Primary Dementias

Primary dementias include Alzheimer's disease, frontotemporal dementia (including the Pick's disease variant), and mixed dementias that have a component of Alzheimer's disease.

Alzheimer's disease

Alzheimer's disease is a primary progressive dementia characterized by neuritic plaques and neurofibrillary tangles. It is the most common form of dementia in the elderly. Diagnosis is by history, physical and mental status examinations, and exclusion of other causes. Treatment can include supportive measures, a cholinesterase inhibitor, and memantine.

Geriatric Essentials

• The 4 allele of apolipoprotein E is a strong risk factor for Alzheimer's disease, but genetic screening for the 4 allele is usually unwarranted.
• Onset is insidious, and progression is typically continuous.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, accounting for about 2/3 of cases. AD becomes increasingly common with aging. It is characterized by an excessive number of senile plaques and neurofibrillary tangles. Plaques consist of neurites (axons or dendrites), astrocytes, and microglial cells around an amyloid core; tangles consist of paired helical filaments that contain a form of tau protein. Plaques and tangles also occur in normal aging but to a much lesser extent than in AD. The degree of dementia correlates better with the number of neurofibrillary tangles than with the number of plaques. Cerebral atrophy eventually occurs; however, atrophy is not strongly correlated with clinical severity. Patients with AD may have concomitant cerebrovascular disease and manifestations of vascular dementia, and many patients with cortical Lewy bodies also have manifestations of AD.

Biochemically, the process may begin with abnormal cleavage of the amyloid precursor protein by a -secretase (at the amino end) and a -secretase (at the carboxy end), producing an A42 protein. This protein accumulates as amyloid in the core of neuritic plaques. The relationship of amyloid to neurofibrillary tangles is controversial. Inflammation, excitotoxic neurotransmitters, and possibly apoptosis cause secondary damage.

Most cases of AD are sporadic and occur after age 60. However, in about 5%, the pattern of inheritance is autosomal dominant; in most of these cases, onset is before age 60. Autosomal dominant mutations can involve the amyloid precursor protein gene, the presenilin 1 gene, or the presenilin 2 gene. The 4 allele of apolipoprotein E (apo E) also appears to be an important risk factor, particularly for onset somewhat later than that of autosomal dominant AD. The 2 allele of apo E appears relatively protective. For example, 4 homozygotes have a > 50% risk of developing AD by age 70, but people with 23 alleles have only a 12 to 14% risk by age 90. The overall risk of developing AD is increased for people with a first-degree relative who had AD, and the younger the age at which the relative developed AD, the higher the risk.

Symptoms

Symptoms may or may not be similar to those of other forms of dementia. Deficits tend to be broad, involving multiple areas of the brain. However, the most common and characteristic early symptom in AD is impaired short-term memory. Patients repeatedly ask the same questions, often after only a few minutes, or they forget where belongings were placed. Word finding becomes difficult; patients may forget a specific word and use an elaborate circumlocution to compensate (eg, a necktie may be called "that thing around the neck"). Besides memory, at least one of the following is almost always significantly impaired: language, visual processing, ability to execute skilled motor activities (not because of weakness), abstract reasoning, or ability to concentrate. Sociability is usually unaffected early in AD, but some patients become increasingly apathetic, irritable, or agitated. Cognitive changes and behavior disorders correlate poorly with each other and reflect different aspects of brain dysfunction. Focal neurologic deficits (eg, weakness, sensory loss, exaggerated reflexes, Babinski's sign, visual field defects, pseudobulbar palsy, incontinence), which are usually symmetric, occur late.

Onset is gradual, although it is not always reported as such by family members. Usually, deterioration is also gradual. The various deficits may progress at different rates. In general, life expectancy for patients who can no longer walk is about 6 mo.

Diagnosis

Clinical diagnosis is based on clinical features of AD and the exclusion of other causes of dementia. Because AD is a common form of dementia, atypical variants of AD, including those with mixed pathophysiology, are common among patients with dementia; thus, deviations from the classic pattern do not rule out the diagnosis. Differentiation of AD from other disorders that cause dementia may be difficult antemortem.

