Alzheimer's disease

Pathophysiology & Etiology - Plaque & Tangle Tussle

• Core Pathology: Two key players lead to synaptic dysfunction and neuronal loss:
  • Extracellular: Amyloid-beta (Aβ) senile plaques.
  • Intraneuronal: Tau neurofibrillary tangles (NFTs).

• Genetic Factors:
  • Late-onset: Apolipoprotein E (ApoE ε4) allele is the strongest risk factor.
  • Early-onset (Autosomal Dominant): Mutations in APP (Chr 21), PSEN1, PSEN2.

⭐ High-Yield: Down syndrome (Trisomy 21) significantly ↑ risk of early-onset Alzheimer's, as the APP gene is located on chromosome 21, leading to Aβ overproduction.

Clinical Presentation - The Slow Fade

• Insidious onset with gradual progression over 8-10 years.
• Short-term memory loss (anterograde amnesia) is the earliest and most prominent feature.
• Progressive Cognitive Decline:
  • Executive dysfunction: Impaired planning, decision-making.
  • Visuospatial deficits: Getting lost in familiar places.
  • Language difficulties: Anomia (difficulty naming objects).
  • Apraxia: Inability to perform learned motor tasks.
• Later stages involve personality and behavioral changes (e.g., apathy, agitation).

⭐ Memory for remote, well-learned facts and procedural memory (e.g., riding a bike) are typically preserved until late in the disease course.

Diagnostic Workup - Ruling It Out

Diagnosis is one of exclusion, focused on ruling out reversible causes of dementia.

• Initial Screening: Cognitive tests.

  • Mini-Mental State Examination (MMSE)
  • Montreal Cognitive Assessment (MoCA)

• Lab Tests: To exclude metabolic/deficiency states.

  • CBC, CMP, TSH, Vitamin B12

• Imaging: CT or MRI to rule out structural causes (tumor, stroke).

  • Medial temporal lobe (hippocampal) atrophy is a characteristic finding.

• CSF Analysis (less common in routine practice):
  • ↓ Amyloid-beta 42 (Aβ-42)
  • ↑ Total Tau & Phosphorylated Tau (p-Tau)

⭐ While imaging can show atrophy, a definitive diagnosis of Alzheimer's disease still requires histopathological confirmation on autopsy.

Management - Holding the Line

• Pharmacotherapy: Primarily symptomatic and supportive.
  • Mild-to-moderate: Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine).
  • Moderate-to-severe: NMDA receptor antagonist (Memantine).
  • 📌 Mnemonic: "Done with my gal, I need a river of memories" (Donepezil, Galantamine, Rivastigmine).
• Non-pharmacologic: Physical activity, cognitive stimulation, and management of behavioral symptoms like agitation.

⭐ Cholinesterase inhibitors can cause significant cholinergic side effects, including nausea, vomiting, diarrhea, and bradycardia.

High‑Yield Points - ⚡ Biggest Takeaways

• Most common cause of dementia in the elderly, presenting with insidious short-term memory loss.
• Key pathology: extracellular amyloid-beta plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau protein).
• Strongest genetic risk factor is the ApoE4 allele; early-onset linked to APP and presenilin mutations.
• Leads to diffuse cortical atrophy, most pronounced in the hippocampus and temporal lobes.
• Caused by a significant deficiency in acetylcholine.
• Treatment involves cholinesterase inhibitors and NMDA receptor antagonists.