Pharmacology of Alzheimer's Disease
Current and emerging drug strategies for Alzheimer's disease, from cholinesterase inhibitors to anti-amyloid monoclonal antibodies.
## Pathophysiology
Alzheimer's disease (AD) is characterized by extracellular amyloid-beta (Abeta) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Cholinergic neurons in the nucleus basalis of Meynert degenerate early, correlating with memory impairment. Neuroinflammation, oxidative stress, and synaptic loss contribute to progressive cognitive decline.
## Cholinesterase Inhibitors
These drugs increase synaptic acetylcholine by inhibiting AChE, partially compensating for cholinergic neuron loss. They provide modest symptomatic improvement in mild-to-moderate AD.
| Drug | Selectivity | Notes |
|------|-----------|-------|
| Donepezil | AChE-selective | Once daily; most widely prescribed |
| Rivastigmine | AChE + BuChE | Transdermal patch available; also for PD dementia |
| Galantamine | AChE + nicotinic allosteric modulator | Dual mechanism may enhance cholinergic transmission |
Common side effects are cholinergic: nausea, diarrhea, bradycardia, insomnia.
## Memantine
Memantine is a low-affinity, uncompetitive NMDA receptor antagonist. By blocking pathological tonic glutamate activation while allowing normal phasic signaling, it reduces excitotoxicity. Approved for moderate-to-severe AD. Often combined with donepezil.
## Anti-Amyloid Monoclonal Antibodies
A new class targeting amyloid-beta clearance:
- **Lecanemab** (Leqembi) -- binds soluble Abeta protofibrils; reduced cognitive decline by 27% over 18 months in the CLARITY AD trial; biweekly IV infusion
- **Donanemab** -- targets N-truncated pyroglutamate Abeta; slowed decline by 35% in the TRAILBLAZER-ALZ 2 trial; treatment stopped after amyloid clearance
**Amyloid-related imaging abnormalities (ARIA)** include cerebral edema (ARIA-E) and microhemorrhages (ARIA-H). Risk is elevated in APOE4 carriers. MRI monitoring is mandatory.
## Emerging Approaches
- **Tau-targeting therapies** -- antisense oligonucleotides and anti-tau antibodies in clinical trials
- **Neuroinflammation modulators** -- targeting TREM2 and microglial activation
- **GLP-1 receptor agonists** -- semaglutide under investigation for neuroprotective effects
- **Combination strategies** -- targeting both amyloid and tau simultaneously
## Key Takeaways
- Cholinesterase inhibitors and memantine provide symptomatic relief but do not alter disease progression
- Anti-amyloid antibodies are the first disease-modifying agents, showing modest but statistically significant slowing of decline
- ARIA monitoring is essential with anti-amyloid therapy, especially in APOE4 carriers
- Multi-target combination therapies are likely needed given AD's complex pathophysiology