Nervous System & Special Senses

Anti-amyloid antibodies for Alzheimer disease (lecanemab, donanemab)

Clinical Overview and When to Suspect Early Alzheimer Disease Amenable to Anti-Amyloid Therapy

— Gradual, progressive episodic memory decline over 6–12+ months

— Functional preservation in most IADLs (still managing finances with help, driving in familiar areas)

— MMSE ≥ 22 or MoCA ≥ 17 roughly; CDR global 0.5 or 1

— Age typically 50–85, with a reliable study partner/caregiver

— Moderate–severe dementia (MMSE <20, CDR ≥2)

— Non-AD dementias (Lewy body, FTD, vascular-predominant)

— Subjective cognitive complaints without objective impairment

— Confirmed amyloid positivity by amyloid PET or CSF Aβ42/Aβ40 ratio + p-tau

— APOE ε4 genotyping (especially before lecanemab — ε4 homozygotes have markedly higher ARIA risk)

— Baseline MRI within 1 year, reviewed for microhemorrhages, superficial siderosis, prior macrohemorrhage, severe white matter disease

— Anticoagulation status reviewed (warfarin/DOACs raise ARIA-H hemorrhage risk → generally avoid)

Step 3 management: When a 72-year-old presents with 18 months of progressive forgetfulness, MoCA 23, intact ADLs, and a normal depression screen, the correct next step is structural MRI + AD biomarker testing (amyloid PET or CSF), not empiric donepezil alone — because biomarker confirmation now opens the door to disease-modifying therapy. Step 3 increasingly tests recognition of the eligibility window: catch patients early, before they progress out of the mild stage where anti-amyloid agents work.

Lecanemab and donanemab are IgG1 monoclonal antibodies targeting aggregated β-amyloid (soluble protofibrils for lecanemab; insoluble plaque/pyroglutamate Aβ for donanemab), FDA-approved for mild cognitive impairment (MCI) due to AD or mild AD dementia with confirmed amyloid pathology.

Suspect candidacy in an outpatient with:

Not indicated for:

Pre-treatment requirements (board-tested gatekeeping):

Presentation Patterns and Key History

— Repeating questions, misplacing items, missed appointments

— Preserved remote memory early; recent memory impaired

— Word-finding pauses, but fluent speech

— Insight often partially preserved → patient may minimize while collateral confirms

— Posterior cortical atrophy (visuospatial > memory)

— Logopenic primary progressive aphasia

— Frontal/dysexecutive AD

— Step 3 stems may include these to test whether you recognize AD pathology beyond amnestic presentation

— Timeline (months–years, gradual) vs stepwise (vascular) vs rapid (prion, autoimmune)

— Functional impact: finances, medications, cooking, driving — defines MCI vs dementia

— Behavioral changes (apathy common in AD; disinhibition early → think FTD)

— Sleep: REM behavior disorder → think DLB/PD dementia, not AD

— Visual hallucinations, fluctuations → DLB

— Falls, parkinsonism early → DLB or PSP

— Vascular risk factors, prior strokes, anticoagulant use (matters for ARIA risk)

— Family history of early-onset dementia (PSEN1/2, APP mutations)

— Medication review: anticholinergics, benzodiazepines, opioids worsening cognition

— Alcohol, B12, thyroid history

— Required for monitoring, infusion logistics, ARIA symptom reporting

— Absence of a reliable partner is a relative contraindication

Board pearl: A patient with cognitive complaints whose collateral informant says they are fine usually does not have AD — depression, anxiety, and normal aging dominate. Conversely, a patient who denies problems but whose spouse reports clear functional decline is the classic AD vignette and the one to biomarker-test for anti-amyloid candidacy.

Core amnestic syndrome (most common AD presentation eligible for therapy):

Atypical AD variants that may still be amyloid-positive but are less validated for antibody therapy:

History elements to extract:

Caregiver/study partner is mandatory:

Physical Exam Findings and Cognitive/Functional Assessment

— No focal weakness, no sensory level, no cerebellar signs

— Normal gait early (gait apraxia, parkinsonism, or ataxia early → think NPH, DLB, PSP, vascular)

— Cranial nerves intact

— No myoclonus (early myoclonus → CJD; late myoclonus can occur in advanced AD)

— MoCA preferred over MMSE (more sensitive to MCI); score <26 abnormal, but adjust for education

— Mini-Cog acceptable as screen in primary care

— Domains: delayed recall (hippocampal), clock draw (visuospatial/executive), category fluency

— CDR (Clinical Dementia Rating): 0.5 = MCI, 1 = mild dementia — the treatment window