Assessment tools (eg, Hachinski Ischemic Score) can help distinguish AD from vascular dementia. Fluctuations in cognition, parkinsonian symptoms, well-formed visual hallucinations, and relative preservation of short-term memory suggest dementia with Lewy bodies rather than AD. Patients with AD are often better groomed and neater than patients with other dementias. Measurement of tau and A42 proteins in CSF can improve diagnostic accuracy to some extent but is not routinely recommended.

Genetic testing is not recommended in routine cases, but testing for the presenilin 1 mutation can be considered if patients have early-onset AD and a strong family history. However, results do not help patients and, because no preventive treatment is available, are not likely to help family members.

Clinical diagnosis of AD is about 75 to 90% accurate. Definitive diagnosis is possible only after brain tissue is examined or when genetic testing detects a mutation in a gene known to cause an autosomal-dominant form of early-onset AD.

Treatment

General treatment measures are the same as for dementia of any cause. Treatment also involves a cholinesterase inhibitor (donepezil, galantamine, rivastigmine, or rarely tacrine); in moderate to severe cases, memantine, an NMDA (N-methyl-D-aspartate) antagonist, is often used.

Cholinesterase inhibitors increase synaptic concentrations of the neurotransmitter acetylcholine. They can modestly improve cognitive performance or delay cognitive decline in many patients. In some patients, cognitive performance is improved to what it was about 6 to 12 mo earlier. However, cholinesterase inhibitors typically have no effect on the progression rate of dementia. These drugs are indicated for mild to moderate AD. How long cholinesterase inhibitors should be continued is unclear, but they are often stopped when AD becomes severe. The most common adverse effects are GI symptoms (eg, nausea, diarrhea). Rarely, dizziness or bradycardia occurs. Adverse effects can be minimized by increasing the dose gradually. Efficacy and overall safety of donepezil, galantamine, and rivastigmine appear comparable; often, other factors (eg, convenience, individual tolerability, cost) dictate which drug to select (see Table 40-3). Tacrine is rarely used because it is hepatotoxic.

Memantine may decrease neuronal toxicity resulting from the excitatory neurotransmitter glutamate at the NMDA receptor. Memantine lessens symptoms or delays decline in some patients with moderate to severe AD; it may slow the progression rate of dementia. Memantine is well tolerated. It may be used with a cholinesterase inhibitor. Memantine is not used for mild AD. The starting dose is 5 mg po once/day for 1 wk; dosage is increased to 5 mg bid the 2nd week, to 5 mg in the AM and 10 mg in the PM the 3rd week, and to a continuing dose of 10 mg bid the 4th week. The dose should be reduced in elderly patients with mild to moderate renal insufficiency; memantine should not be used if renal insufficiency is severe.

There is no convincing evidence that estrogen, aspirin, NSAIDs, combined doxycycline and rifampin, or ginkgo biloba can help slow the progression of or prevent AD. However, according to some experts, vitamin E 1000 IU bid or selegiline 10 mg once/day can be used to slow functional loss. Caution is required because vitamin E increases risk of bleeding and mortality and, for patients with diabetes, risk of heart failure and selegiline can cause anxiety and hallucinations. Research about the use of these and other drugs is ongoing.

Prevention: Preliminary, observational evidence suggests that risk of AD can be decreased by continuing to do challenging mental activities (eg, learning new skills, doing crossword puzzles) well into old age and by exercising, controlling hypertension, lowering cholesterol levels, following a diet rich in -3 fatty acids and low in saturated fats, and drinking alcohol in modest amounts. There is no convincing evidence that people who do not drink alcohol should start.

Frontotemporal dementia

Frontotemporal dementia (including the Pick's disease variant) often begins at a relatively young age. It differs from Alzheimer's disease (AD) in that personality changes and behavioral disturbances are typically the most prominent early symptoms, and memory may be relatively spared. Progression is usually more rapid and frontal lobe signs may be more prominent than in AD. However, clinical differentiation from AD is sometimes difficult.

Diagnosis is similar to that of other dementias. No specific treatments are available; treatment focuses on disruptive behaviors.

This topic was last updated February 2006.