Published: April 2014
Originally described by Dr. Alois Alzheimer in 1907, Alzheimer disease (AD) is the most common cause of dementia.1,2 AD is defined pathologically by plaques and neurofibrillary tangles (NFT) in the cerebral cortex. Plaques and tangles are associated with synaptic dysfunction, neuronal degeneration, and progressive cognitive decline (AD dementia).
An estimated 5.5 million people in the United States have AD.2 At age 60 years, the prevalence of AD is about 1%. For each 5 years of age thereafter, AD prevalence approximately doubles, reaching 30% to 50% by age 85.2 Women are more affected than men at a ratio of almost 2:1, partly because of the larger population of women who are older than 70 years; however, the prevalence is higher in women even after statistical correction for longevity.2 Other reported risk factors include lower levels of intelligence and primary education, small head size, and a family history of the disease.2 Potentially preventable risk factors include diabetes, hypertension, sedentary lifestyle, smoking, and obesity.3 Head injury is also implicated as a risk factor for AD in men.2 The cost of caring for AD patients in the United States is estimated at more than $183 billion annually and rising.2
About 70% of AD risk at any given age is attributable to genetics. The most common genetic risk factor for AD is the e4 allele of the gene for apolipoprotein E (ApoE), which is present in approximately 50% of individuals with AD.4 e4 heterozygosity triples the risk of AD compared with non-carriers; homozygotes have a sevenfold risk. Other less prevalent risk genes and familial tendencies have also been identified.4
Mutations in the genes for amyloid precursor protein (APP, on chromosome 21), presenilin 1 (PS1, chromosome 14), and presenilin 2 (PS2, chromosome 1) cause autosomal dominant early-onset AD. These mutations account for the majority of familial midlife-onset AD, but represent less than 5% of all AD cases. Sortilin 1 (SorL1) mutations cause late-onset AD.4
AD's core neuropathologic findings include extracellular amyloid plaques, intracellular NFTs, synaptic deterioration, and neuronal death.1 Granulovacuolar degeneration in the hippocampus and amyloid deposition in blood vessels (congophilic angiopathy) may also be seen on tissue examination, but are not required for the diagnosis.4 The "amyloid cascade" hypothesis posits that amyloid plaques interfere with synaptic activity and initiate a series of downstream effects that cause increasing inter- and intraneuronal dysfunction and, ultimately, cell death.4
Although amyloid plaques may be subclassified according to their composition, all contain forms of β-amyloid protein (Aβ). Aβ is an amino acid peptide formed by proteolytic cleavage of APP by β- and γ-secretase. The main products of this cleavage are Aβ1–40 and Aβ1–42. A relative surplus of Aβ1–42 predisposes toward amyloid aggregation into oligomers and fibrils, which assemble into amyloid plaques.4,5 An important role for amyloid in AD pathophysiology is implied by the fact that the proteins encoded by APP, PS1, PS2, SorL1, and ApoE are all associated with amyloid generation, processing, and/or trafficking. However, several lines of evidence indicate that amyloid plaques are not the primary cause of AD. Amyloid plaque burden (a) can be found in cognitively normal adults, (b) does not correlate with degree of cognitive impairment in individuals with AD dementia and, (c) is associated with cognitive improvement in some AD mouse models.5
Tau, a protein involved in microtubule assembly, is essential for normal axonal growth and neuronal development. However, hyperphosphorylated tau protein aggregates into helical filamentous NFT that are deposited preferentially within neurons of the mesial temporal lobe (especially hippocampus), lateral parietotemporal region, and the frontal association cortices. The critical role of NFT in AD pathophysiology is suggested by the correlation between location and density of tau NFT and the symptoms and severity of AD dementia.4 Moreover, some studies have demonstrated that Aβ oligomers are not toxic unless tau is also present.5
The distribution of neuronal cell death and synapse loss is similar to that of NFT.4 In typical AD, the death of neurons in the nucleus basalis of Meynert leads to a deficit in acetylcholine (Ach), a neurotransmitter involved in memory. This cholinergic deficit is the target of most current treatments. In the brainstem, loss of median raphe and locus ceruleus neurons leads to deficits in serotonin and norepinephrine, respectively. Abnormal cerebral serotonergic and adrenergic activity likely contribute to dysphoria and insomnia in AD.6
AD causes progressive dementia in which difficulty forming new memories is typically the earliest and most prominent manifestation. Initially, there is only loss of recent memories (sometimes referred to as "short term"), but remote memory is increasingly affected over the course of the disease.
