Alzheimer / Dementia Agents

In Alzheimer’s disease, some of the earliest neurons lost are the cholinergic ones — the neurons that use acetylcholine (ACh), the neurotransmitter most tied to memory and learning. As these neurons die, ACh signaling falls and cognition declines. This is the cholinergic hypothesis, and it points to an obvious (if modest) fix: raise the amount of ACh left in the synapse.

The cholinesterase inhibitors (donepezil, rivastigmine, galantamine) do exactly that. They block acetylcholinesterase, the enzyme that breaks ACh down, so the ACh that remaining neurons release lingers longer and signals harder. Crucially, these drugs treat symptoms — they can slow the decline and improve day-to-day function — but they do not cure or stop the underlying disease.

The catch is that you cannot raise ACh only in the memory circuits. More ACh throughout the body means more parasympathetic ("rest-and-digest") activity — the same overshoot seen with the cholinergic agonists in the Autonomic system. That produces the predictable cholinergic effects: nausea, vomiting, diarrhea, anorexia and weight loss (GI is dose-limiting), increased secretions, urinary urgency, and — importantly — a vagotonic slowing of the heart.

Because ACh stimulates the vagus nerve, cholinesterase inhibitors can cause bradycardia, heart block, and syncope, even in patients without known conduction disease. That is the highest-yield safety fact of this class: assess heart rate, and use caution in patients with sick sinus syndrome, AV block, active peptic ulcer disease, asthma/COPD, or seizures.

Memantine attacks the problem from the opposite direction. In the failing brain, the excitatory neurotransmitter glutamate floods NMDA receptors, and this chronic overstimulation ("excitotoxicity") damages neurons. Memantine is an NMDA-receptor antagonist that blocks the excess pathological glutamate signal while still allowing normal signaling — protecting neurons without shutting learning down.

It is used in moderate-to-severe disease and is often combined with a cholinesterase inhibitor (the two mechanisms are complementary). Memantine is generally well tolerated — its side effects (dizziness, headache, confusion, constipation) are mild compared with the cholinergic load of the inhibitors — but it is renally cleared, so the dose is reduced in significant renal impairment.