— IADLs (finances, meds, transportation, cooking) impaired first

— Basic ADLs (bathing, dressing, toileting) preserved in mild disease

— Loss of IADLs with preserved ADLs = mild dementia → still eligible

— Screen with PHQ-9 — depression can mimic or coexist with dementia ("pseudodementia")

— Assess for psychosis, agitation — typically late, not early

— BP control matters: uncontrolled HTN increases ARIA-H risk

— AFib detection critical — anticoagulation need vs. anti-amyloid eligibility creates real tension

— Magnetic gait + incontinence → NPH

— Resting tremor, bradykinesia → PD/DLB

— Asymmetric apraxia → CBD

Key distinction: Normal elemental neurologic exam + isolated amnestic cognitive deficit + impaired IADLs = the prototypical anti-amyloid candidate. Any prominent early motor, gait, or behavioral finding should redirect workup before committing to lecanemab/donanemab.

General neuro exam in early AD is typically normal — this is itself a diagnostic clue:

Cognitive bedside testing drives staging:

Functional assessment (Step 3 favorite):

Mood and behavior:

Vitals and cardiovascular exam:

Look for signs suggesting alternative diagnoses:

Diagnostic Workup — Initial Labs, Structural Imaging, and Reversible Cause Screen

— CBC, CMP, TSH, B12 — exclude reversible/contributing causes

— Consider RPR/HIV if risk factors; homocysteine, folate selectively

— Depression screen (PHQ-9)

— Medication reconciliation: stop anticholinergics (diphenhydramine, oxybutynin), taper benzodiazepines

— Assess for:

— Hippocampal/medial temporal atrophy (supports AD)

— Cerebral microbleeds — count matters

— Superficial siderosis — exclusionary

— Prior macrohemorrhage (>1 cm) — exclusionary

— Significant white matter disease, lacunes (vascular contribution)

— NPH features (ventriculomegaly with tight high convexities)

— Mass lesions, subdural hematoma

— CT acceptable only if MRI contraindicated, but MRI is required for lecanemab/donanemab safety baseline

— >4 cerebral microhemorrhages → generally exclude

— Any area of superficial siderosis → exclude

— Prior macrohemorrhage → exclude

— Vasogenic edema → exclude

— Review antiplatelets, anticoagulants

— Document falls history

— Optimize BP (<130/80 reasonable) before initiating therapy

Step 3 management: When a 70-year-old with new MCI has TSH 12 and B12 180, treat the hypothyroidism and B12 deficiency and reassess cognition in 3–6 months before pursuing amyloid PET. Anti-amyloid therapy is never the answer in a stem with unaddressed reversible contributors — the boards reward the methodical workup.

Standard dementia workup must precede biomarker testing (Step 3 loves this sequencing):

Structural MRI brain (without contrast) — required before anti-amyloid therapy:

ARIA exclusion thresholds at baseline MRI:

Cardiovascular and bleeding risk assessment:

Diagnostic Workup — Amyloid Biomarker Confirmation

— Amyloid PET (florbetapir, florbetaben, flutemetamol) — visual read positive/negative; gold standard imaging

— CSF biomarkers — low Aβ42, low Aβ42/Aβ40 ratio, elevated p-tau181 and total tau

— Plasma biomarkers (p-tau217 increasingly used as a screening/triage test; high negative predictive value, but confirmatory PET or CSF often still required for treatment initiation)

— Donanemab trial enrolled by tau burden

— Patients with very high tau (advanced stage) showed less benefit

— Patients with no tau uptake also excluded in trials

— In practice, intermediate tau is the sweet spot

— Required before lecanemab (boxed warning emphasizes ε4 homozygotes)

— ε4/ε4 homozygotes: ARIA-E ~33%, ARIA-H ~39% — higher than heterozygotes or non-carriers

— Counsel about genetic implications for family members (insurance, psychological impact) — informed consent issue

— FDG-PET can show temporoparietal hypometabolism (supports AD pattern)

— MRI volumetry for hippocampal atrophy

— Neuropsychological testing for ambiguous cases

Board pearl: A positive amyloid PET in a cognitively normal older adult is not an indication for treatment — amyloid positivity is common in normal aging (~30% at age 75). Treatment requires biomarker positivity PLUS objective cognitive impairment in the MCI/mild dementia range. Treating asymptomatic amyloid-positive patients outside a trial is inappropriate.

Amyloid positivity must be documented before lecanemab or donanemab — this is non-negotiable for FDA labeling and insurance coverage.