Other signs and symptoms of parietal and temporal lobe dysfunction usually increase in number and severity over the course of the disease. Language dysfunction (e.g., searching for words) may occur as an early feature in AD dementia, and can interfere considerably with communication as the patient's vocabulary and comprehension become impoverished. Spatial disorientation leads to lost objects and difficulty navigating. Acalculia may manifest as inability to maintain a checkbook or household accounts. Apraxia is an inability to carry out practiced motor tasks, such as brushing teeth or using a remote control. Although these classic AD symptoms are attributable to posterior cerebral dysfunction, AD dementia usually causes some frontal (executive) dysfunction even early in the disease course. Some variants of AD present with predominant non-memory symptoms, including severe visuospatial dysfunction (posterior cortical atrophy, or Benson variant), language problems (semantic aphasia), or behavioral dysfunction (frontal variant).4,7
The vast majority of AD dementia patients exhibit behavioral problems during their disease course.8 Depression, sleep disturbance, and/or apathy may be present early. Psychotic symptoms, psychomotor agitation, verbal and physical aggression, and inappropriate sexual behavior tend to appear during later stages of dementia.9 In advanced stages of AD, some patients also develop motor signs such as tremor, gait disturbance, urinary incontinence, and myoclonus. Seizures are also more prevalent in patients with AD than in age-matched controls. AD's terminal stage is a vegetative state in which purposeful brain activity is not evident.
In 1984, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Diseases Association (NINCDS-ADRDA) established diagnostic criteria designed to improve research homogeneity and clinical accuracy of AD diagnosis.7,10 Although identifying diagnostic criteria was a critical step forward, the maximum specificity of AD diagnoses under this framework is less than 90%, and definitive diagnosis (demonstration of amyloid plaques and tau tangles) has been possible only with biopsy or autopsy.
Although their nomenclature and precise definitions remain unsettled, there are three distinguishable clinical phases in individuals with AD pathology (see Table 1): asymptomatic (normal cognition), prodromal or mild cognitive impairment (MCI) due to AD (symptoms present but not severe enough to cause dementia), and AD dementia (symptoms sufficiently severe to interfere with daily activities). It is increasingly evident that AD's asymptomatic phase may last for several years. Progression through these clinical stages is nonlinear, and appears to be influenced by density and distribution of plaques and tangles and numerous other factors.
|Normal Cognition||Mild Symptoms||Dementia|
|International Working Group||At risk with AD pathology||Prodromal AD||AD dementia|
|National Institute on Aging
and Alzheimer's Association
|Preclinical AD||Mild cognitive impairment due to AD||AD dementia|
AD, Alzheimer disease.
MCI (prodromal) represents a stage of illness in which measured cognitive performance is abnormal, yet not so poor as to affect the patient's usual lifestyle and activities. Individuals with MCI are at much higher risk for developing dementia than are individuals with normal cognition. Standardized neuropsychological testing is quite useful during this prodromal stage, because such testing can help to distinguish between normal aging and abnormal cognitive decline. Neuropsychological testing can also provide a baseline measure with which to compare future cognitive performance, and can help to distinguish MCI due to AD (AD-MCI) from non-AD-related MCI.7 Not all people with MCI will progress to dementia, and increasing evidence suggests that preventable risk factors (see Epidemiology) play an important role in determining whether or how quickly someone progresses from AD-MCI to AD dementia. Other features that predict risk for progression from AD-MCI to AD dementia include mesial temporal atrophy, failure of recognition memory on neuropsychological testing, ApoE4 status, parietotemporal hypometabolism on FDG-PET (see Imaging Studies), and AD-type cerebrospinal fluid (CSF) findings (see Laboratory Studies).4,7
In individuals aged 65 years or more, the most common causes of dementia after AD are Lewy body disease (LBD) and cerebrovascular disease (VaD). Both LBD and VaD have symptoms that overlap with those of AD. Moreover, LBD and VaD pathology are often found combined with AD pathology in autopsy samples. In younger patients, frontotemporal lobar degeneration (FTLD) and dementia from chronic alcohol use are also common.11 Most of these entities can be differentiated from AD by detailed clinical history, careful examination, and attention to diagnostic criteria. Potentially treatable conditions that can mimic or exacerbate AD dementia include depression, hypothyroidism, vitamin B12 deficiency, hypocalcemia, neurosyphilis (in endemic regions), and normal pressure hydrocephalus. Certain medications, particularly those with anticholinergic, amnestic, or sedating properties, can be cognitoxic.12 Symptoms and signs that suggest non-AD etiologies are listed in Table 2.
