the possible procoagulant effect of ginkgo biloba, and the herb should probably be avoided in patients taking anticoagulant medication or high doses of antiplatelet agents and in patients with thrombocytopenia and coagulopathies.

Epidemiologic studies indicate that estrogen replacement therapy may delay the onset or reduce the risk of AD.17 However, due to limited information from controlled clinical trials, estrogen replacement therapy is not currently recommended for AD treatment. There are 2 ongoing prospective clinical trials which should provide valuable information in this area.

Inflammation may be important in the pathogenesis of AD, and epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of AD.18 However, controlled clinical trial data with anti-inflammatory drug therapy in AD are limited, and these drugs may produce gastrointestinal toxicity. As a result, anti-inflammatory drugs are not currently recommended for AD treatment.

Caregiver Burden. Patients with AD place a large burden on caregivers, and this burden may not be recognized by healthcare providers. Most caregivers are women, and many caregivers miss work or discontinue work due to the demands of providing care.19 Approximately one-third of caregivers experience depression, and among caregivers, there are higher frequencies of outpatient medical visits and hospitalizations.5

Alzheimer’s disease is under-diagnosed. Despite the fact that the clinical manifestations of AD are widely recognized, AD is under-diagnosed. Studies indicate that a diagnosis of AD is usually made approximately 3 years after the onset of symptoms. A dementia diagnosis is noted in the medical record less than 25% of the time in patients with moderate-to-severe cognitive dysfunction.20 There are many factors on the part of patients as well as physicians that may be involved in the under-diagnosis of AD. These include social stigma, lack of awareness that treatment is available, physician discomfort in establishing or discussing a diagnosis of AD, and inadequate time during physician visits to evaluate and diagnose cognitive disorders. Since treatment is now available that may improve cognitive function and slow disease progression, it is in the patient’s best interest to establish a definite diagnosis and initiate treatment as early as possible in patients with AD.

Pathogenesis of AD. We may now just be learning how to ask the correct questions about the pathogenesis of AD. We used to ask, “What is the cause of AD?” We currently realize that there are multiple possible causes, and, with these different causes, there may be different initial pathologic events and different forms of AD. The correct question may be, “What are the causes of Alzheimer’s diseases?”

The possible causes of AD include genetic and acquired factors.21 The genetic factors include the apolipoprotein E genotype, which is a risk factor, and extremely rare mutations in 3 different genes, which cause the disease. Acquired risk factors may include free radicals, estrogen deficiency, and head trauma. In the future, AD may be viewed in a similar manner to coronary artery disease: There may be many different known genetic and acquired factors, and an individual’s risk of developing the disease may increase as the number of involved factors increases.

Conclusion. There has been an enormous increase recently in our understanding of the cause, diagnosis, and treatment of AD and other dementias. Recent studies have identified new risk factors for AD, possible AD pathologic processes, and the clinical features of the more common non-AD dementias. Clinical trials have led to the use of cholinesterase inhibitors, which may improve cognition, and the use of vitamin E, which may slow disease progression. The availability of these therapies makes it important to diagnose and treat AD early.
 

Address comments and questions to:

Allen C. Bowling, MD, PhD
701 East Hampden Avenue
Suite 420
Englewood, CO 80113

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