Alzheimer's Disease - Short Note (MBBS 1st Year Physiology)

Figure: Comparison of healthy vs. Alzheimer's brain and neuron - showing brain atrophy, beta-amyloid plaques, tau tangles, and synaptic failure (Guyton & Hall, Fig. 60.8)

Definition

Epidemiology

• Affects approximately 7 million people in the USA
• Prevalence doubles every 5 years after age 65
• ~30% of people aged 85+ are affected
• Two-thirds of patients are women (due to longer life expectancy)

Pathophysiology - The Two Hallmarks

1. Beta-Amyloid Plaques (Senile/Neuritic Plaques)

• Amyloid precursor protein (APP) encoded on chromosome 21 is abnormally cleaved to produce beta-amyloid (Aβ) peptide
• Aβ accumulates extracellularly as amyloid plaques (10 µm to several hundred µm diameter)
• Found in: cerebral cortex, hippocampus, basal ganglia, thalamus, and cerebellum
• Plaque density correlates with severity of disease
• Evidence for amyloid's role:
  • All known AD mutations increase Aβ production
  • Trisomy 21 (Down syndrome) patients have 3 copies of APP gene and develop AD pathology by midlife
  • ApoE4 isoform (APOE gene) accelerates amyloid deposition - increases risk 3x (one E4 allele) or 8x (two E4 alleles)
  • Transgenic mice overproducing APP develop memory deficits + amyloid plaques

2. Neurofibrillary Tangles (NFTs)

• Tau protein normally stabilizes microtubules in axons
• In AD, tau becomes hyperphosphorylated due to imbalance in protein kinases and phosphatases
• Hyperphosphorylated tau dissociates from microtubules, which then disassemble
• Free tau aggregates into paired helical filaments forming intraneuronal NFTs ("tombstones of dead neurons")
• NFTs cause neuroinflammation, worsening neuronal injury
• Distribution: cortex, hippocampus, substantia nigra, locus ceruleus

Gross Neuropathology

Neurotransmitter Changes (Cholinergic Hypothesis)

• Acetylcholine (ACh) is the primary neurotransmitter affected
• Degeneration of cholinergic neurons in the nucleus basalis of Meynert (basal forebrain)
• Decreased choline acetyltransferase (ChAT) - the key enzyme for ACh synthesis
• Decreased ACh concentrations in the cortex
• Norepinephrine is also decreased (loss of neurons in locus ceruleus)
• Somatostatin and corticotropin concentrations are also reduced

• Cholinergic antagonists (scopolamine, atropine) worsen cognition
• Cholinergic agonists (physostigmine, arecoline) improve cognition

Genetics

Clinical Features (Triad)

1. Amnestic memory impairment (earliest and most prominent)
2. Deterioration of language (aphasia)
3. Visuospatial deficits

• Early: Forgetfulness, personality changes, mild memory loss
• Middle: Inability to perform activities of daily living (ADLs), behavioral disturbances
• Late: Motor symptoms, incontinence, complete dependence

Vascular Contribution

• ~50% of AD patients have pathological evidence of "silent strokes"
• Vascular risk factors overlap with AD risk factors

Treatment Basis (from Physiology)

Key Points for Exam

• Pathognomonic findings: senile plaques + NFTs
• Most common dementia - accounts for 70% of all dementia
• Key chromosome: Chr 21 (APP gene) - explains Down syndrome link
• ApoE4 = biggest genetic risk for sporadic/late-onset AD
• Cholinergic hypothesis = basis for pharmacological treatment
• Tau becomes hyperphosphorylated - forms paired helical filaments
• Amyloid is extracellular, tau tangles are intraneuronal
• Brain shows diffuse atrophy + enlarged ventricles on gross examination