• Clinical science

Alzheimer disease

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. 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 3–10 years.

Epidemiology

  • AD is the leading cause of dementia; and the sixth most common cause of death in the US.
  • Incidence and prevalence increase with age.
    • Incidence
      • ∼ 200:100,000 in patients 65–74 years of age
      • ∼ 3700:100,000 in patients ≥ 85 years of age
    • Prevalence
      • 1/10 individuals 65 years of age
      • 1/3 individuals ≥ 85 years of age
  • Sex: >
  • In the US, AD is more common in African Americans and Hispanics than in whites.

References:[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Genetic factors

Genes (chromosome) Proteins Characteristics
Amyloid precursor protein (APP) gene

APP

  • Linked to 10–15% of early-onset familial AD cases
  • Patients with trisomy 21 have an increased risk of early-onset AD because of APP overexpression (the APP gene is located on chromosome 21).
Presenilin-1 PSEN1
  • Linked to ∼ 50% of familial AD cases
  • Earlier onset compared to AD due to mutations of other genes (median is ∼ 43 years)
Presenilin-2

PSEN2

  • Mutations cause the rarest form of familial AD.
Apo ε Apolipoprotein E (ApoE)
  • Risk of late-onset AD increases with the number of carried Apo ε4 alleles.
  • Apo ε2 alleles may have a protective effect.
  • Apo ε3 alleles neither decrease nor increase risk of developing AD

Other risk factors

  • Age
  • Family history of dementia
  • Low socioeconomic and/or educational status
  • Diabetes, obesity, dyslipidemia
  • Hypertension, peripheral atherosclerosis, and cerebrovascular disease
  • Lack of physical activity (independent risk factor)
  • Traumatic brain injuries
  • Environmental factors (e.g., secondhand smoke)
  • Sleep deprivation

References:[1][2][4][5][6][7]

Pathophysiology

The following pathophysiological mechanisms contribute to AD:

  1. Extracellular senile plaques (neuritic plaques) 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-secretaseAβ peptide aggregation → formation of insoluble plaques together with tau protein and microglia → neurotoxic effect
  2. Intracellular neurofibrillary tangles
    • Tangles are composed of hyperphosphorylated tau protein(a microtubule-associated protein).
    • Increased phosphorylation (hyperphosphorylation) of tau → formation of intracellular fibrils → neurotoxic effect
  3. Overall reduction of cholinergic function

References:[1]

Clinical features

Cognitive

  • Common symptoms of cognitive impairment
    • Short-term memory impairment (insidious onset, slow progress with 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

Patients with mild to moderate AD are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines).
References:[1][8]

Diagnostics

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)
  • Cerebrospinal fluid
  • CT/MRI
  • EEG: slower basic rhythm
    • Evoked potentials: long latency
  • PET
    • FDG-PET: temporoparietal hypometabolism
    • Amyloid PET: increased amyloid uptake signal
  • Neuropsychological testing (e.g., MMSE and MoCA): Repeated performance measurement is used to track disease progression.

References:[9][8][10][11]

Pathology

References:[1]

Differential diagnoses

See differential diagnosis of subtypes of dementia.

The differential diagnoses listed here are not exhaustive.

Treatment

There is currently no curative therapy; only symptomatic therapies are available.

Pharmacological treatment of dementia

Supportive care (nonpharmacological treatment)

  • Lifestyle modifications; : e.g., 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:[1][12][2]

Complications

References:[13]

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

Prognosis

The reported survival rate is approximately 3 to 10 years after diagnosis.

References:[2]