|Alzheimer disease||Gradual, insidious onset
Repeating questions, statements, and stories
Decline in IADLs
|Memory affected out of proportion to other cognitive functions||Failure of encoding on memory testing
Disproportionate atrophy of mesial temporal lobes and/or parietal lobes
Sudden onset or stepwise progression
Apathy or depression
Vascular risk factors
Asymmetry of sensation, movement, or reflexes
|Diffuse white matter disease
Large/strategic lacunar or cortical infarction
|Lewy body disease||REM sleep behavior disorder
Unexplained loss of consciousness
Marked fluctuations in attention and/or cognition
|Extrapyramidal signsâ€”rigidity, tremor, slowness
|Marked visuospatial dysfunction on neuropsychological testing
Occipital hypometabolism on FDG-PET
|Frontotemporal lobar degeneration||Changes in personality
Disinhibition or euphoria
Early inability to communicate meaningfully
Age 55-65 years
|Expressive aphasia||Disproportionate atrophy of frontal lobes or one temporal lobe|
|Delirium||Sudden or subacute onset||Fluctuating level of alertness
IADLs, instrumental activities of daily living; REM, rapid eye movement.
Structural brain imaging with noncontrast computed tomography (CT) or magnetic resonance imaging (MRI) is recommended in the evaluation of dementia, as about 5% of patients have causative structural abnormalities that are otherwise undetectable.13 MRI, by virtue of its superior spatial resolution, is more sensitive than CT to VaD, neoplasm, and atrophy.
Until recently, detecting evidence of non-AD lesions had been the only role for structural imaging. However, recent advances have yielded useful imaging biomarkers of AD. Disproportionate atrophy of the hippocampus and nearby mesial temporal structures is common even in prodromal/MCI AD, and can be detected on MRI. Automated volumetric measurements of hippocampal volumes can be compared with normative data to estimate how an individual's hippocampal size compares with others in their age group. This type of MRI analysis is approximately 85% sensitive and specific for AD but not yet widely utilized.7
Although not recommended as part of a routine workup, functional imaging can play an important role in clinically atypical cases. Hypometabolism on FDG-PET of the parietal and temporal lobes and posterior cingulate gyrus is useful for distinguishing AD from FTLD (wherein the hypometabolic regions are frontal and anterior temporal lobes) and LBD (occipital lobe hypometabolism) when characteristic symptoms and signs of AD are equivocal or absent.
PET imaging for Aβ plaque deposition is available, but expensive and not yet covered by most insurance carriers. Because amyloid PET detects the absence or presence of Aβ aggregates, it is highly sensitive to AD, making a normal (negative) amyloid scan inconsistent with AD. It is important to point out that an abnormal (positive) amyloid scan indicates that plaques are present, but does not provide information about other pathologies that may be present, or to what extent the brain's function is compromised.4,7
Routine blood tests are normal in AD. Measurements of thyroid function and vitamin B12 are recommended for evaluation of all dementia cases, because of the high prevalences of hypocobalaminemia and hypothyroidism in the elderly. Measurement of calcium, B1 (thiamine), and B9 (folate) should be considered in atypical cases. Testing for syphilis (RPR) is recommended only in endemic areas.13
CSF protein, cell counts, and glucose are normal in AD. CSF analysis for low levels of Aβ1–42 and elevated levels of phosphorylated tau is commercially available and yields sensitivity and specificity higher than 90% for AD.7 Low Aβ and high phospho-tau are also predictive of progression from AD-MCI to AD dementia.
