Newer / Current Drug Therapy for Alzheimer's Disease

Newer / Current Drug Therapy for Alzheimer's Disease Fifteen–Twenty High-Yield Points Principles

Drug therapy in AD has two aims: symptomatic benefit (cholinergic and glutamatergic agents) and disease modification (anti-amyloid immunotherapy). Non-pharmacological care remains essential alongside both.

The cholinergic hypothesis underlies symptomatic therapy: degeneration of the nucleus basalis of Meynert reduces cortical acetylcholine, and inhibiting its breakdown partially restores transmission.

Donepezil — reversible, selective acetylcholinesterase inhibitor. Dose 5 mg once daily at night, increased to 10 mg after 4–6 weeks. Long half-life; once-daily dosing. Licensed across mild, moderate and severe AD.

Rivastigmine — pseudo-irreversible inhibitor of both acetylcholinesterase and butyrylcholinesterase. Available orally and as a transdermal patch, which markedly reduces gastrointestinal side effects. Also effective in Parkinson's disease dementia and Lewy body dementia, and is the best-evidence agent for apathy in PD.

Galantamine — acetylcholinesterase inhibitor with additional allosteric modulation of nicotinic receptors. Given twice daily or as a modified-release capsule.

Tacrine is of historical interest only — withdrawn because of hepatotoxicity.

Efficacy: meta-analyses of donepezil, galantamine and rivastigmine show small but consistent benefit on cognition and global function, possible delay in nursing-home placement, and a several-month delay in progression. Benefit is marginal in many patients and must be weighed against cost and adverse effects individually.

Adverse effects are predominantly cholinergic: nausea, vomiting, diarrhoea, anorexia, weight loss, abdominal cramps; bradycardia, heart block and syncope; insomnia and nightmares; muscle cramps; increased bronchial secretions; urinary frequency.

Cautions: sick sinus syndrome and conduction defects, active peptic ulcer, asthma/COPD, and concurrent use with beta-blockers. Note the interaction with enzyme-inducing antiepileptics, which increase the metabolism of donepezil and galantamine.

Memantine is a low-affinity, uncompetitive NMDA receptor antagonist that blocks pathological tonic glutamate activation while preserving physiological signalling, reducing excitotoxicity.

Indicated in moderate-to-severe AD, either alone or added to a cholinesterase inhibitor. Titrated from 5 mg to 20 mg daily. Dose reduction is needed in renal impairment.

Side effects are usually mild: dizziness, headache, constipation, somnolence, hypertension and occasionally confusion or hallucinations.

Depression in AD is treated with SSRIs; sertraline has trial evidence. Tricyclics and drugs with anticholinergic action must be avoided as they worsen cognition.

Behavioural and psychological symptoms: non-pharmacological approaches first. Atypical antipsychotics carry an FDA black-box warning for increased mortality and cause weight gain; they are reserved for patients who are frankly psychotic or an immediate danger.

Every new or worsening behavioural symptom requires a search for a precipitant. Empirical paracetamol for undetected pain has shown efficacy in severely demented nursing-home residents.

Donepezil does not treat agitation in AD — a specific negative trial result worth quoting.

Anti-amyloid monoclonal antibodies bind aggregated Aβ and promote microglial clearance of plaque, producing measurable amyloid clearance on PET and modest slowing of clinical decline.

Indication: confirmed amyloid pathology with MCI or mild dementia due to AD only. They are not indicated in moderate or severe dementia.

Key toxicity is ARIA, requiring baseline and serial MRI monitoring; anticoagulation and thrombolysis for stroke need special caution in treated patients.

Drugs that must be avoided or deprescribed in AD are as important as drugs prescribed: anticholinergics, benzodiazepines, sedative antihistamines, and other agents on the Beers and STOPP/START lists.