Drugs for Dementia

Dementia Overview & Targets - Brain Fog Busters

• Dementia: Progressive neurocognitive decline; impairs memory, thinking, daily activities.
• Major Types:
  • Alzheimer's Disease (AD): Most common.
  • Vascular Dementia.
  • Dementia with Lewy Bodies (DLB).
• Key Drug Targets (Primarily AD):
  • Cholinergic deficit: ↓ Acetylcholine (ACh).
  • Glutamatergic excitotoxicity: ↑ NMDA receptor activity.
  • Pathological proteins: Amyloid-β (Aβ) plaques & Tau neurofibrillary tangles (NFTs).

⭐ Alzheimer's Disease accounts for approximately 60-80% of all dementia cases.

Cholinesterase Inhibitors - Memory Menders

• Mechanism: Reversibly inhibit acetylcholinesterase (AChE) → ↑ acetylcholine (ACh) levels in brain → improve cholinergic transmission.
  • Primarily symptomatic relief; do not alter disease progression.
• Indications:
  • Mild to moderate Alzheimer's Disease (AD).
  • Donepezil also for severe AD.
  • Rivastigmine also for Parkinson's Disease Dementia (PDD).
• Key Drugs: 📌 "Don Riva dances Gaily" (Donepezil, Rivastigmine, Galantamine)
  • Donepezil (Aricept):
    • Once daily dosing (long t½).
    • Metabolized by CYP2D6 & CYP3A4.
  • Rivastigmine (Exelon):
    • Inhibits both AChE & Butyrylcholinesterase (BuChE).
    • Available as oral & transdermal patch (↓ GI side effects).
  • Galantamine (Reminyl):
    • Dual mechanism: AChE inhibition & nicotinic receptor modulation.
    • Metabolized by CYP2D6 & CYP3A4.
• Common Side Effects (Cholinergic):
  • GI: Nausea, vomiting, diarrhea (most common).
  • CNS: Insomnia, dizziness, headache.
  • CV: Bradycardia, syncope. ⚠️ Caution in patients with cardiac conduction defects or sick sinus syndrome.
• Drug Interactions:
  • Anticholinergics (↓ efficacy).
  • Beta-blockers (↑ risk of bradycardia).
  • CYP inhibitors/inducers for donepezil & galantamine.

⭐ Rivastigmine is unique as it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and its transdermal patch formulation improves tolerability by reducing gastrointestinal side effects.

NMDA Antagonists - Excitotoxicity Erasers

• Memantine: Key drug. 📌 MEMAntine aids MEMOry by blocking NMDA overactivity.
• Mechanism: Non-competitive NMDA receptor antagonist.
  • Blocks pathological glutamate overstimulation.
  • Reduces excessive $Ca^{2+}$ influx, ↓ excitotoxicity & neuronal damage.
  • Low affinity, voltage-dependent: spares physiological receptor function.
• Indication: Moderate to severe Alzheimer's Disease.
  • Monotherapy or adjunct to AChE inhibitors.
• Dosing: Start 5 mg/day; titrate weekly to 10 mg BID (max 20 mg/day).
• Side Effects: Generally mild; dizziness, headache, confusion.

⭐ Memantine uniquely targets the glutamatergic pathway in Alzheimer's, complementing cholinergic therapies.

Novel Dementia Therapies - Amyloid Annihilators

• Focus: Reduce Aβ plaque burden in early Alzheimer's Disease (AD).
• Mechanism: Monoclonal antibodies (mAbs) targeting various Aβ species.
• Key Drugs & Targets:
  • Aducanumab (Aduhelm): Targets aggregated Aβ forms (plaques).
    • FDA accelerated approval; use is limited.
  • Lecanemab (Leqembi): Targets soluble Aβ protofibrils.
    • Slows cognitive decline by 27% (CDR-SB over 18 months).
    • Full FDA approval for early AD.
  • Donanemab: Targets N-terminal pyroglutamate Aβ (N3pG Aβ) in plaques.
    • Phase 3 trials show significant plaque clearance and clinical benefit.
• Major Side Effect Profile:
  • Amyloid-Related Imaging Abnormalities (ARIA):
    • ARIA-E: Vasogenic edema or sulcal effusions.
    • ARIA-H: Microhemorrhages or superficial siderosis.
  • Requires regular MRI monitoring, especially during initiation.

⭐ Lecanemab is the first anti-amyloid antibody to receive full FDA approval demonstrating both amyloid plaque reduction and a statistically significant slowing of clinical decline in early AD.

• Indicated for mild cognitive impairment (MCI) or mild dementia stage of AD with confirmed amyloid pathology.

High‑Yield Points - ⚡ Biggest Takeaways

• Acetylcholinesterase inhibitors (AChEIs) like Donepezil, Rivastigmine, Galantamine are first-line for mild-moderate Alzheimer's.
• Memantine, an NMDA antagonist, treats moderate-severe Alzheimer's, often combined with AChEIs.
• AChEIs commonly cause GI side effects; Rivastigmine patch may reduce these.
• Memantine works by blocking glutamate excitotoxicity.
• Current drugs offer symptomatic relief, not a cure for dementia.
• Avoid anticholinergics with AChEIs due to opposing mechanisms.