Drugs for Dementia

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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 Brain Pathology: Plaques, Tangles, Atrophy

⭐ 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.

Acetylcholine neurotransmission and breakdown

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 mechanism in Alzheimer's disease

⭐ 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. MRI showing ARIA from anti-amyloid Alzheimer's therapy

  • 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.

Practice Questions: Drugs for Dementia

Test your understanding with these related questions

A 60-year-old man with Alzheimer's disease has been started on donepezil. What is the primary mechanism of action of this medication?

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Flashcards: Drugs for Dementia

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Typical antipsychotics are associated with anti-cholinergic effects, such as _____ and constipation

TAP TO REVEAL ANSWER

Typical antipsychotics are associated with anti-cholinergic effects, such as _____ and constipation

dry mouth

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