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Alzheimer disease

Last updated: December 31, 2020

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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.

  • AD is the leading cause of dementia and the sixth most common cause of death in the US. [1]
  • Incidence and prevalence increase with age.
    • 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
    • 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%)
  • 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.

Genetic factors [1][2]

Overview of genetic factors in Alzheimer disease
Genes Proteins Characteristics
Amyloid precursor protein (APP) gene
  • Linked to 10–15% of early-onset familial AD cases
  • Since the APP gene is located on chromosome 21, individuals with trisomy 21 have an increased risk of early-onset AD due to APP overexpression
  • Age at disease onset usually resembles parental age at disease onset (median ∼ 49 years).
Presenilin-1
  • PSEN1
  • Earlier onset compared to AD due to mutations of other genes (median is ∼ 43 years)
  • Linked to ∼ 50% of familial AD cases
Presenilin-2 [3]
  • PSEN2
  • Mutations cause the rarest form of familial AD.
  • Later onset (average ∼ 54 years)
Apo ε
  • Risk of late-onset AD increases with the number of carried Apo ε4 alleles.
  • Apo ε2 alleles may have a protective effect (reduce the risk of late-onset sporadic AD).
  • Apo ε3 alleles neither decrease nor increase risk of developing AD.

Other risk factors [1][2]

The following pathophysiological mechanisms contribute to AD: [2]

  • 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
  • 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]
  • 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.

Cognitive [2]

  • Common symptoms of cognitive impairment
    • 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
  • Less common symptoms

Noncognitive [2]

Patients with mild to moderate AD are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines).

Approach

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

  • Cognitive testing: Repeated performance measurement is used to track disease progression.
  • Functional testing
    • Functional Assessment Questionnaire (FAQ)
    • Physical Self-Maintenance Scale (PSMS)
  • Global testing: Global Deterioration Scale (GDS)
  • Caregiver-based testing: Neuropsychiatric Inventory (NPI)

EEG

Neuroimaging

Cerebrospinal fluid

Macroscopic

Microscopic

References:[2]

See “Differential diagnosis of subtypes of dementia.”

The differential diagnoses listed here are not exhaustive.

There is currently no curative therapy available.

Pharmacological treatment of dementia

Supportive care (nonpharmacological treatment)

  • 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:

Avoid drugs with strong anticholinergic effects (e.g., diphenhydramine).

References:[2]

We list the most important complications. The selection is not exhaustive.

The mean survival time is ∼ 3 to 10 years after diagnosis.

  1. The Alzheimer's Association. 2020 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2020; 16 (3): p.391-460. doi: 10.1002/alz.12068 . | Open in Read by QxMD
  2. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
  3. Jayadev S, Leverenz JB, Steinbart E, et al. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010; 133 (4): p.1143-1154. doi: 10.1093/brain/awq033 . | Open in Read by QxMD
  4. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature. Journal of Neuropathology & Experimental Neurology. 2012; 71 (5): p.362-381. doi: 10.1097/nen.0b013e31825018f7 . | Open in Read by QxMD