Professor Thomas about Alzheimer Disease Overview
Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. Approximately 25% of all AD is familial (i.e., ≥2 persons in a family have AD) of which approximately 95% is late onset (age >60-65 years) and 5% is early onset (age <65 years).
Establishing the diagnosis of Alzheimer disease relies on clinical-neuropathologic assessment. Neuropathologic findings of β-amyloid plaques and intraneuronal neurofibrillary tangles remain the gold standard for diagnosis. The clinical diagnosis of AD, based on signs of slowly progressive dementia and findings of gross cerebral cortical atrophy on neuroimaging, is correct approximately 80%-90% of the time. The association of the APOE e4 allele with AD is significant; however, APOE genotyping is neither fully specific nor sensitive. While APOE genotyping may have an adjunct role in the diagnosis of AD in symptomatic individuals, it appears to have little role at this time in predictive testing of asymptomatic individuals. Three forms of early-onset familial AD (EOFAD) – caused by mutation of one of three genes (APP, PSEN1, PSEN2) – are recognized.
Because AD is genetically heterogeneous, genetic counseling of persons with AD and their family members must be tailored to the information available for that family. It should be pointed out that AD is common and that the overall lifetime risk for any individual of developing dementia is approximately 10%-12%. Genetic counseling for people with non-familial AD and their family members must be empiric and relatively nonspecific. First-degree relatives of a simplex case of AD (i.e., single occurrence in a family) have a cumulative lifetime risk of developing AD of approximately 15%-30%, which is typically reported as a 20%-25% risk. This risk is approximately 2.5 times that of the background risk (~27% vs 10.4%). In contrast, early-onset familial Alzheimer disease (EOFAD) is inherited in an autosomal dominant manner.
Treatment of manifestations: Treatment is supportive; each symptom is managed on an individual basis; assisted living arrangements or care in a nursing home is usually necessary; drugs that increase cholinergic activity by inhibiting acetylcholinesterase produce a modest but useful behavioral or cognitive benefit in a minority of affected individuals (e.g., donepezil [Aricept®], rivastigmine [Exelon®], galantamine). Memantine, an NMDA receptor antagonist, is also used. Antidepressant medication may improve associated depression.
Clinical Manifestations of Alzheimer Disease
The clinical manifestation of Alzheimer disease (AD) is dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Bacanu et al  have shown evidence for heritability of psychotic features in AD (delusions and hallucinations).
Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur [Bird & Miller 2008].
Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range of from one to 25 years.
Establishing the Diagnosis of Alzheimer Disease
Establishing the diagnosis of Alzheimer disease relies on clinical-neuropathologic assessment. Neuropathologic findings on autopsy examination remain the gold standard for diagnosis of AD. The clinical diagnosis of AD (prior to autopsy confirmation) is correct approximately 80%-90% of the time [Mayeux et al 1998]:
Clinical signs. Slowly progressive dementia
Gross cerebral cortical atrophy on CT or MRI
Diffuse cerebral hypometabolism on PET
Neuropathologic findings. Microscopic β-amyloid neuritic plaques, intraneuronal neurofibrillary tangles (containing tau protein), and amyloid angiopathy at postmortem examination. The plaques should stain positively with β-amyloid antibodies and negative for prion antibodies, which are diagnostic of prion diseases. The numbers of plaques and tangles must exceed those found in age-matched controls without dementia. Guidelines for the quantitative assessment of these changes exist [Braak & Braak 1991, National Institute on Aging-Reagan Working Group 1997]. Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala [Popescu et al 2004].
Cerebrospinal fluid (CSF). Decreased Aβ amyloid 42 and increased tau [Snider et al 2009].
Differential Diagnosis of Alzheimer Disease
Differential diagnosis of Alzheimer disease includes other causes of dementia, especially treatable forms of cognitive decline including depression, chronic drug intoxication, chronic CNS infection, thyroid disease, vitamin deficiencies (especially B12 and thiamine), CNS angitis, and normal-pressure hydrocephalus [Bird & Miller 2008].
Other degenerative disorders associated with dementia, such as frontotemporal dementia (including frontotemporal dementia with parkinsonism-17; FTDP-17), Picks disease, Parkinson disease, diffuse Lewy body disease (LBD), Creutzfeldt-Jakob disease, and CADASIL, may also be confused with AD [Rogan & Lippa 2002].
CT and MRI are valuable for identifying some of these other causes of dementia, including neoplasms, normal-pressure hydrocephalus, and cerebral vascular disease.
Prevalence of Alzheimer Disease
AD is the most common cause of dementia in North America and Europe, with an estimate of four million affected individuals in the US.
The prevalence of AD increases with age:
Approximately 10% of persons over age 70 years have significant memory loss and more than half of these individuals have AD.
An estimated 25%-45% of persons over age 85 years have dementia.
The incidence of AD rises from 2.8 per 1,000 person years in the 65-69 year age group to 56.1 per 1,000 person years in the older than 90 year age group [Kukull et al 2002].
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