Drugs Used in Alzheimer's & Dementia

A compact, exam-ready pharmacology set built around two pillars: acetylcholinesterase inhibitors (AChEIs) for the cholinergic deficit and the NMDA antagonist memantine for glutamate excitotoxicity. Master the stage-appropriate use, the rivastigmine-in-Lewy-body angle, and the adverse-effect profile — these three carry almost every question asked from this topic.

Why these drugs? — The two pathophysiologic targets

Alzheimer's disease (AD) is a neurodegenerative dementia defined neuropathologically by extracellular amyloid-β plaques (from abnormal cleavage of amyloid precursor protein by β- and γ-secretase) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The earliest and most consistent neurochemical lesion, however, is degeneration of cholinergic neurons in the nucleus basalis of Meynert, producing a cortical acetylcholine (ACh) deficit that correlates with memory loss.

This gives the classic "cholinergic hypothesis" — and the rationale for therapy:

1. Boost ACh → inhibit its breakdown with AChEIs (donepezil, rivastigmine, galantamine).
2. Limit glutamate excitotoxicity → block over-activated NMDA receptors with memantine.

High-yield: Current symptomatic drugs do NOT halt or reverse neurodegeneration — they slow the rate of cognitive decline and offer modest, temporary symptomatic benefit. They are disease-modulating at best, not disease-modifying.

The newer anti-amyloid monoclonal antibodies (aducanumab, lecanemab, donanemab) are the first genuinely disease-modifying agents, clearing amyloid plaque — covered briefly below.

Classification of anti-dementia drugs

Class	Drugs	Mechanism	Primary indication (stage)
Acetylcholinesterase inhibitors	Donepezil, Rivastigmine, Galantamine, (Tacrine — obsolete)	↑ synaptic ACh by inhibiting AChE	Mild → moderate AD (donepezil also severe)
NMDA receptor antagonist	Memantine	Blocks excitotoxic Ca²⁺ influx	Moderate → severe AD
Anti-amyloid monoclonal Abs	Aducanumab, Lecanemab, Donanemab	Clear amyloid-β plaque	Early/mild AD (disease-modifying)

High-yield: Tacrine was the first AChEI approved but is now obsolete because of hepatotoxicity (raised transaminases) and a short half-life requiring four-times-daily dosing.

The acetylcholinesterase inhibitors

Mechanism and key distinctions

All three current AChEIs raise synaptic ACh, but their enzyme selectivity and pharmacology differ — and the differences are testable.

Feature	Donepezil	Rivastigmine	Galantamine
Enzyme inhibited	AChE (selective, centrally)	AChE + butyrylcholinesterase (BuChE)	AChE
Type of inhibition	Reversible, non-competitive	Pseudo-irreversible (carbamylating)	Reversible, competitive
Extra mechanism	—	—	Allosteric nicotinic receptor modulation (↑ ACh release)
Half-life	Long (~70 h) → once daily	Short (~1–2 h, but long enzyme effect)	Intermediate (~7 h)
Routes	Oral (OD)	Oral + transdermal patch	Oral
Metabolism	CYP2D6 / CYP3A4	Non-hepatic (esterase hydrolysis)	CYP2D6 / CYP3A4
Approved stage	Mild, moderate and severe	Mild–moderate (AD + Parkinson dementia)	Mild–moderate

High-yield (very frequently asked): Rivastigmine inhibits both AChE and butyrylcholinesterase. Donepezil and galantamine inhibit only AChE. BuChE inhibition becomes relevant in advanced disease as glial BuChE activity rises.

High-yield: Galantamine is unique for its dual action — AChE inhibition plus allosteric potentiation of presynaptic nicotinic receptors, enhancing ACh release.

High-yield: Donepezil has the longest half-life (~70 h), allowing convenient once-daily dosing, and is the only AChEI also approved for severe AD.

Mnemonic — "Don't Rivet Galan": Donepezil = once Daily, Dementia of all stages. Rivastigmine = both enzymes + patch + PaRkinson/Lewy body. Galantamine = nicotinic allosteric action.

Rivastigmine — the Lewy body / Parkinson's angle

This is the single most distinctive fact in the topic.

High-yield (classic exam favourite): Rivastigmine is the preferred AChEI in Dementia with Lewy Bodies (DLB) and Parkinson's disease dementia (PDD). It is the only cholinesterase inhibitor with an approved indication for PDD, and it improves both cognition and the prominent neuropsychiatric features (visual hallucinations, fluctuating cognition) of these synucleinopathies.

The rationale: DLB and PDD have an even more severe cholinergic deficit than AD, and rivastigmine's additional BuChE inhibition plus transdermal delivery (smoother levels, fewer GI peaks) suit these patients well.

