Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common underlying cause of dementia, accounting for roughly two-thirds of cases either alone or as the dominant component of mixed pathology.^[1] It is defined biologically by two hallmark abnormalities — extracellular aggregation of beta-amyloid into neuritic plaques, and intracellular accumulation of hyperphosphorylated tau into neurofibrillary tangles — which the NIA-AA Research Framework formalizes into an amyloid/tau/neurodegeneration ("AT[N]") biomarker system that defines AD biologically rather than only by its clinical symptoms.^[2]

This chapter is deliberately scoped to Alzheimer disease-specific pharmacotherapy: cholinesterase-inhibitor and memantine dosing and titration, the new anti-amyloid disease-modifying monoclonal antibodies and their required ARIA monitoring, and AD-specific behavioural/psychological symptom (BPSD) and deprescribing considerations. It complements, rather than replaces, the Dementia chapter, which covers the broader multi-subtype diagnostic workup shared across vascular, Lewy body, and frontotemporal dementia, and the general cross-subtype non-pharmacologic BPSD toolkit — neither is re-derived here.

The typical amnestic trajectory

Most AD begins with a gradually progressive, amnestic-predominant pattern: new difficulty learning and retaining recent information — repeating questions, misplacing items, forgetting recent conversations or appointments — while remote memories and well-learned skills are relatively preserved early on. Language (word-finding), visuospatial ability (getting lost in familiar places), and executive function (managing finances, following a recipe, multi-step planning) decline progressively over years, moving from impaired instrumental activities of daily living to impaired basic self-care.^[1]

Atypical and early-onset presentations

A minority of patients present with a non-amnestic variant — posterior cortical atrophy (progressive visuospatial/visuoperceptual impairment, often with preserved memory early on), logopenic-variant primary progressive aphasia (word-finding and sentence-repetition difficulty), or a dysexecutive/frontal-predominant variant. Early-onset AD (symptom onset before age 65) is more likely to present atypically and more likely to have an identifiable autosomal dominant cause — a family history of dementia onset in multiple generations before age 65 should prompt specialist referral for genetic counselling rather than routine primary-care management.

• Older age — the single strongest risk factor for AD.
• Family history of AD in a first-degree relative, and ApoE epsilon-4 allele carriage (heterozygote or homozygote) — the strongest common genetic risk factor for late-onset AD, though carriage is neither necessary nor sufficient for the disease to develop.
• An identified autosomal dominant mutation (APP, PSEN1, or PSEN2) — rare, but causes early-onset AD with near-complete penetrance.
• Down syndrome — triplication of chromosome 21, which carries the APP gene, leads to near-universal AD neuropathology by middle age and a markedly increased lifetime clinical AD risk; presentation can be obscured by baseline intellectual disability.
• Female sex (partly, though not entirely, explained by longer life expectancy).
• Cardiovascular risk factors across midlife — hypertension, diabetes, obesity, physical inactivity, smoking — increase AD risk in addition to their established vascular-dementia risk.
• Traumatic brain injury.
• Lower educational attainment and reduced lifelong cognitive/social engagement (reduced "cognitive reserve").
• Untreated hearing loss and social isolation.
• Late-life depression.

Clinical diagnosis

A clinical diagnosis of AD dementia, or mild cognitive impairment (MCI) due to AD, rests on documented decline in at least one cognitive domain — most often episodic memory — confirmed by collateral history and objective testing, with a gradual, progressive course and no better alternative explanation. The Montreal Cognitive Assessment (MoCA) is the more sensitive tool for MCI/early disease; the Mini-Mental State Exam (MMSE) is well validated for tracking moderate-stage disease. The Clinical Dementia Rating (CDR) scale and the Functional Assessment Staging Tool (FAST) formally stage severity, and FAST staging specifically underlies eligibility/reimbursement criteria for some AD-specific therapies.^[1]

The biomarker framework — what makes a diagnosis specifically "Alzheimer disease"

