Alzheimer disease, a neurocognitive disorder, is the most common cause of dementia; it accounts for 60 to 80% of dementias in older people. In the US, an estimated 10% of people ≥ 65 have Alzheimer disease. The percentage of people with Alzheimer disease increases with age (1):
The disease is twice as common among women as among men, partly because women have a longer life expectancy. Prevalence in industrialized countries is expected to increase as the proportion of older people increases.
Most cases of Alzheimer disease are sporadic, with late onset (≥ 65 years) and unclear etiology. Risk of developing the disease is best predicted by age. However, about 5 to 15% of cases are familial; half of these cases have an early (presenile) onset (< 65 years) and are typically related to specific genetic mutations.
At least 5 distinct genetic loci, located on chromosomes 1, 12, 14, 19, and 21, influence initiation and progression of Alzheimer disease.
Mutations in genes for the amyloid precursor protein, presenilin I, and presenilin II may lead to autosomal dominant forms of Alzheimer disease, typically with presenile onset. In affected patients, the processing of amyloid precursor protein is altered, leading to deposition and fibrillar aggregation of beta-amyloid; beta-amyloid is the main component of senile plaques, which consist of degenerated axonal or dendritic processes, astrocytes, and glial cells around an amyloid core. Beta-amyloid may also alter kinase and phosphatase activities in ways that eventually lead to hyperphosphorylation of tau and formation of neurofibrillary tangles.
Other genetic determinants include the apolipoprotein (apo) E (epsilon) alleles. Apo E proteins influence beta-amyloid deposition, cytoskeletal integrity, and efficiency of neuronal repair. Risk of Alzheimer disease is substantially increased in people with 2 epsilon-4 alleles and may be decreased in those who have the epsilon-2 allele. For people with 2 epsilon-4 alleles, risk of developing Alzheimer disease by age 75 is about 10 to 30 times that for people without the allele.
The relationship of other factors (eg, low hormone levels, metal exposure) and Alzheimer disease is under study, but no definite causal links have been established.
The 2 pathologic hallmarks of Alzheimer disease are
The beta-amyloid deposition and neurofibrillary tangles lead to loss of synapses and neurons, which results in gross atrophy of the affected areas of the brain, typically starting at the mesial temporal lobe.
The mechanism by which beta-amyloid peptide and neurofibrillary tangles cause such damage is incompletely understood. There are several theories.
The amyloid hypothesis posits that progressive accumulation of beta-amyloid in the brain triggers a complex cascade of events ending in neuronal cell death, loss of neuronal synapses, and progressive neurotransmitter deficits; all of these effects contribute to the clinical symptoms of dementia.
Prion mechanisms have been identified in Alzheimer disease. In prion diseases, a normal cell-surface brain protein called prion protein becomes misfolded into a pathogenic form termed a prion. The prion then causes other prion proteins to misfold similarly, resulting in a marked increase in the abnormal proteins, which leads to brain damage. In Alzheimer disease, it is thought that the beta-amyloid in cerebral amyloid deposits and tau in neurofibrillary tangles have prion-like, self-replicating properties.
Patients with Alzheimer disease have symptoms and signs of dementia.
The most common first manifestation of Alzheimer disease is
Other cognitive deficits tend to involve multiple functions, including the following:
Impaired reasoning, difficulty handling complex tasks, and poor judgment (eg, being unable to manage bank account, making poor financial decisions)
Language dysfunction (eg, difficulty thinking of common words, errors speaking and/or writing)
Visuospatial dysfunction (eg, inability to recognize faces or common objects)
Alzheimer disease progresses gradually but may plateau for periods of time.
Behavior disorders (eg, wandering, agitation, yelling, persecutory ideation) are common.
Generally, diagnosis of Alzheimer disease is similar to the diagnosis of other dementias. However, despite clinical and specific laboratory and imaging characteristics, definitive diagnosis of Alzheimer disease can only be confirmed by histologic evaluation of brain tissue.
Evaluation includes a thorough history and standard neurologic examination. Clinical criteria are 85% accurate in establishing the diagnosis and differentiating Alzheimer disease from other forms of dementia, such as vascular dementia and dementia with Lewy bodies.
Traditional diagnostic criteria for Alzheimer disease include all of the following:
Dementia established clinically and documented by a formal mental status examination
Deficits in ≥ 2 areas of cognition
Gradual onset (ie, over months to years, rather than days or weeks) and progressive worsening of memory and other cognitive functions
No disturbance of consciousness
Onset after age 40, most often after age 65
No systemic or brain disorders (eg, tumor, stroke) that could account for the progressive deficits in memory and cognition
However, deviations from these criteria do not exclude a diagnosis of Alzheimer disease, particularly because patients may have mixed dementia.