Three accepted methods:

Tau PET is specifically required before donanemab in many protocols:

APOE ε4 genotyping:

Additional supportive studies:

Risk Stratification and Treatment Decision Framework

— Clinical stage: MCI due to AD or mild AD dementia (CDR 0.5–1)

— Amyloid-positive by PET or CSF

— Baseline MRI without disqualifying findings

— APOE genotype known and discussed

— No anticoagulation (warfarin, DOACs) — relative/absolute contraindication

— No active bleeding disorder, recent stroke, uncontrolled HTN

— Reliable care partner for monitoring

— Patient capacity to consent (or surrogate engaged)

— High risk: APOE ε4 homozygote, >4 microbleeds at baseline (but if 0–4, still eligible with caution), concurrent antithrombotics

— Moderate: ε4 heterozygote

— Lower: ε4 non-carrier

— Modest clinical benefit: ~27% slowing of decline on CDR-SB over 18 months (lecanemab); donanemab similar magnitude

— Not a cure, not a reversal — slows progression

— ARIA risk: ~21% lecanemab, ~36% donanemab (any ARIA)

— Infusion burden: lecanemab IV q2 weeks; donanemab IV q4 weeks

— MRI monitoring schedule (multiple scans in first 6–12 months)

— Cost (~$26,000–32,000/year drug cost), Medicare Part B coverage with CMS registry participation

— Moderate/severe dementia

— Non-AD pathology

— High bleeding risk that cannot be modified

— Inability to attend infusions or MRI monitoring

Step 3 management: The right answer is often "discuss risks/benefits and shared decision-making" rather than auto-initiating therapy. Document the conversation: expected benefit magnitude, ARIA risks, monitoring burden, alternatives (symptomatic therapy alone, supportive care, clinical trials).

Eligibility checklist (memorize for Step 3):

Risk stratification for ARIA:

Shared decision-making elements:

When NOT to offer:

Pharmacotherapy — Lecanemab and Donanemab Regimens

— 10 mg/kg IV every 2 weeks, indefinite duration per current labeling (though optimal stopping point debated)

— Infusion ~1 hour; observe for infusion reactions (~26%, usually first dose)

— Premedication (acetaminophen, antihistamine) often used after first reaction

— Targets soluble Aβ protofibrils

— 700 mg IV every 4 weeks × 3 doses, then 1400 mg IV every 4 weeks

— Can be stopped once amyloid PET shows plaque clearance (a distinguishing feature — finite treatment duration possible)

— Targets pyroglutamate Aβ in established plaques

— Infusion reactions ~9%

— Lecanemab: MRI before infusions 5, 7, and 14

— Donanemab: MRI before infusions 2, 3, 4, and 7

— Additional MRI any time new neurologic symptoms occur

— Cholinesterase inhibitors: donepezil, rivastigmine, galantamine — for mild–moderate AD

— Memantine: NMDA antagonist, for moderate–severe AD (not typically in the mild population that gets antibodies, but used as disease progresses)

— These provide symptomatic benefit; anti-amyloid antibodies provide disease-modifying benefit

— Anticoagulants — tPA contraindicated for stroke if on anti-amyloid therapy (increased ICH risk)

— Antiplatelets allowed but increase ARIA-H risk

— Avoid initiating during active infection or perioperative period

Board pearl: If a patient on lecanemab presents with acute ischemic stroke, IV thrombolytics are contraindicated due to catastrophic ICH risk. Mechanical thrombectomy is preferred. This is the highest-yield safety pearl for Step 3 cross-system stems.

Lecanemab (Leqembi):

Donanemab (Kisunla):

MRI monitoring schedule (high-yield):

Concomitant symptomatic AD therapy (can continue alongside):

Avoid/cautious:

Procedures and Infusion Logistics / ARIA Management

— IV access, baseline vitals, observation period (esp. first 1–3 doses)

— Treat infusion reactions: slow rate, antihistamines, corticosteroids if severe

— Document any new neuro symptoms each visit

— ARIA-E: vasogenic edema/effusion — appears as FLAIR hyperintensity, sulcal effusion

— ARIA-H: hemorrhage — microbleeds (SWI/GRE), superficial siderosis

— Often asymptomatic (~75% of ARIA cases); detected on surveillance MRI

— Symptomatic ARIA: headache, confusion, dizziness, visual changes, nausea, gait instability, seizures

— Asymptomatic mild ARIA-E or limited ARIA-H (≤4 new microbleeds): usually continue therapy with closer MRI monitoring

— Symptomatic ARIA or moderate radiographic ARIA: suspend therapy until clinical and radiographic resolution, then consider resumption

— Severe ARIA-E, macrohemorrhage, superficial siderosis, >10 microbleeds, or recurrent ARIA: permanently discontinue

— Severe symptomatic ARIA-E: IV methylprednisolone sometimes used (off-label, expert-driven)

— Seizures: standard AED management

— Donanemab: plaque clearance on follow-up amyloid PET (typical at 6–18 months)

— Lecanemab: no defined stopping point — continue while tolerated

— Possible after mild ARIA-E resolves

— Generally not after macrohemorrhage or severe events

CCS pearl: A patient on donanemab presents with new headache and confusion 4 months in. Orders: STAT MRI brain with FLAIR/SWI, hold next infusion, neurology consult, BP control. Don't order CT first — MRI is far more sensitive for ARIA-E. If ARIA-E confirmed with significant symptoms, suspend drug and consider IV steroids; reimage in 4–8 weeks.