The NIA-AA Research Framework defines AD biologically using three biomarker categories, summarized as A/T/(N): Amyloid deposition (amyloid PET, or CSF/plasma Aβ42:Aβ40 ratio), Tau pathology (tau PET, or CSF/plasma phosphorylated tau), and neurodegeneration, (N) (structural MRI atrophy pattern, FDG-PET hypometabolism, or CSF total tau) — a patient with abnormal amyloid and abnormal tau meets the biological definition of AD regardless of clinical stage.^[2]

• Amyloid PET or CSF Aβ42:Aβ40 ratio confirms amyloid pathology; both are required before initiating an anti-amyloid disease-modifying antibody (see Choose Initial Treatment).
• Plasma phosphorylated tau (p-tau217) assays are an increasingly accessible blood-based triage step — a strongly positive or strongly negative result can reduce the need for PET/CSF testing in many patients, though an equivocal result still requires confirmatory imaging or CSF testing; availability and validated cutoffs vary by laboratory and are evolving rapidly.
• ApoE genotyping is not diagnostic on its own, but is a mandatory eligibility and risk-stratification step before anti-amyloid antibody therapy, since epsilon-4 homozygosity substantially increases ARIA risk (see Special Populations).

Routine amyloid/tau biomarker testing is not indicated for every patient with typical, later-onset AD dementia managed with symptomatic cholinesterase-inhibitor/memantine therapy alone — its main current clinical role is confirming eligibility for anti-amyloid disease-modifying therapy in MCI/mild AD, and clarifying an atypical, early-onset, or diagnostically uncertain presentation.

Laboratory and structural workup

CBC, electrolytes, calcium, renal function, TSH, and vitamin B12 in every new assessment, to identify a reversible or contributing metabolic cause. Structural MRI (preferred) or CT excludes a mass lesion, significant cerebrovascular disease, or normal pressure hydrocephalus, and characterizes the atrophy pattern (medial temporal lobe atrophy supports AD). The full delirium and reversible-cause differential is the Dementia chapter's responsibility and is not re-derived here.

• Provide a modest, evidence-based symptomatic benefit to cognition and function using cholinesterase inhibitors and memantine, matched to disease stage.
• In the narrowly-defined MCI/mild-AD population who qualify, offer disease-modifying anti-amyloid therapy with an honest, realistic framing of the magnitude of benefit — a modest slowing of decline, not a cure, reversal, or halt.
• Prevent, recognize early, and manage BPSD with the lowest-risk effective strategy, reserving antipsychotics for genuine safety risk after an adequate nonpharmacologic trial.
• Minimize medication-related harm across the entire disease course, with an ongoing deprescribing lens rather than a one-time decision.
• Support caregiver capacity and connect the patient/family to community resources throughout the disease course, not only at diagnosis.

• Structured group cognitive stimulation therapy has the best evidence base of any nonpharmacologic cognitive intervention in mild-moderate AD.
• Regular physical exercise benefits mood, function, and possibly cognitive trajectory across every stage of AD.
• Correct hearing and vision impairment where possible — both worsen apparent cognitive impairment and contribute to withdrawal and BPSD.
• Caregiver psychoeducation and structured support programs measurably reduce caregiver burden and can delay long-term-care placement; refer early to the local Alzheimer Society chapter rather than waiting for a crisis.
• Address advance care planning — a healthcare directive and substitute decision-maker/power of attorney — while the patient retains decision-making capacity, ideally at or soon after diagnosis rather than during a later crisis.
• For BPSD specifically: person-centred communication, a consistent daily routine, environmental modification (reduce clutter and noise, ensure adequate evening lighting to reduce "sundowning"), meaningful activity and social engagement, and caregiver training in distraction/redirection rather than confrontation or correction.
• Reassess and simplify the full medication regimen at every visit — the Dementia chapter's anticholinergic-burden medication-review table applies equally here and is not re-derived in this chapter.
• Counsel on driving cessation once visuospatial, executive, or insight deficits make driving unsafe — most provinces have mandatory reporting obligations at this stage.

