Alzheimer disease

Last updated: December 1, 2022

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Alzheimer disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. The clinical spectrum of AD ranges from preclinical to severe. Risk factors include age > 65 years and genetic factors. The main histopathological features are extraneuronal β-amyloid () plaques and intraneuronal tau protein neurofibrillary tangles. The most common initial presentation is short-term memory loss, which insidiously progresses to dementia with deficits in other cognitive domains. Patients commonly have neuropsychiatric symptoms (e.g., depression, anxiety, and apathy) alongside cognitive deficits. The diagnosis is based on clinical criteria. Specialized imaging (PET-CT) and cerebrospinal fluid (CSF) analysis can be used to help clarify diagnostic uncertainty. There is no curative therapy; patients should receive supportive management. Pharmacotherapy (e.g., cholinesterase inhibitors and/or memantine) are modestly effective at slowing symptom progression. Average survival following diagnosis usually ranges from 3 to 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 AD.
      • 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 → 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]

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 [5][6][7]

Diagnostic criteria for Alzheimer disease [9]

DSM-5 diagnostic criteria for major neurocognitive disorder due to Alzheimer disease [9][10][11]
Probable major neurocognitive disorder due to AD Possible major neurocognitive disorder due to AD
Criteria
  • All of the following:
    • Objective impairment in learning and memory and ≥ 1 other cognitive domain
    • Steady cognitive decline with no plateaus
    • No evidence of other causes
  • OR evidence of a causative genetic mutation
  • Absence of any features indicating probable AD

MRI brain [7][8]

Advanced studies [8][12]

PET Scan

  • FDG-PET [13]
    • Used to:
      • Differentiate between types of dementia, as well as between AD subtypes
      • Assess severity and prognosis
    • Supportive finding: ↓ glucose metabolism in temporal and parietal cortices
  • Amyloid-β ()-PET [13]
    • A negative result reduces the probability of AD.
    • Supportive finding: amyloid uptake signal
  • Tau-PET [14]
    • To assess prognosis based on tau uptake signal in temporal and parietal cortices

Additional studies

Patients with preclinical Alzheimer disease are asymptomatic but have measurable brain changes (e.g., abnormal on PET-CT or CSF analysis). There is often a duration of several years between the onset of mild cognitive symptoms and the diagnosis of dementia. [16]

Macroscopic

Microscopic

References:[2]

See “Differential diagnosis of subtypes of dementia.”

The differential diagnoses listed here are not exhaustive.

General principles [6]

  • There is currently no curative therapy for AD.
  • Management should include:
  • Overall goals
    • Maintain function
    • Delay symptom progression

Pharmacological treatment [6][7]

Recommendations are based on disease severity, which is based on symptoms , and the results of a functional status assessment and a cognitive assessment.

Pharmacological therapies provide only modest delay in the progression of cognitive decline. Treatment choices should be a shared decision.

Antidementia medications [6][17][18]
Indications Mechanism of action Adverse effects
Acetylcholinesterase inhibitors (AChEIs)

Rivastigmine

Galantamine
Donepezil

NMDA receptor antagonist: memantine

  • Moderate to severe AD
  • Often used in combination with donepezil
monoclonal antibody: aducanumab [19][20]

Cholinesterase inhibitors affect the sinoatrial and atrioventricular nodes and increase the risk of bradycardia, syncope, and heart block. Check heart rate and obtain a 12-lead ECG prior to initiating a cholinesterase inhibitor, and screen for bradyarrhythmias at each visit thereafter. [21]

Think “Gallantly Down the River“ to remember the centrally acting AChE inhibitors used in the treatment of dementia: Galantamine, Donepezil, and Rivastigmine.

Supportive management

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

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

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

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  21. Young S, Chung E, Chen MA. Cardiovascular Complications of Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Narrative Review. Ann Geriatr Med Res. 2021; 25 (3): p.170-177. doi: 10.4235/agmr.21.0079 . | Open in Read by QxMD

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