Infusion center workflow:

ARIA — Amyloid-Related Imaging Abnormalities (the central safety issue):

ARIA management algorithm:

Stopping criteria:

Re-challenge after ARIA:

Special Populations — Elderly and Renal/Hepatic Impairment

— Trials enrolled primarily age 50–85; data above 85 limited

— Older patients have higher microbleed prevalence at baseline — exclusion thresholds disqualify many

— Frailty, falls, polypharmacy reduce real-world benefit/risk ratio

— Life expectancy <3–5 years argues against initiation (benefit accrues over time; ARIA risk is upfront)

— Monoclonal antibodies are not renally cleared — no dose adjustment for CKD

— But CKD-associated hypertension and cerebral small vessel disease raise ARIA risk

— Dialysis patients: no specific data, generally excluded

— No hepatic metabolism issues — no dose adjustment

— Coagulopathy from advanced liver disease increases bleeding/ARIA-H risk

— Atrial fibrillation requiring anticoagulation is the most common real-world disqualifier

— Step 3 stems exploit this: patient otherwise perfect, but on apixaban for AFib → anti-amyloid therapy generally not offered

— Alternative: rate control + accept stroke risk vs. forgo anti-amyloid — usually anticoagulation wins, anti-amyloid forgone

— Not absolute contraindication

— Counsel about elevated ARIA-H risk

— Consider whether antiplatelet truly indicated (primary prevention aspirin in elderly often unnecessary per USPSTF)

— Assess decision-making capacity for consent

— Engage healthcare proxy/POA early; reassess capacity over time as disease progresses

Key distinction: Symptomatic AD therapies (donepezil, memantine) have no MRI requirement and minimal ARIA-type concerns — they remain options for patients ineligible for antibodies due to anticoagulation, frailty, or microbleed burden. Don't withhold symptomatic therapy just because disease-modifying therapy is off the table.

Age considerations:

Renal impairment:

Hepatic impairment:

Cardiovascular comorbidity:

Concurrent antiplatelet therapy (aspirin, clopidogrel):

Cognitive capacity:

Special Populations — Genetics, Early-Onset AD, and Atypical Cases

— Highest ARIA risk; in lecanemab CLARITY-AD: ARIA-E 32.6%, ARIA-H 39%

— FDA recommends APOE testing before lecanemab initiation

— Some experts advise against treating ε4 homozygotes given risk/benefit

— Counseling must include genetic implications for first-degree relatives:

— Avoid disclosing relatives' implied risk without their consent

— Genetic counseling referral recommended

— GINA protects against employment/health insurance discrimination but not life/disability/long-term care insurance

— Early-onset (often <60), strong family history

— Not formally studied in lecanemab/donanemab pivotal trials

— Clinical trial referral (e.g., DIAN-TU) preferred over off-label use

— Trisomy 21 → extra APP gene → near-universal AD pathology by age 40

— Anti-amyloid antibodies not yet validated in this population

— Specialized clinics; trial enrollment encouraged

— Not applicable to the typical AD population, but if encountered (rare early-onset case): avoid — no safety data; IgG1 antibodies cross placenta in 2nd/3rd trimester

— Pivotal trials underrepresented Black, Hispanic, and Asian populations

— Plasma biomarker thresholds may differ across populations

— Counsel about uncertainty in generalizability

Board pearl: An ε4/ε4 homozygote with mild AD asks about lecanemab. The correct Step 3 response is shared decision-making with explicit disclosure of ~3-fold higher ARIA risk, genetic counseling referral, and consideration of whether the modest cognitive benefit justifies the elevated risk. There is no single "right" treatment answer — but failing to disclose APOE-specific risk is wrong.