Renal and hepatic impairment

Memantine is renally cleared — reduce the target dose (e.g., 5 mg PO BID rather than 10 mg BID) in moderate-severe renal impairment. Galantamine should be avoided in severe hepatic or severe renal impairment. Donepezil is metabolized via CYP2D6/3A4 — use caution with significant hepatic impairment or strong CYP2D6/3A4 inhibitors. Rivastigmine is not hepatically metabolized via the cytochrome P450 system and has no established interactions through that pathway, which can make it the preferred choice when interactions are a specific concern.

Cardiac disease

All cholinesterase inhibitors carry a small risk of bradycardia and QT-interval prolongation through vagotonic effects. Consider a baseline ECG before starting one in a patient already bradycardic, on multiple other rate-limiting drugs (beta-blockers, non-dihydropyridine calcium channel blockers, amiodarone, digoxin), or with a history of unexplained syncope.

Anticoagulant use and anti-amyloid therapy

Concurrent anticoagulation, and to a lesser extent antiplatelet therapy, increases the consequence of any ARIA-related microhemorrhage — this is a specific, individualized specialist discussion before initiating lecanemab or donanemab, not an absolute contraindication in every case.

ApoE epsilon-4 homozygotes

Substantially higher rates of both symptomatic and radiographically-detected ARIA are seen in ApoE epsilon-4 homozygotes than in non-carriers or heterozygotes.^[3][4] Most current Canadian reimbursement criteria and much real-world specialist practice restrict anti-amyloid antibody use to non-carriers/heterozygotes for this reason — verify the specific product's currently authorized and reimbursed population before counselling a patient.^[7]

Down syndrome-associated AD

Adults with Down syndrome develop AD neuropathology at a markedly accelerated rate and typically present clinically 20-30 years earlier than the general population; presentation can be obscured by baseline intellectual disability, and diagnosis relies more heavily on caregiver-reported decline from the individual's own baseline than on cognitive screening tools normed for the general population. This population was excluded from the major anti-amyloid antibody trials, so eligibility and dosing guidance for that drug class do not directly apply — cholinesterase-inhibitor and memantine use follows the same general principles as sporadic late-onset AD, individualized with specialist input.

Early-onset and genetic AD

A confirmed autosomal dominant mutation (APP, PSEN1, or PSEN2) carries near-complete penetrance — first-degree relatives should be offered genetic counselling before predictive testing, ideally through a specialized genetics service given the psychosocial implications of a presymptomatic result.

Pregnancy and breastfeeding

AD in patients of reproductive age is rare, and cognitive impairment in this group should first be worked up for an alternative, potentially reversible cause. Cholinesterase inhibitors, memantine, and the anti-amyloid antibodies all have limited or no human pregnancy/lactation safety data — individualize with specialist input if this scenario genuinely arises.

Older adults generally

Start low and titrate slowly across every drug class in this chapter; weigh fall risk carefully with any sedating medication, and minimize overall anticholinergic burden.

• Reassess the specific target symptoms defined at treatment initiation 2-4 weeks after starting or increasing the dose of a cholinesterase inhibitor or memantine, then periodically thereafter.
• An annual MMSE decline of under 2 points on cholinesterase-inhibitor therapy is generally interpreted as a beneficial treatment effect relative to the expected 2-4 point/year untreated decline, though MMSE alone is a poor tool for judging response day-to-day — weigh it alongside caregiver-reported function.^[1]
• Monitor for cholinesterase-inhibitor adverse effects (GI symptoms, weight loss, bradycardia); reassess renal function periodically to confirm memantine dosing remains appropriate.
• For lecanemab: brain MRI at baseline, then before the 3rd, 5th, 7th, and 14th infusions, reviewed before proceeding with each subsequent dose; clinical vigilance for ARIA is heightened through roughly the first 14 weeks of treatment, when incidence is highest.^[3]
• For donanemab: brain MRI at baseline, then before the 2nd, 3rd, 4th, and 7th infusions; treatment follows a fixed-duration course, typically stopped once amyloid clearance is confirmed on follow-up PET imaging (commonly within 12-18 months), rather than continued indefinitely like lecanemab.^[4]
• Ask specifically about new headache, confusion, visual change, dizziness, nausea, or seizure at every contact between scheduled anti-amyloid infusions/scans — do not wait for the next scheduled MRI if these appear.
• For any antipsychotic started for BPSD, reassess the ongoing need at least every 3-6 months; when tapering, reduce the dose by 25-50% every 1-2 weeks toward discontinuation — most patients do not need indefinite therapy.^[8]
• Ask about caregiver wellbeing and burden at every visit as an explicit monitoring parameter, not a courtesy question.