Other biomarkers indicate downstream neuronal degeneration or injury:
Elevated levels of tau protein in CSF
Decreased cerebral metabolism in the temporoparietal cortex measured using PET with fluorine-18 (18F)–labeled deoxyglucose (fluorodeoxyglucose, or FDG)
Local atrophy in the medial, basal, and lateral temporal lobes and the medial parietal cortex, detected by MRI
These findings increase the probability that dementia is due to Alzheimer disease. However, the guidelines (1, 2) do not advocate routine use of these biomarkers for diagnosis because standardization and availability are limited at this time. Also, they do not recommend routine testing for the apo epsilon-4 allele.
Laboratory tests (eg, thyroid-stimulating hormone, vitamin B12 levels) and neuroimaging (MRI or CT) are done to check for other, treatable causes of dementia and disorders that can worsen symptoms. If clinical findings suggest another underlying disorder (eg, HIV, syphilis), tests for those disorders are indicated.
Distinguishing Alzheimer disease from other dementias is difficult. Assessment tools (eg, Hachinski Ischemic Score—see table Modified Hachinski Ischemic Score) can help distinguish vascular dementia from Alzheimer disease. Fluctuations in cognition, parkinsonian symptoms, well-formed visual hallucinations, and relative preservation of short-term memory suggest dementia with Lewy bodies rather than Alzheimer disease (see table Differences Between Alzheimer Disease and Dementia With Lewy Bodies).
Patients with Alzheimer disease are often better-groomed and neater than patients with other dementias.
Modified Hachinski Ischemic Score
Differences Between Alzheimer Disease and Dementia with Lewy Bodies
1. Jack CR Jr, Albert MS, Knopman DS, et al: Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7 (3):257–262, 2011. doi: 10.1016/j.jalz.2011.03.004.
2. McKhann GM, Knopman DS, Chertkow H, et al: The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7 (3):263–269, 2011. doi: 10.1016/j.jalz.2011.03.005.
Safety and supportive measures for Alzheimer disease are the same as those for all dementias. For example, the environment should be bright, cheerful, and familiar, and it should be designed to reinforce orientation (eg, placement of large clocks and calendars in the room). Measures to ensure patient safety (eg, signal monitoring systems for patients who wander) should be implemented.
Providing help for caregivers, who may experience substantial stress, is also important. Nurses and social workers can teach caregivers how to best meet the patient’s needs. Health care practitioners should watch for early symptoms of caregiver stress and burnout and, when needed, suggest support services.
Cholinesterase inhibitors modestly improve cognitive function and memory in some patients. Four are available. Generally, donepezil, rivastigmine, and galantamine are equally effective, but tacrine is rarely used because of its hepatotoxicity.
Donepezil is a first-line drug because it has once-a-day dosing and is well-tolerated. The recommended dose is 5 mg orally once a day for 4 to 6 weeks, then increased to 10 mg once a day. Donepezil 23 mg once a day may be more effective than the traditional 10 mg once-a-day-dose for moderate to severe Alzheimer disease. Treatment should be continued if functional improvement is apparent after several months, but otherwise it should be stopped. The most common adverse effects are gastrointestinal (eg, nausea, diarrhea). Rarely, dizziness and cardiac arrhythmias occur. Adverse effects can be minimized by increasing the dose gradually (see table Drugs for Alzheimer Disease).
Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, appears to improve cognition and functional capacity of patients with moderate to severe Alzheimer disease. The dose is 5 mg orally once a day, which is increased to 10 mg orally twice a day over about 4 weeks. For patients with renal insufficiency, the dose should be reduced or the drug should be avoided. Memantine can be used with a cholinesterase inhibitor.
Efficacy of high-dose vitamin E (1000 IU orally once or twice a day), selegiline, nonsteroidal anti-inflammatory drugs (NSAIDs), Ginkgo biloba extracts, and statins is unclear. Estrogen therapy does not appear useful in prevention or treatment and may be harmful. Clinical trials with investigational drugs that target beta-amyloid peptide accumulation and clearance have not been successful although some studies are still ongoing.
Drugs for Alzheimer Disease
Because insight and judgment deteriorate in patients with dementia, appointment of a family member, guardian, or lawyer to oversee finances may be necessary. Early in dementia, before the patient is incapacitated, the patient’s wishes about care should be clarified, and financial and legal arrangements (eg, durable power of attorney, durable power of attorney for health care) should be made. When these documents are signed, the patient’s capacity should be evaluated, and evaluation results recorded. Decisions about artificial feeding and treatment of acute disorders are best made before the need develops.
In advanced dementia, palliative measures may be more appropriate than highly aggressive interventions or hospital care.
Preliminary, observational evidence suggests that risk of Alzheimer disease may be decreased by the following:
However, there is no convincing evidence that people who do not drink alcohol should start drinking to prevent Alzheimer disease. Once dementia develops, abstaining from alcohol is usually recommended because alcohol can worsen dementia symptoms.
Although genetic factors can be involved, most cases of Alzheimer disease are sporadic, with risk predicted best by patient age.
Differentiating Alzheimer disease from other causes of dementia (eg, vascular dementia, dementia with Lewy bodies) can be difficult but is often best done using clinical criteria, which are 85% accurate in establishing the diagnosis.
Treat Alzheimer disease similarly to other dementias.