APOE ε4 homozygotes (~2% of population, ~15% of AD patients):

Autosomal dominant AD (PSEN1, PSEN2, APP mutations):

Down syndrome:

Pregnancy/lactation:

Pediatric: not applicable — no indication

Race/ethnicity considerations:

Complications and Adverse Outcomes

— ARIA-E: ~13% lecanemab, ~24% donanemab

— ARIA-H: ~17% lecanemab, ~31% donanemab

— Symptomatic ARIA: ~3% lecanemab, ~6% donanemab

— ARIA-related deaths reported, especially with concomitant tPA or anticoagulation

— Lecanemab ~26% (mostly first infusion), donanemab ~9%

— Manifestations: chills, fever, nausea, hypertension, hypoxia, rash

— Management: slow/stop infusion, antihistamines, acetaminophen, corticosteroids if severe; premedicate subsequent infusions

— Common; overlap with ARIA symptoms — low threshold for MRI

— Rare but devastating

— Higher risk with anticoagulation, tPA, severe HTN, ε4 homozygotes

— Underlying cerebral amyloid angiopathy (CAA) is the substrate — anti-amyloid antibodies appear to acutely destabilize amyloid-laden vessels

— Trial-level mortality not significantly increased, but case reports of fatal ICH exist, particularly with anticoagulation/tPA exposure

— Can transiently or permanently worsen cognition — counterproductive to therapeutic goal

— Effects beyond 18–36 months not fully characterized

— Cognitive trajectory after stopping (donanemab) being studied

Step 3 management: A patient on lecanemab presents to the ED with acute focal deficit. Order non-contrast CT head immediately to rule out ICH; if negative and within window, MRI before considering thrombolysis — because tPA is contraindicated on anti-amyloid therapy due to fatal hemorrhage risk. Mechanical thrombectomy remains an option for large vessel occlusion.

ARIA — the dominant complication (covered in chunk 8):

Infusion reactions:

Headache, dizziness, falls:

Macrohemorrhage / lobar ICH:

Seizures: associated with severe ARIA-E

Mortality:

Cognitive worsening from ARIA:

Long-term unknowns:

When to Escalate Care — Consults, Imaging, and Hospitalization

— Any new neurologic symptom on therapy → urgent MRI, hold next infusion, neurology contact same day

— Headache pattern change, visual disturbance, focal weakness, confusion, gait change, seizure

— Falls with head trauma → CT head urgently

— Suspected stroke or ICH

— Seizure

— Severe headache with neurologic findings (concern for symptomatic ARIA-E or macrohemorrhage)

— Severe infusion reaction (anaphylaxis, hypoxia)

— Confirmed macrohemorrhage → neuro/neurosurgery, ICU-level monitoring

— Severe symptomatic ARIA-E: admission for IV methylprednisolone (off-label), seizure precautions, BP control

— Status epilepticus from ARIA-related seizures

— Behavioral neurology / cognitive specialist drives initial workup, candidacy, and ongoing management

— Neuroradiology for MRI interpretation (ARIA grading)

— Genetic counseling for APOE disclosure and family planning discussions

— Palliative care when disease progresses despite therapy or for goals-of-care discussions

— Social work for caregiver support, advance directives

— Hospitalized AD patient on anti-amyloid therapy: flag in chart, alert ED/neurology to tPA contraindication

— At discharge after any neuro event: clear documentation of whether antibody continued/held/discontinued

— Communicate with outpatient infusion center

CCS pearl: When ordering thrombolytics for any patient with AD or MCI, screen for active anti-amyloid antibody therapy before administration. This question increasingly appears in stroke stems — the right answer is withhold tPA, pursue thrombectomy if eligible.

Outpatient escalation triggers:

Indications for ED referral:

Inpatient admission:

Consultations:

Transitions of care (Step 3 emphasis):

Key Differentials — Other Neurodegenerative Dementias

— Fluctuating cognition, visual hallucinations, parkinsonism, REM sleep behavior disorder

— Severe neuroleptic sensitivity

— Cognitive deficits prominently visuospatial/executive, less amnestic early

— Amyloid PET can be positive (co-pathology common) but anti-amyloid therapy not indicated — primary pathology is α-synuclein

— Behavioral variant: disinhibition, apathy, hyperorality, loss of empathy

— Language variants: nonfluent, semantic, logopenic (logopenic often AD pathology)

— Younger onset (50s–60s)

— Tau or TDP-43 pathology; amyloid PET typically negative → not eligible

— Cognitive decline >1 year after motor PD onset

— Similar α-synuclein pathology to DLB

— Vertical gaze palsy, axial rigidity, early falls

— Tauopathy; not amyloid

— Asymmetric apraxia, alien limb, cortical sensory loss

— Stepwise decline, focal deficits, extensive white matter disease/lacunes on MRI

— Can coexist with AD (mixed dementia)

— Anti-amyloid therapy not effective for vascular component; AD component may still respond if biomarker-positive — but heavy vascular burden raises ARIA risk

Key distinction: Amyloid positivity ≠ AD as the driving pathology. A DLB patient with positive amyloid PET should still be managed as DLB (carbidopa-levodopa, rivastigmine, melatonin/clonazepam for RBD, avoid typical antipsychotics) — anti-amyloid antibodies will not address the dominant synucleinopathy and expose the patient to ARIA risk.