1. Confirm adherence to the current regimen, including correct titration timing, before concluding a drug has failed.
2. If one cholinesterase inhibitor is not tolerated or does not appear to help, trial a different one within the class before concluding the entire class has failed — response and tolerability are genuinely individual.
3. If disease progresses from mild-moderate to moderate-severe on a cholinesterase inhibitor, add memantine rather than stopping the cholinesterase inhibitor.
4. If BPSD persists despite an adequate nonpharmacologic trial and an optimized cholinesterase-inhibitor/memantine regimen, reassess specifically for an untreated precipitant before escalating to a psychotropic.
5. If an SSRI trial for agitation with mood/anxiety features is inadequate, reassess target symptoms and the diagnosis itself before moving directly to an antipsychotic.
6. If an antipsychotic response is inadequate at an appropriately titrated dose within a defined trial period, taper and stop it rather than continuing indefinitely or adding a second antipsychotic.
7. If ARIA is detected on a scheduled or symptom-triggered MRI, manage per severity: asymptomatic, radiographically mild ARIA may allow continued dosing with closer monitoring, while symptomatic or radiographically severe ARIA requires holding or permanently discontinuing therapy per specialist direction — this decision belongs to the prescribing specialist, not primary care or community pharmacy.
8. Reassess the diagnosis itself if decline is unexpectedly rapid or the clinical picture becomes atypical at any point — consider a second process rather than assuming simple AD progression (see Red Flags).

• Switching from a cholinesterase inhibitor to memantine alone at disease progression instead of adding memantine — combination therapy, not substitution, is what the evidence supports.
• Starting a cholinesterase inhibitor or memantine for isolated MCI outside the specific anti-amyloid-eligible population — neither is proven effective for MCI itself.
• Assuming anti-amyloid antibody eligibility or same-day access without confirmed amyloid pathology, ApoE genotyping, and current reimbursement/access verification — regulatory approval alone does not mean the drug is readily accessible to a given patient today.
• Treating antipsychotic-induced akathisia as inadequate drug effect and increasing the dose rather than recognizing it as an adverse effect.
• Reaching for an antipsychotic as a first-line or routine response to agitation without an adequate nonpharmacologic trial and explicit mortality-risk counselling.
• Dismissing a new headache or confusion in a patient on lecanemab/donanemab as unrelated without considering ARIA.
• Missing an anticholinergic-burden medication as a reversible contributor to worsening cognition.
• Treating a single low MMSE score as the sole basis for stopping a cognitive enhancer, rather than the full clinical/functional picture.
• Overlooking caregiver burden and support needs as part of the ongoing treatment plan.

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Cholinesterase inhibitors

Block acetylcholinesterase, increasing synaptic acetylcholine — 1st-line cognitive/functional therapy for mild-moderate AD. Start at the lowest dose and titrate slowly; starting at a high dose without gradual titration is associated with more adverse events.^[1]

NMDA receptor antagonist

Anti-amyloid disease-modifying monoclonal antibodies (specialist-initiated only)

Health Canada-approved for MCI due to AD or mild AD dementia with confirmed amyloid pathology and a permitted ApoE genotype; public/private reimbursement is still evolving rapidly in Canada — see Choose Initial Treatment for the current access-status callout.^[5][6][7]

Pharmacotherapy for BPSD in AD — reserve for severe, dangerous, or significantly distressing symptoms after nonpharmacologic measures fail