Alzheimer disease

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 histopathologic features are extraneuronal amyloid beta (Aβ) plaques and intraneuronal tau protein neurofibrillary tangles. The most common initial presentation is short-term memory loss, which insidiously progresses to dementia and deficits in other cognitive domains. Patients commonly have neuropsychiatric symptoms (e.g., depression, anxiety, apathy) alongside cognitive deficits. The diagnosis is based on clinical criteria, and may involve formal neuropsychological testing. Advanced studies such as PET-CT and cerebrospinal fluid (CSF) analysis may be performed if there is diagnostic uncertainty and to guide management. There is no curative therapy; patients should receive supportive management. Pharmacological treatment (e.g., cholinesterase inhibitors, memantine, anti-Aβ monoclonal antibodies) is modestly effective at slowing symptom progression. Patients eligible for anti-Aβ monoclonal antibody therapy should be promptly referred to a specialist. Average survival after 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]

Other risk factors ^[1][2]

• Age ≥ 65 years (strongest predisposing factor for regular AD) ^[1]
• 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 ^[4]

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]

• 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
  • Primary progressive aphasia
  • Apraxia
  • Alexia
  • Agnosia
  • Acalculia

Noncognitive ^[2]

• Behavioral changes
  • Apathy
  • Agitation, aggression, irritability
• 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).

Approach ^[5][6]

• Consider AD in patients with major or mild neurocognitive disorder: See “Diagnosis of major neurocognitive disorder.”
• Perform an initial evaluation of major neurocognitive disorder, including MRI brain.
• Establish the diagnosis based on clinical diagnostic criteria for AD, which may involve neuropsychological testing. ^[5]
• Refer to a specialist if advanced studies are indicated, e.g.:
  • Diagnostic uncertainty after standard evaluation
  • Atypical clinical features (e.g., nonamnestic AD)
  • Early-onset dementia (< 65 years of age)
  • Rapidly progressive dementia
  • Mild AD prior to intiation of anti-Aβ monoclonal antibodies ^[7]
• A definitive diagnosis requires neurohistopathological confirmation (biopsy is rarely performed premortem).

Diagnostic criteria for AD ^[6]

Multiple sets of diagnostic criteria for AD exist, with varying emphasis on clinical features and biomarkers. The National Institute on Aging–Alzheimer's Association criteria presented here focus on clinical manifestations. ^[6]

Probable AD dementia

• Diagnostic criteria for major neurocognitive disorder are fulfilled.
• Additionally, the following characteristics are present:
  • Insidious onset over months to years
  • Confirmed progressive cognitive decline by history or observation
  • Objective impairment in ≥ 2 cognitive domains, most commonly including learning and memory
  • No evidence of another cause

Mild cognitive impairment due to AD

• Confirmed progressive cognitive decline by history or observation
• Objective impairment in ≥ 1 cognitive domain, typically including memory
• No loss of function
• Diagnostic criteria for major neurocognitive disorder are not fulfilled.
• Supportive features include:
  • Insidious cognitive decline
  • No evidence of another cause
  • History consistent with AD genetic factors

The likelihood of cognitive impairment being due to AD increases if biomarkers are present: Aβ (Aβ-PET or CSF), phosphorylated tau protein (CSF), or neuronal injury (MRI, FDG-PET). ^[6]

MRI brain ^{[6][8][9][10]}

• Indications
  • All patients as part of the initial evaluation
  • MRI may be repeated before initiation of anti-Aβ monoclonal antibody therapy to assess the risk of amyloid-related imaging abnormalities (ARIA). ^[7]
• Supportive findings
  • Signs of generalized or focal cerebral atrophy
    • Enlarged ventricles (ventriculomegaly)
    • Narrowing of gyri
    • Prominent cerebral sulci (hydrocephalus ex vacuo)
  • Disproportionate atrophy of the medial temporal lobe including the hippocampi, amygdala, cingulate cortex, and parahippocampal gyrus

Advanced studies ^[5][6][11]

Consider advanced studies in selected cases under specialist guidance.

PET scan

• FDG-PET ^[12]
  • Used to:
    • Differentiate between types of dementia and between AD subtypes
    • Assess severity and prognosis
  • Supportive finding: ↓ glucose metabolism in temporal and parietal cortices
• Aβ-PET ^[13]
  • Used to:
    • Differentiate between types of dementia
    • Confirm eligibility for anti-Aβ monoclonal antibodies
  • A negative result reduces the probability of AD. ^[10]
  • Supportive finding: ↑ amyloid uptake signal

Laboratory studies

• CSF analysis
  • Used to:
    • Differentiate between types of dementia
    • Confirm eligibility for anti-Aβ monoclonal antibodies
  • Supportive findings
    • ↑ Phosphorylated tau protein
    • Abnormal Aβ profile (e.g., ↓ Aβ₄₂) ^[6]
• Blood tests
  • ↑ Phosphorylated tau protein
  • Genetic factors for AD (e.g., APOE genotyping to evaluate ARIA risk from treatment with anti-Aβ monoclonal antibodies) ^[7]

Macroscopic

• Cerebral atrophy
  • 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.

Microscopic

• 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
• 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]

See “Differential diagnosis of subtypes of dementia.”

The differential diagnoses listed here are not exhaustive.

The goals of treatment in AD are to delay symptom progression and maintain function.

Approach ^[7][14][15]

• Promptly refer patients eligible for anti-Aβ monoclonal antibodies to a specialist (neurology, psychiatry, or geriatrics).
• Initiate symptomatic pharmacological treatment for AD (cholinesterase inhibitors and/or memantine) as indicated, based on shared decision-making. ^[7]
• Check heart rate and obtain a 12-lead ECG before initiating a cholinesterase inhibitor, and screen for bradyarrhythmias at each visit thereafter.
• Regularly reassess the tolerability and benefit of symptomatic pharmacological treatment.
  • If no perceived benefit by 12 weeks, consider discontinuation based on shared decision-making. ^[16]
  • Assess for adverse effects and other indications for discontinuation (e.g., very severe cognitive or functional impairment, dysphagia) every 6–12 months. ^[7]
• Provide supportive care for dementia, including lifestyle modifications.
• Manage conditions commonly associated with dementia (e.g., major depressive disorder, agitation, psychosis).

There is currently no curative therapy for AD.

Anti-Aβ monoclonal antibody therapy should be started as soon as possible for maximum benefit. ^[7]

Pharmacological treatment

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 before initiation, and screen for bradyarrhythmias at each visit thereafter.^[18]

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

Supportive management ^[7]

• Similar to management in other types of dementia
• Includes lifestyle modifications (e.g., maintaining sleep hygiene and a predictable schedule)
• Pharmacological therapy for common comorbidities: See "Management of behavioral and psychological symptoms of dementia."
• See “Management of major neurocognitive disorder” for further details.

Avoid strong anticholinergic drugs (e.g., diphenhydramine) because of the heightened impact of adverse effects (e.g., confusion, blurred vision, xerostomia). ^[7]

• 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.

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

See “Prevention of dementia.”

• One-Minute Telegram 147-2026-2/3: Amyloid antibodies for Alzheimer disease: much ado about nothing?
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