As they do not have any AD-specific features, there is little diagnostic role for electroencephalogram (EEG), nerve conduction studies, or electromyogram unless there is suspicion of a specific non-AD dementiaâ€”e.g., Creutzfeldt-Jakob disease is associated with abnormal EEG, hypocobalaminemia may cause polyneuropathy.13
There are no medications proven to slow progression of AD, although symptomatic decline can be slowed by the drugs that are currently approved by the U.S. Food and Drug Administration (FDA) (Table 3).
|Mechanism of Action||Daily Dose Range and Formulations||Common side effects|
|Dose: 2.5 mg-23 mg
5/10/23 mg daily tab
5/10 mg oral dissolvable daily tab
23 mg extended-release daily tab
|Galantamine||Dose: 4 mg-24 mg
4/8/12 mg BID tab
4 mg/mL oral solution
8/16/24 mg extended-release daily tab
|Rivastigmine||Dose: 1.5 mg-12 mg|
1.5/3/4.5/6 mg BID tab
2 mg/mL oral solution
|4.6/9.5/13.3 mg daily patch||As above, plus skin irritation||Memantine||NMDA glutamate receptor antagonist||Dose: 5 mg-28 mg
Titration pack of 5 and 10 mg
5/10 mg BID tab
10 mg/5 mL oral solution
7/14/21/28 mg extended-release daily tab
BID, twice a day; NMDA, N-methyl-D-aspartate.
Acetylcholinesterase inhibitors increase levels of ACh in the brain by retarding its enzymatic breakdown. Rationale for these treatments is that the ACh deficit in AD (see Pathophysiology) is responsible for a significant portion of the cognitive dysfunction. Cholinesterase inhibitorsâ€”donepezil, galantamine, and rivastigmineâ€”are approved by the FDA for use in mild and moderate AD dementia. Donepezil and rivastigmine are also FDA-approved for use in severe AD dementia.
Memantine is an N-methyl-D-aspartate glutamate receptor antagonist, intended to reduce glutamatergic neuronal excitotoxicity. It is approved for use in moderate to severe AD dementia.
Medications for AD dementia have repeatedly demonstrated statistically significant effects on the rate of symptom progression. However, their overall clinical effect is small in magnitude and often temporary.14 No medicines are approved for asymptomatic or MCI AD.
Behavioral problems, including mood dysfunction, anxiety, and psychotic symptoms are quite prevalent in AD, and are more stressful for patients and caregivers than are the cognitive symptoms.9 Nevertheless, no medication has been approved by the FDA to treat behavioral problems in AD. In general, trials of psychotropic medications, including antidepressants, anxiolytics, and antipsychotic medications have yielded mostly marginal results in AD patients. Antipsychotic medications, although sometimes effective, are demonstrated to cause increased rates of sudden death, acute hospitalization, and cerebrovascular events when used for agitation in dementia patients.9,15,16 There is increasing interest in the use of non-pharmacologic behavioral modification, such as psychological tactics or environmental adjustments.9
The patient's environment should also be considered; some studies have shown a reduced need for antipsychotics and physical restraints as well as a decrease in behavioral disturbances in AD patients who reside in specialized memory care or dementia units. Education and psychosocial support for the caregiver is an integral part of AD management. Support groups, respite care, family medical leave, and other services should be available to caregivers for AD patients.14
AD is the most common of many causes of dementia, and its prevalence is increasing worldwide. Disease pathology starts years before noticeable symptoms. Neuropsychological, imaging, and spinal fluid tests can establish the diagnosis with high accuracy.
Although there are currently no treatments that slow the disease process, management of the cognitive and behavioral symptoms of AD dementia can significantly improve the lives of patients and their caregivers.