Dementia with Lewy bodies (DLB):

Frontotemporal dementia (FTD):

Parkinson disease dementia:

Progressive supranuclear palsy (PSP):

Corticobasal degeneration:

Vascular cognitive impairment:

Key Differentials — Reversible and Non-Degenerative Causes

— Subjective complaints often exceed objective deficits

— "I don't know" answers (vs. confabulation in AD)

— Anhedonia, sleep/appetite changes

— Improves with antidepressant trial — always screen PHQ-9 before biomarker workup

— Classic triad: gait apraxia ("magnetic gait"), urinary incontinence, cognitive impairment

— Ventriculomegaly out of proportion to atrophy; DESH sign

— Improves with large-volume LP → consider VP shunt

— Not an anti-amyloid candidate (unless biomarker-confirmed mixed AD/NPH, complex)

— Reversible; always check

— RPR, HIV testing in appropriate risk profiles

— Anticholinergics, benzodiazepines, opioids, gabapentinoids, sedating antihistamines

— Deprescribe before committing to dementia diagnosis

— Daytime cognitive impairment improves with CPAP

— Often in elderly on antithrombotics with falls; MRI/CT diagnostic

— Subacute course (weeks–months), seizures, psychiatric features

— Anti-LGI1, anti-NMDAR, paraneoplastic panels

— Rapid progression (weeks–months), myoclonus, ataxia

— MRI: cortical ribboning, basal ganglia hyperintensity; RT-QuIC CSF positive

Board pearl: A patient labeled "early AD" who shows rapid decline over weeks, myoclonus, or prominent psychiatric features is not AD — pursue CJD or autoimmune encephalitis workup. Anti-amyloid antibodies are absolutely the wrong answer in a rapidly progressive dementia stem.

Pseudodementia (depression):

Normal pressure hydrocephalus (NPH):

B12 deficiency, hypothyroidism, hyponatremia:

Neurosyphilis, HIV-associated neurocognitive disorder:

Medication-induced cognitive impairment:

Obstructive sleep apnea:

Chronic subdural hematoma:

Autoimmune/limbic encephalitis:

CJD:

Long-Term Plan, Adjunctive Therapy, and Secondary Prevention

— Donepezil 5 mg → 10 mg daily (cholinesterase inhibitor) for mild–moderate AD

— Rivastigmine patch (useful if GI intolerance)

— Galantamine

— Memantine 5 mg → 10 mg BID, added as disease progresses to moderate stage

— Combination donepezil + memantine standard in moderate AD

— BP target <130/80 (SPRINT-MIND showed reduced MCI/dementia)

— LDL per ASCVD risk

— Diabetes control (A1c individualized, avoid hypoglycemia)

— Smoking cessation, moderate alcohol only

— Aerobic exercise 150 min/week

— Mediterranean or MIND diet

— Social engagement, cognitive stimulation

— Sleep hygiene, treat OSA

— Hearing aids — hearing loss is the largest modifiable dementia risk factor (Lancet Commission)

— Anticholinergics, benzodiazepines, sedating antihistamines, chronic PPIs without indication

— Antipsychotics for BPSD only with caution (black-box mortality warning in dementia)

— Initiate while capacity is preserved

— POLST/MOLST, healthcare proxy, financial POA, driving discussion, future placement preferences

— Refer to Alzheimer's Association, local support groups

— Screen caregiver for burnout/depression at every visit

Step 3 management: Anti-amyloid therapy is one component of an AD care plan, not the whole plan. Step 3 stems reward selecting hearing aid referral, exercise prescription, BP optimization, caregiver support, and advance directive discussion alongside (or instead of) pharmacotherapy.

Symptomatic AD medications (continue or initiate alongside antibodies):

Vascular risk factor optimization (modifies progression and ARIA risk):

Lifestyle interventions (evidence-supported):

Avoid/deprescribe:

Vaccinations: influenza, COVID-19, pneumococcal, RSV, shingles — maintain per age-based schedule

Advance care planning:

Caregiver support:

Follow-Up, Monitoring, and Counseling Cadence

— Lecanemab: pre-dose MRI before infusions 5, 7, 14; additional MRI for any new symptoms

— Donanemab: pre-dose MRI before infusions 2, 3, 4, 7; additional MRI as clinically indicated

