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Alzheimer's Disease

Chapter 442 | Harrison's 22e · Part 13 – Neurologic Disorders · Chapter 442

Key Clinical Points

  1. Approximately 55 million people worldwide live with dementia; Alzheimer’s disease (AD) is the most common cause, accounting for 60–70% of all cases.
  2. Pathology is defined by two hallmarks: amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments.
  3. The ε4 allele of the apolipoprotein E (ApoE) gene is the primary genetic risk factor; 1 ε4 allele increases risk 2–3 fold in women, while 2 ε4 alleles increase risk 10–15 fold in both sexes.
  4. Preclinical AD can precede clinical symptoms by 20 years or more, providing a window for early intervention.
  5. Mild Cognitive Impairment (MCI) has a high conversion rate: ~50% of patients progress to dementia over 4 years (~12% per year).
  6. Clinical presentation varies; while memory loss is typical, non-memory variants include logopenic aphasia and posterior cortical atrophy.
  7. Biomarkers for Aβ and phosphorylated tau in CSF or plasma allow detection of pathological hallmarks in living patients.
  8. Molecular imaging (PiB, FTP, FDG) differentiates between amyloid deposition, tau pathology, and metabolic activity.
  9. Anti-amyloid therapies require monitoring for Amyloid-Related Imaging Abnormalities (ARIA).
  10. ARIA-E refers to brain edema; ARIA-H refers to microhemorrhages or superficial siderosis.

DEFINITION & CLASSIFICATION

• Preclinical AD:

Definition: A person with biomarker evidence of amyloid pathology (with or without tau pathology) in the absence of symptoms. → Can precede clinical symptoms by 20 years or more.

• Mild Cognitive Impairment (MCI):

Definition: Subjective cognitive decline (self-perceived worsening in memory or other cognitive abilities) or apparent on formal neuropsychological testing. → ~50% of patients progress to dementia over 4 years (~12% per year).

• Early Symptomatic AD:

Definition: A patient who remains functionally compensated but has clinical or biomarker evidence that AD is the underlying disease.

EPIDEMIOLOGY

• Prevalence: → ~55 million people worldwide living with dementia. → AD accounts for 60–70% of all cases.

• Economic Impact: → Estimated at $360 billion in 2024. → Average cost of ~$25,000 per patient.

ETIOLOGY & PATHOPHYSIOLOGY

• Pathological Hallmarks: → Amyloid-beta (Aβ) plaques: Extracellular deposits. → Neurofibrillary tangles (NFTs): Composed of hyperphosphorylated tau filaments.

• Amyloid Processing (Figure 1): → Non-amyloidogenic pathway: APP → α-secretase (ADAM10 or ADAM17 [TACE]) → nontoxic products. → Amyloidogenic pathway: APP → β-secretase (BACE) → γ-secretase → Aβ_{42} (toxic) or Aβ_{40} (nontoxic).

• Genetics: → Primary risk factor: ε4 allele of the apolipoprotein E (ApoE) gene. → 1 ε4 allele → 2–3 fold increased risk in women. → 2 ε4 alleles → 10–15 fold increased risk in both sexes.

CLINICAL FEATURES

• Typical Amnestic AD: → Presentation: Insidious loss of episodic memory → slowly progressive dementia.

• Non-memory Variants: → Posterior cortical atrophy (visual processing dysfunction). → Logopenic aphasia (difficulty with naming and repetition) → may persist for years before involving memory. → Corticobasal syndrome (asymmetric akinetic-rigid-dystonic). → Frontal variant (dysexecutive/behavioral; includes depression, social withdrawal, and anxiety).

• Prodromal Phase: → Depression, social withdrawal, and anxiety may appear before cognitive symptoms.

DIAGNOSTIC APPROACH

  1. Biomarker Assessment • Identify Aβ and phosphorylated tau in CSF or plasma. • Detect pathological hallmarks in living patients to enable early detection.
  2. Molecular Imaging (Figure 2) • [11C]PiB: Assess amyloid plaque distribution. • [18F]FTP: Assess neurofibrillary tangles (tau). • FDG-PET: Measure glucose metabolism → indicates reduced synaptic activity.
  3. Radiographic Monitoring of ARIA (Figure 4) • ARIA-E (Edema): Detected on FLAIR. → Mild: <5 cm involvement. → Moderate: 5–10 cm involvement. → Severe: >10 cm involvement. • ARIA-H (Hemorrhage/Siderosis): Detected on SWI or T2*. → Staged by count of microhemorrhages and areas of siderosis.

KEY PEARLS & HIGH-YIELD POINTS

• Early Detection: Preclinical AD offers a window for intervention 20+ years before symptoms. • Risk Factors: ApoE ε4 is the primary genetic risk factor; risk increases exponentially with multiple alleles. • Clinical Diversity: Not all AD patients present with memory loss; look for logopenic aphasia or posterior cortical atrophy. • Treatment Monitoring: ARIA (Edema and Hemorrhage) must be monitored during anti-amyloid therapy.