• Clinical science

Alzheimer disease

Abstract

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 various risk factors (e.g., old age) have been identified, although the exact mechanism that causes dementia is still unknown. Histopathological evidence of AD primarily includes senile plaques from the deposition of beta-amyloid protein (Aβ protein) and neurofibrillary tangles from the accumulation of tau protein. The most common presenting symptom is short term memory loss. During the course of the disease, many cognitive functions are affected, such as attention control and reasoning, orientation, and language. Patients 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 (ChEIs) and N-methyl-D-aspartate (NMDA) antagonists (e.g., memantine). AD features a highly variable progression, with the mean survival following diagnosis between 3 and 10 years.

Definition

References:[1][2]

Epidemiology

  • AD is the leading cause of dementia; and the 6th 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 and older
    • Prevalence: up to 20–40% in patients ≥ 85 years
  • Sex: >
  • In the US, AD is more common in African Americans and Hispanics than in whites.

References:[3][2][4][5]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Genetic factors

Genes (chromosome) Proteins Characteristics
Amyloid precursor protein (APP) gene (chr 21)

APP

  • Linked to 10–15% of early-onset familial AD cases (full penetrance)
  • Age at disease onset usually resembles parental age at disease onset (median ≈ 49 years).
  • Patients with trisomy 21 frequently develop AD at around age 50.
Presenilin-1 (chr 14) PSEN1
  • Linked to ∼ 50% of familial AD cases (full penetrance)
  • Earlier onset (median ≈ 43 years)
Presenilin-2 (chr 1)

PSEN2

  • Rare form of familial AD (penetrance ≈ 95% )
  • Later onset (average ≈ 54 years)
Apo ε (chr 19) Apolipoprotein E (ApoE)
  • Risk of late-onset familial AD increases with number of carried Apo ε4 alleles
  • Apo ε2 alleles may have a protective quality, whereas Apo ε3 alleles seem to be neutral in AD.

Other risk factors

References:[3][2][5][6][7][8]

Pathophysiology

  • Extracellular senile plaques: composed of Aβ protein
  • Intracellular neurofibrillary tangles: composed of hyperphosphorylated tau protein
  • Damage to the hippocampus and parahippocampal cortex (medial temporal lobe structures) is the earliest gross pathological change → diffuse cortical atrophy occurs as the disease progresses
  • Degeneration of cholinergic neurons in the nucleus basalis of Meynert (basal forebrain structure); impaired cholinergic transmission to cortex, reduced levels of choline acetyltransferase and acetylcholine overall reduction of cholinergic function

References:[3]

Clinical features

Cognitive

  • Common order of cognitive impairments
    • Short term memory (insidious onset and slow progress with episodic memory affected first)
    • Language (typical sequence: impaired naming → impaired comprehension → impaired fluency)
    • Temporal and spatial orientation (e.g., disorientation, inability to judge distances)
  • Less common symptoms
    • Apraxia, alexia, agnosia, acalculia
    • Primary progressive aphasia (particularly the logopenic subtype characterized by word-finding difficulties)
    • Impairment of executive functions and judgment (e.g., disorganization)
  • Patients are usually not oriented to person, place time and events (e.g., in earlier stages, patients may get lost while driving home).

Non-cognitive

  • Behavioral changes
    • Apathy
    • Aggression, irritability, and agitation
  • Mood disorders
    • Earlier stages: usually symptoms of depression
    • Later stages: patients are often unconcerned and happy and tend to downplay their cognitive impairments
  • Anxiety and mutism
  • Hallucinations and paranoia
  • Hyposmia
  • Insomnia
  • Late stage

Patients with mild to moderate Alzheimer disease are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines)!
References:[3][9]

Diagnostics

Approach

Diagnostic findings

  • Synopsis of diagnostic criteria
    • Insidious onset
    • Objectively confirmed progressive loss of function in at least two cognitive domains (usually, but not necessarily, including memory impairment)
    • Impairment of activities of daily life (e.g., difficulties at the workplace)
    • No other plausible explanation (e.g., delirium)
  • Cerebrospinal fluid
    • ↑ Phospho-tau protein
    • ↓ β-amyloidproteins Aβ1-42
  • CT/MRI:
  • EEG: slower basic rhythm
    • Evoked potentials: long latency
  • PET: temporoparietal hypometabolism
  • Neuropsychological testing: (e.g., MMSE) repeat measurement of performance on such tests is helpful to track the progress of the disease in individual patients over time.
    • Cognitive testing: Alzheimer disease assessment scale – cognitive behavior subscale (ADAS-Cog), Mini-cog, Blessed Information-Memory-Concentration Test (BIMC), Clinical Dementia Rating Scale (CDR)
    • Functional testing: e.g., Functional Assessment Questionnaire (FAQ), Physical Self-Maintenance Scale (PSMS)
    • Global testing: e.g., Global Deterioration Scale (GDS)
    • Caregiver-based testing: e.g., Neuropsychiatric Inventory (NPI)

References:[10][9][11][12]

Pathology

  • Cerebral atrophy: particularly in the temporal lobe (cortex and hippocampus) and the nucleus basalis of Meynert
  • Amyloid beta (Aβ): stains with Congo red under polarization
    • Cerebral amyloid angiopathy (can cause intracerebral hemorrhages)
    • Intracellular neurofibrillary tangles
    • Extracellular senile plaques
  • Axonal degeneration

References:[3]

Differential diagnoses

See differential diagnosis of subtypes of dementia.

The differential diagnoses listed here are not exhaustive.

Treatment

There is no curative therapy available; only symptomatic therapies.

Pharmacological treatment of dementia

Supportive care (nonpharmacological treatment)

  • Lifestyle modifications; (behavioral interventions for patients and care-givers): for example, adhering to a regular sleep schedule, maintaining a consistent and familiar environment, removing ambient noise
  • Cognitive rehabilitation: memory training (e.g., puzzles, interactive games) to maintain memory and develop strategies to compensate for cognitive and functional decline
  • Physical exercise: improve physical strength and decelerate the functional decline
  • Occupational therapy: develop coping skills and behavior to improve functionality and performance of activities of daily living

Pharmacological treatment of associated symptoms

Indicated in patients with poor response to supportive care. Examples:

Drugs with strong anticholinergic effects (e.g., diphenhydramine) should be avoided!
References:[3][13][2]

Complications

References:[14]

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

Prognosis

  • The reported mean survival varies from approximately 3 to 10 years after diagnosis
  • The median survival following diagnosis is 3 years.

References:[2]