— APOE ε4 homozygotes: consider additional surveillance scans

— MoCA or MMSE every 6 months

— CDR or functional assessment annually

— Caregiver-reported functional measures (FAQ) at each visit

— Every infusion (q2 wk lecanemab, q4 wk donanemab) — brief safety check

— Quarterly comprehensive visit: cognition, function, mood, caregiver status, medication review

— Repeat amyloid PET at 6–12 months to assess clearance → stop drug when amyloid-negative

— Reassess every 6–12 months for re-emergence

— Reinforce ARIA symptom recognition: new headache, confusion, dizziness, visual change, weakness, seizure — call immediately

— Driving safety reassessment (especially after cognitive decline or ARIA events)

— Fall prevention

— Medication reconciliation each visit — flag new anticoagulants from other providers

— Medicare Part B coverage requires participation in a CMS-approved registry (e.g., ALZ-NET) collecting safety and effectiveness data

— Confirm enrollment for billing/coverage

— Communicate with PCP, infusion center, neuroradiology

— Update problem list and allergy/alert list with "on anti-amyloid antibody — tPA contraindicated"

Board pearl: The single most important patient/caregiver education point: any new neurologic symptom = call the office and hold the next infusion until MRI is done. Underreporting of ARIA symptoms is the most common preventable cause of severe outcomes.

MRI surveillance schedule:

Cognitive reassessment:

Clinical visits:

Donanemab-specific follow-up:

Counseling at each visit:

CMS registry requirement:

Care coordination:

Ethical, Legal, and Patient Safety Considerations

— Modest benefit (slowing decline by ~5 months over 18 months) vs. real ARIA risk

— Cost burden (~$26,000–32,000/year drug + infusion + MRI costs)

— Time burden (q2–4 week infusions, multiple MRIs)

— Discuss explicitly: "This does not restore function or stop the disease."

— Document discussion of alternatives: symptomatic therapy only, supportive care, clinical trials

— Patients with MCI may have preserved capacity, but capacity should be reassessed periodically as disease progresses; involve healthcare proxy early

— Genetic testing affects family members who haven't consented

— Counsel about GINA protections (employment, health insurance) and gaps (life, disability, long-term care insurance)

— Offer genetic counseling referral

— If capacity lost, document substituted judgment standard

— Re-consent annually or after clinical changes

— Reassess driving capacity periodically; involve OT driving evaluation

— State-specific mandatory reporting laws for unsafe drivers (varies — California, Pennsylvania, others require physician reporting)

— Firearms in the home: counsel on safe storage/removal

— Patients on anti-amyloid antibodies presenting to ED: chart alert/wristband noting "tPA contraindicated"

— Discharge summaries must list therapy status

— Surgical/procedural planning: hold antibodies perioperatively per institutional protocol; bridging not required (long half-life means no quick reversal anyway)

— Access disparities by race, insurance, geography (need infusion center + MRI access)

— Trials underrepresented minorities — discuss uncertainty

— Stop anti-amyloid therapy when patient progresses to moderate dementia, develops disqualifying ARIA, or transitions to hospice/comfort care

— Reassess goals at each major clinical change

Step 3 management: Always document capacity assessment, shared decision-making, and caregiver engagement for any anti-amyloid initiation. Failure to involve a surrogate in a patient with borderline capacity is a tested pitfall.

Informed consent — high stakes:

APOE disclosure ethics:

Surrogate decision-making:

Driving and firearms safety:

Transition-of-care safety (Step 3 emphasis):

Equity concerns:

End-of-life transitions:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: If a Step 3 stem mentions a patient on lecanemab/donanemab presenting with any acute neurologic change, the answer involves urgent MRI and holding the infusion — almost never "continue therapy and observe."

Lecanemab = anti-protofibril; q2 weeks IV; MRI before doses 5, 7, 14

Donanemab = anti-pyroglutamate plaque; q4 weeks IV; MRI before doses 2, 3, 4, 7; can stop after plaque clearance

Both indicated for MCI due to AD or mild AD dementia — not moderate/severe

Amyloid positivity required (PET or CSF Aβ42/40 + p-tau)

APOE ε4 homozygotes: ~3× higher ARIA risk — test before lecanemab

ARIA-E = edema (FLAIR); ARIA-H = hemorrhage (SWI/microbleeds)

Most ARIA is asymptomatic — detected on surveillance MRI

tPA is contraindicated in patients on anti-amyloid antibodies (fatal ICH risk) → use thrombectomy if eligible

Anticoagulants (warfarin, DOACs) — generally exclusionary

>4 microbleeds, superficial siderosis, or prior macrohemorrhage on baseline MRI → exclude

Modest benefit: ~27% slowing of decline (CDR-SB) — not a cure

CMS registry participation required for Medicare coverage

Donepezil/memantine remain standard symptomatic therapy — can be continued

Hearing loss is the single largest modifiable dementia risk factor — always ask about hearing aids