High-yield: In DLB/PDD, avoid typical antipsychotics (e.g. haloperidol) for hallucinations — patients show severe neuroleptic sensitivity (worsening parkinsonism, autonomic instability, NMS-like reactions). Use rivastigmine first; if an antipsychotic is unavoidable, low-dose quetiapine or pimavanserin is preferred.

Adverse effects of AChEIs

Predictable from excess cholinergic (parasympathetic) tone — recall the muscarinic SLUDGE/DUMBELS pattern but clinically the GI and cardiac effects dominate.

• GI (most common, dose-limiting): nausea, vomiting, diarrhoea, anorexia, weight loss. The transdermal rivastigmine patch reduces GI effects vs oral.
• Cardiovascular: bradycardia, AV block, syncope (vagotonic effect). Caution in sick sinus syndrome / conduction defects; can cause falls.
• CNS: insomnia, vivid/abnormal dreams and nightmares (notably donepezil — give in the morning if troublesome), agitation, dizziness, headache.
• Respiratory: bronchoconstriction → caution in asthma/COPD.
• GU/other: urinary incontinence, increased gastric acid (caution in active peptic ulcer disease), muscle cramps.

High-yield: A demented patient on an AChEI presenting with syncope or bradyarrhythmia is a classic vignette — the drug's vagotonic action is the culprit. Check pulse/ECG before and during therapy.

High-yield: AChEIs increase gastric acid secretion → relative caution in patients with peptic ulcer disease or on NSAIDs.

Memantine — the NMDA antagonist

Mechanism: Memantine is a moderate-affinity, uncompetitive, voltage-dependent NMDA-receptor antagonist with fast off-rate. In AD, chronic low-level glutamate causes pathological tonic NMDA activation → sustained Ca²⁺ influx → excitotoxicity and disruption of the signal-to-noise ratio underlying memory. Memantine blocks this pathological tonic activation while its rapid dissociation preserves the phasic, high-level glutamate signalling needed for physiological learning — hence it improves function without the dissociative/psychotomimetic effects of high-affinity blockers like ketamine/PCP.

High-yield: Memantine's uncompetitive, low-to-moderate affinity, voltage-dependent block (rapid off-kinetics) is what spares normal synaptic transmission — the key conceptual distinction from ketamine/PCP.

Indication: Moderate-to-severe AD — either as monotherapy or, more commonly, combined with an AChEI (e.g. donepezil + memantine) for additive benefit in advanced disease.

Pharmacokinetics: Largely renally excreted unchanged → reduce dose in renal impairment; minimal hepatic metabolism, so few CYP interactions (contrast donepezil/galantamine).

Adverse effects: Generally well tolerated — dizziness, headache, confusion, constipation, hypertension. Notably, memantine does NOT cause the cholinergic GI/bradycardic effects of AChEIs, making it useful where AChEIs are poorly tolerated.

High-yield: Memantine is the drug of choice for moderate-to-severe AD; AChEIs (especially donepezil) for mild-to-moderate. The two classes act on different targets and can be safely combined.

Stepwise management approach

Mild-to-moderate AD → start an AChEI (donepezil / rivastigmine / galantamine) → titrate slowly to limit GI effects → assess response at 3 months.

Moderate-to-severe AD → add or switch to memantine → in practice AChEI + memantine combination for moderate–severe disease.

DLB or Parkinson's disease dementia → rivastigmine first-line → avoid typical antipsychotics → manage parkinsonism cautiously (levodopa may worsen hallucinations).

Behavioural/psychotic symptoms (BPSD) → first non-pharmacological measures → optimise AChEI → if severe agitation/psychosis, cautious atypical antipsychotic (small ↑mortality/stroke risk — counsel and review).

Early/mild AD with confirmed amyloid → consider anti-amyloid monoclonal antibody (specialist setting; MRI monitoring for ARIA).

Disease-modifying anti-amyloid antibodies (newer high-yield)

Drug	Target	Key note
Aducanumab	Aggregated amyloid-β	First approved (controversial accelerated approval)
Lecanemab	Amyloid-β protofibrils	Slows decline in early AD; FDA traditional approval
Donanemab	Amyloid plaque (pyroglutamate form)	Plaque clearance in early symptomatic AD

High-yield: Anti-amyloid monoclonals cause ARIA — Amyloid-Related Imaging Abnormalities (ARIA-E = oedema/effusion; ARIA-H = microhaemorrhages). Risk is higher in APOE ε4 homozygotes → genotype before treatment and monitor with serial MRI.

Diagnosis & assessment (so you can place the drug)

• AD is a clinical diagnosis supported by cognitive testing (MMSE, MoCA, ADAS-Cog) and exclusion of reversible causes.
• MMSE staging guide (commonly cited): mild ≈ 21–26, moderate ≈ 10–20, severe < 10 — used to choose AChEI vs memantine.
• MRI shows medial temporal / hippocampal atrophy.
• CSF biomarkers: ↓ amyloid-β42, ↑ total tau and phospho-tau — the classic AD CSF triad.
• Amyloid/tau PET confirms pathology; supports antibody therapy.
• Always exclude reversible dementias: hypothyroidism, B12 deficiency, neurosyphilis, normal-pressure hydrocephalus, depression (pseudodementia).

