Summary
Alzheimer disease (AD) is a chronic neurodegenerative disease and the leading cause of dementia. Several causative gene defects (e.g., amyloid precursor protein gene mutations) and risk factors (e.g., old age) have been identified, although the exact mechanism that causes Alzheimer disease is still unknown. The main histopathological features of AD are senile plaques caused by the extracellular deposition of beta-amyloid protein (Aβ protein) in the grey matter of the brain and neurofibrillary tangles due to intracellular accumulation of tau protein. The most common symptom of AD is short-term memory loss. Many cognitive functions, including attention control, reasoning, orientation, and language, are affected during the course of the disease. Individuals with AD are typically capable of maintaining a social façade as the disease progresses. The diagnosis is primarily based on clinical examination, but neuropsychological tests, cerebrospinal fluid (CSF) analysis, and imaging are sometimes used as well. To date, there is no curative therapy. Symptomatic therapy can be attempted with cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists (e.g., memantine). AD has a highly variable progression. The mean survival time following diagnosis is usually between 3 and 10 years.
Epidemiology
- AD is the leading cause of dementia and the sixth most common cause of death in the US. [1]
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Incidence and prevalence increase with age.
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Incidence
- ∼ 400:100,000 in individuals between 65 and 74 years of age
- ∼ 3200:100,000 in individuals 75–84 years of age
- ∼ 7600:100,000 in individuals ≥ 85 years of age
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Prevalence: A total number of ∼ 5.8 million individuals in the US have Alzheimer disease.
- 65–74 years of age: 1 million individuals (17%)
- 75–84 years of age: 2.7 million individuals (47%)
- ≥ 85 years of age: 2.1 million individuals (36%)
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Incidence
- Sex: ♀ > ♂
- Early-onset (before the age of 65) familial AD represents ∼ 10% of all AD cases
Epidemiological data refers to the US, unless otherwise specified.
Etiology
Genetic factors [1][2]
Overview of genetic factors in Alzheimer disease | ||
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Genes | Proteins | Characteristics |
Amyloid precursor protein (APP) gene |
| |
Presenilin-1 |
|
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Presenilin-2 [3] |
|
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Apo ε |
Other risk factors [1][2]
- Age (strongest predisposing factor for regular AD)
- Family history of dementia (strongest predisposing factor for early-onset AD)
- Low socioeconomic and/or educational status
- Diabetes, obesity, dyslipidemia
- Hypertension, peripheral atherosclerosis, and cerebrovascular disease
- African American or Hispanic descent (compared to White individuals)
- Lack of physical activity (independent risk factor)
- Traumatic brain injuries
- Environmental factors (e.g., secondhand smoke)
- Sleep deprivation
Pathophysiology
The following pathophysiological mechanisms contribute to AD: [2]
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Senile plaques (neuritic plaques)
- Extracellular
- Located in the grey matter of the brain
- Aβ protein is the main component of the plaques.
- Enzymatic cleavage of transmembranous APP by β-secretase and γ-secretase → Aβ peptide aggregation → formation of insoluble plaques together with tau protein and microglia → neurotoxic effect
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Neurofibrillary tangles
- Intracellular
- Tangles are composed of hyperphosphorylated tau protein (an insoluble microtubule-associated protein).
- ↑ Phosphorylation (hyperphosphorylation) of tau → formation of intracellular fibrils → neurotoxic effect (number of tangles correlates with the degree of cognitive impairment) [4]
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Reduced cholinergic function
- Acetylcholine deficiency is related to the degeneration of cholinergic neurons and likely plays a role in the decline of cognitive abilities.
- Other neurotransmitter systems (e.g., noradrenergic transmission) are affected less severely.
Clinical features
Cognitive [2]
- Common symptoms of cognitive impairment
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Short-term memory impairment
- Insidious onset
- Slow progression
- Episodic memory affected first
- Language impairment
- Temporal and spatial disorientation (patients are usually not oriented to person, place, time, or events)
- Impairment of executive functions and judgment
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Short-term memory impairment
- Less common symptoms
Noncognitive [2]
- Behavioral changes
- Mood disorders (e.g., symptoms of depression)
- Urinary incontinence
- Anxiety and mutism
- Hallucinations and paranoia
- Hyposmia
- Insomnia
- Myoclonus
- Seizures
Patients with mild to moderate AD are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines).
Diagnostics
Approach
- Use neuropsychological testing (e.g., Mini-Mental State Examination, Montreal Cognitive Assessment) to diagnose dementia in patients with memory loss, cognitive and/or functional decline.
- Rule out reversible causes of dementia.