Mediterranean/MIND diet, aerobic exercise, BP <130/80, treat OSA — all evidence-supported

Largest modifiable risks (Lancet Commission): hearing loss, LDL, education, smoking, depression, social isolation, physical inactivity, diabetes, obesity, alcohol, HTN, head injury, air pollution, visual impairment

Avoid anticholinergics, benzodiazepines, antipsychotics in AD patients

Visual hallucinations + parkinsonism + RBD = DLB, not AD — antibodies not indicated

Rapidly progressive dementia + myoclonus = CJD — workup, not antibodies

Magnetic gait + incontinence + dementia = NPH — LP trial, possible shunt

Board Question Stem Patterns

Step 3 management: The board's favorite trap is offering "start lecanemab" as a distractor when the patient is anticoagulated, has disqualifying microbleeds, has moderate dementia, lacks biomarker confirmation, or has a non-AD diagnosis. Default to the gating checklist.

Stem 1 — Eligibility gating: 70-year-old, MoCA 24, intact ADLs, hippocampal atrophy on MRI, B12 and TSH normal. Next step? → Amyloid PET or CSF biomarker testing (not empiric antibody, not donepezil alone).

Stem 2 — Anticoagulant conflict: 74-year-old with MCI, amyloid-positive, on apixaban for AFib. Next step? → Do not initiate anti-amyloid antibody; continue anticoagulation, optimize symptomatic therapy and risk factors.

Stem 3 — Stroke crossover: Patient on lecanemab presents with acute hemiparesis, NIHSS 12, within 3-hour window. Best treatment? → Mechanical thrombectomy (if LVO); avoid tPA (contraindicated).

Stem 4 — ARIA recognition: 4 months into donanemab, new headache and confusion. Next step? → Urgent MRI brain (FLAIR + SWI), hold next infusion.

Stem 5 — APOE counseling: ε4/ε4 homozygote considering lecanemab. Best response? → Disclose ~3× higher ARIA risk, shared decision-making, genetic counseling referral.

Stem 6 — Wrong diagnosis: Patient with fluctuations, visual hallucinations, RBD, parkinsonism, amyloid PET positive. Best therapy? → Rivastigmine + carbidopa-levodopa for DLB; avoid anti-amyloid antibody and typical antipsychotics.

Stem 7 — Reversible cause first: New cognitive complaints, TSH 15, B12 150. Next step? → Treat hypothyroidism and B12 deficiency, reassess in 3 months — not biomarker testing yet.

Stem 8 — Capacity: Patient with mild AD dementia, family wants antibody therapy, patient ambivalent. Next step? → Formal capacity assessment, shared decision-making with patient and surrogate.

Stem 9 — Stopping rule: Patient on donanemab × 12 months. Repeat amyloid PET negative. Next step? → Stop donanemab, continue surveillance.

Stem 10 — Disqualifying MRI: Baseline MRI shows superficial siderosis or 6 microbleeds. Next step? → Do not initiate antibody therapy; pursue symptomatic management.

One-Line Recap

Anti-amyloid monoclonal antibodies (lecanemab, donanemab) modestly slow cognitive decline in biomarker-confirmed MCI or mild AD dementia but require strict eligibility gating, structured MRI surveillance for ARIA, careful APOE-informed counseling, and avoidance of anticoagulants/tPA — they slow, they do not cure.

Eligibility checklist: MCI/mild AD (CDR 0.5–1) + amyloid-positive (PET or CSF) + acceptable baseline MRI (no superficial siderosis, ≤4 microbleeds, no macrohemorrhage) + APOE genotyped + no anticoagulation + reliable care partner + informed consent.

Safety dominates management: ARIA-E (edema) and ARIA-H (hemorrhage) detected on scheduled MRIs (lecanemab pre-doses 5/7/14; donanemab pre-doses 2/3/4/7); any new neurologic symptom → urgent MRI + hold infusion; tPA contraindicated if acute stroke — pursue thrombectomy.

Comprehensive AD care: combine antibodies with donepezil/memantine symptomatic therapy, BP <130/80, Mediterranean/MIND diet, exercise, hearing aids, OSA treatment, deprescribing anticholinergics/benzodiazepines, caregiver support, and early advance care planning while capacity is preserved.

Step 3 traps: don't initiate in moderate dementia, anticoagulated patients, non-AD pathology (DLB, FTD, vascular), unaddressed reversible causes (B12, TSH, depression), or without biomarker confirmation; donanemab can be stopped after amyloid PET clearance (a unique distinguishing feature from lecanemab).