High-yield: CSF in AD = low Aβ42, high tau/p-tau. (Amyloid is "stuck" in plaques, so it falls in CSF.)

Key differentials of dementia (drug implications)

Dementia type	Distinguishing feature	Drug pearl
Alzheimer's	Insidious memory-first decline; hippocampal atrophy	AChEI ± memantine
Dementia with Lewy bodies	Visual hallucinations, fluctuating cognition, parkinsonism, REM-sleep behaviour disorder	Rivastigmine; avoid typical antipsychotics
Parkinson's disease dementia	Dementia >1 yr after motor PD	Rivastigmine (only PDD-approved AChEI)
Vascular dementia	Stepwise decline, focal signs, vascular risk factors	Treat vascular risk; AChEI modest benefit
Frontotemporal dementia	Early behaviour/personality change, language; younger	AChEIs may worsen behaviour — generally avoided; SSRIs for behaviour
Normal-pressure hydrocephalus	Gait apraxia + incontinence + dementia (Hakim triad)	Reversible with VP shunt

High-yield: AChEIs are not recommended in frontotemporal dementia and may aggravate behavioural symptoms — a frequent trap.

Drug interactions & cautions worth memorising

• Donepezil & galantamine are metabolised by CYP2D6/3A4 → levels altered by inhibitors (ketoconazole, paroxetine, quinidine).
• Rivastigmine is not CYP-dependent (esterase hydrolysis) → cleaner interaction profile; preferred when polypharmacy is an issue.
• Avoid combining AChEIs with anticholinergic drugs (oxybutynin, antihistamines, TCAs) — they pharmacologically antagonise the therapeutic effect and worsen cognition.
• AChEIs prolong the action of succinylcholine (depolarising blocker) during anaesthesia — flag in pre-op vignettes.
• Beta-blockers + AChEIs → additive bradycardia.
• Memantine — caution with other NMDA agents (amantadine, dextromethorphan, ketamine); urinary alkalinisers reduce its clearance.

Recently asked / exam angle

• One-liner MOA match: "Inhibits both AChE and BuChE" → Rivastigmine; "longest half-life, once-daily" → Donepezil; "nicotinic allosteric modulation" → Galantamine; "uncompetitive NMDA antagonist" → Memantine.
• Best AChEI for Lewy body / Parkinson's disease dementia → Rivastigmine (repeatedly asked).
• Drug of choice for moderate-to-severe AD → Memantine (often combined with donepezil).
• First AChEI / withdrawn due to hepatotoxicity → Tacrine.
• AChEI causing bradycardia/syncope — mechanism = vagotonic/cholinergic → caution in conduction block.
• CSF biomarker pattern in AD → ↓Aβ42, ↑tau/p-tau.
• ARIA as adverse effect of anti-amyloid monoclonals; higher in APOE ε4 carriers.
• Which drug class to avoid in frontotemporal dementia → AChEIs.
• Memantine route of elimination → renal (dose-reduce in renal failure), contrasting with hepatic CYP metabolism of donepezil/galantamine.
• Neuroleptic sensitivity in DLB → avoid haloperidol; prefer quetiapine/pimavanserin.

Rapid revision

1. AChEIs = donepezil, rivastigmine, galantamine; memantine = NMDA antagonist — symptomatic, not curative.
2. Donepezil: longest t½ (~70 h), once daily, only AChEI approved for all stages including severe AD; causes vivid dreams.
3. Rivastigmine: inhibits AChE + BuChE, pseudo-irreversible, available as a patch (fewer GI effects), drug of choice in DLB and Parkinson's disease dementia; non-CYP metabolism.
4. Galantamine: AChE inhibitor plus allosteric nicotinic receptor modulation.
5. Tacrine: first AChEI, obsolete due to hepatotoxicity.
6. Commonest AChEI side effects = GI (nausea, vomiting, diarrhoea, weight loss); watch for bradycardia/syncope (vagotonic).
7. Memantine: uncompetitive, voltage-dependent, moderate-affinity NMDA blocker; moderate-to-severe AD; renally excreted; well tolerated.
8. Donepezil + memantine combination is standard in advanced AD.
9. CSF AD triad: ↓ amyloid-β42, ↑ total tau, ↑ phospho-tau; MRI = hippocampal atrophy.
10. Avoid AChEIs in frontotemporal dementia; avoid typical antipsychotics in DLB (neuroleptic sensitivity).
11. Anti-amyloid mAbs (lecanemab, donanemab, aducanumab) are disease-modifying; key adverse effect = ARIA, higher in APOE ε4.
12. Anticholinergic drugs antagonise AChEIs — never co-prescribe in dementia.