- Review medications.
- Laboratory tests (rule out hypothyroidism and vitamin B12 deficiency)
- Neuroimaging (rule out vascular dementia, hydrocephalus, tumors)
- Clinical assessment for depression to rule out pseudodementia (see “Diagnostic criteria for major depressive disorder.”)
- AD can only be confirmed via neurohistopathological examination, which can only be conducted post mortem.
Diagnostic findings
Synopsis of diagnostic criteria
- Insidious onset (symptoms are often first noticed by the patient's relatives)
- Objectively confirmed progressive loss of function in at least two cognitive domains (usually including memory impairment)
- Impaired activities of daily living (e.g., difficulties at the workplace)
- No other plausible explanation (e.g., delirium)
Neuropsychological testing
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Cognitive testing: Repeated performance measurement is used to track disease progression.
- Mini-Mental State Examination (MMSE)
- Montreal Cognitive Assessment (MoCa)
- Alzheimer disease assessment scale – cognitive behavior subscale (ADAS-Cog)
- Mini-cog
- Blessed Information-Memory-Concentration Test (BIMC)
- Clinical Dementia Rating Scale (CDR)
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Functional testing
- Functional Assessment Questionnaire (FAQ)
- Physical Self-Maintenance Scale (PSMS)
- Global testing: Global Deterioration Scale (GDS)
- Caregiver-based testing: Neuropsychiatric Inventory (NPI)
EEG
- Slower basic rhythm
- Evoked potentials: long latency
Neuroimaging
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CT/MRI
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Signs of generalized or focal cerebral atrophy
- Enlarged ventricles (ventriculomegaly)
- Narrowing of gyri
- Prominent cerebral sulci (hydrocephalus ex vacuo)
- Disproportionate atrophy of the hippocampus and/or medial temporal lobe
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Signs of generalized or focal cerebral atrophy
- PET
Cerebrospinal fluid
- ↑ Phospho-tau protein
- ↓ β-amyloid proteins Aβ1–42
Pathology
Macroscopic
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Cerebral atrophy
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Damage to the hippocampus and parahippocampal cortex (medial temporal lobe structures) is the earliest gross pathological change.
- Axonal degeneration
- Neuronal loss
- Degeneration of cholinergic neurons in the nucleus basalis of Meynert
- Diffuse cortical atrophy occurs as the disease progresses.
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Damage to the hippocampus and parahippocampal cortex (medial temporal lobe structures) is the earliest gross pathological change.
Microscopic
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Amyloid beta (Aβ): stains with Congo red under polarization
- Cerebral amyloid angiopathy
- Extracellular senile plaques (beta-amyloid core) in gray matter
- Tau protein: intracellular neurofibrillary tangles that stain with Gallyas silver
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Hirano bodies
- Intracellular rod-shaped eosinophilic aggregates of actin and actin-associated proteins in neurons, especially in hippocampus
- Also found in other neurodegenerative diseases (e.g., Creutzfeldt–Jakob disease) and sometimes in normal elderly as well
References:[2]
Differential diagnoses
See “Differential diagnosis of subtypes of dementia.”
The differential diagnoses listed here are not exhaustive.
Treatment
There is currently no curative therapy available.
Pharmacological treatment of dementia
- Mild–moderate (determined by neuropsychological testing): acetylcholinesterase inhibitors
- Moderate–severe (may be given in addition to acetylcholinesterase inhibitors): NMDA-receptor antagonist (memantine)
- Aggression and psychosis: low dose antipsychotics
Supportive care (nonpharmacological treatment)
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Lifestyle modifications
- Adhering to a regular sleep schedule
- Maintaining a familiar environment
- Removing ambient noise
- Cognitive rehabilitation: memory training (e.g., puzzles, interactive games) to support memory retention and strategies to compensate for cognitive and functional decline
- Physical activity: improves physical strength, which slows functional decline
Pharmacological treatment of associated symptoms
In patients who have not adequately responded to supportive care, the following classes of drugs may be considered:
- Atypical antipsychotics (e.g., risperidone): in individuals showing signs of agitation, hallucinations, insomnia
- SSRIs (e.g., citalopram): in individuals with depression
Avoid drugs with strong anticholinergic effects (e.g., diphenhydramine).
References:[2]
Complications
- Infections: Aspiration pneumonia is the most common contributing factor to AD-related mortality.
- Malnourishment/dehydration
- Intracerebral hemorrhage (↑ risk due to cerebral amyloid angiopathy)
We list the most important complications. The selection is not exhaustive.
Prognosis
The mean survival time is ∼ 3 to 10 years after diagnosis.