Alzheimer's & Dementia: Cholinesterase Inhibitors & Memantine
The memory that fades in Alzheimer's disease has a chemical signature: the brain's acetylcholine — the transmitter of memory — is running out as the neurons that make it die. Today's main drugs work by squeezing more out of what remains, plus one that shields neurons from a different kind of damage. They don't stop the disease, but understanding them shows exactly how two ideas from earlier in this course come together in the ageing brain.
A family watches their grandmother slip away by degrees — first the misplaced keys and repeated questions, then forgetting names, then whole recent events vanishing while childhood memories stay vivid. This is Alzheimer's disease, the commonest cause of dementia. In her brain, the acetylcholine-making neurons of the basal forebrain are dying, protein plaques and tangles are accumulating, and memory circuits are failing. There is no cure — but there are drugs that can modestly slow the decline, and they come straight from chemistry we've already met.
The cholinergic strategy
Alzheimer's involves a loss of acetylcholine. Because acetylcholine is central to memory and the neurons that make it are dying, the first drug strategy is to preserve what acetylcholine remains — by blocking the enzyme that breaks it down. These cholinesterase inhibitors — donepezil, rivastigmine, and galantamine — are the same class we met treating myasthenia gravis and reversing muscle relaxants, but chosen here because they cross into the brain and raise acetylcholine there. They give a modest, real benefit: they can improve symptoms a little and slow the decline for a time, but they don't halt the underlying disease. Their side effects are predictably cholinergic — nausea, diarrhoea, and a slow heart (bradycardia) — the SLUDGE pattern in gentler form.
The glutamate strategy: memantine
The second drug attacks a different problem. Remember from the foundations article that too much glutamate is toxic — excess stimulation of NMDA receptors floods neurons with calcium and damages them (excitotoxicity). In Alzheimer's, this chronic over-excitation is thought to contribute to neuron loss. Memantine is an NMDA-receptor blocker that dampens this excess glutamate signalling without switching off normal transmission — shielding neurons from the slow burn. It's used for moderate-to-severe disease, is generally well tolerated, and can be combined with a cholinesterase inhibitor so the two strategies work together: boost the failing acetylcholine, and calm the toxic glutamate.
- Alzheimer's involves loss of acetylcholine (memory) plus amyloid plaques and tau tangles.
- Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) raise brain acetylcholine — modest benefit.
- Their side effects are cholinergic: nausea, diarrhoea, bradycardia.
- Memantine blocks NMDA receptors, reducing glutamate excitotoxicity (moderate–severe disease).
- These drugs slow symptoms but do NOT cure or stop the disease.
Alzheimer's treatment is a neat convergence of two threads from this whole course: the cholinergic system (boost fading acetylcholine, exactly as the anticholinesterases do) and the excitatory glutamate system (block toxic NMDA overactivity, exactly what the foundations article warned about). Two of the brain's core chemistries, two drugs, one disease. But be honest with families: these are symptomatic drugs that buy time and function — they are not a cure, and they don't stop the underlying loss.
- Promising a cure. These drugs modestly slow symptoms; they don't reverse the disease.
- Ignoring cholinergic side effects (bradycardia) — caution in heart-conduction problems.
- Combining a cholinesterase inhibitor with an anticholinergic drug — they directly oppose each other.
- Overlooking reversible causes of confusion (drugs, infection, thyroid, B12) before assuming Alzheimer's.
Which pair of mechanisms do today's main Alzheimer's drugs use?
- Alzheimer's = dying acetylcholine neurons + amyloid/tau; no cure yet.
- Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) raise acetylcholine — modest benefit.
- Memantine blocks NMDA to reduce glutamate excitotoxicity (moderate–severe).
- The two strategies can be combined; they treat symptoms, not the disease.
- Katzung BG. Basic & Clinical Pharmacology — Drugs Used in Alzheimer's disease & dementia.
- Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics — Treatment of Alzheimer's disease.
- Rang HP, Dale MM, et al. Rang & Dale's Pharmacology — Neurodegenerative diseases: dementia.
- Whalen K. Lippincott Illustrated Reviews: Pharmacology — Drugs for Alzheimer's disease.
- Clinical guidelines — Cholinesterase inhibitors, memantine & emerging anti-amyloid therapies.
