Nervous System & Special Senses

Alzheimer disease: diagnosis and management

Clinical Overview and When to Suspect Alzheimer Disease

— Pathology: extracellular β-amyloid plaques and intracellular hyperphosphorylated tau (neurofibrillary tangles) with cortical/hippocampal atrophy

— Onset is insidious, gradually progressive over months to years — never acute or stepwise

— Patient or, more often, family member/informant reports memory loss interfering with daily function (missed appointments, repetitive questions, getting lost in familiar places)

— Subtle decline noted on routine wellness visits in adults ≥65, especially when the patient is a poor historian and brings a collateral source

— New difficulty with instrumental ADLs (IADLs) first — managing finances, medications, driving, cooking — before basic ADLs

— Unexplained weight loss, social withdrawal, or worsening control of previously stable chronic disease (missed insulin doses, HTN meds)

— Age (doubles every 5 years after 65), female sex, family history, APOE ε4 allele

— Cardiovascular risk factors (HTN, DM, hyperlipidemia, smoking), low education, head trauma, hearing loss, social isolation, depression

— Down syndrome — universal AD pathology by age 40

Alzheimer disease (AD) is the most common cause of dementia in adults >65, accounting for 60–80% of cases

When to suspect in an outpatient encounter:

Risk factors to elicit:

USPSTF: insufficient evidence to screen asymptomatic older adults, but Medicare Annual Wellness Visit mandates cognitive assessment

Board pearl: A reliable informant noting functional decline (not just forgetfulness) is the single most important historical feature distinguishing dementia from normal aging or subjective cognitive complaints.

Step 3 management: When AD is suspected, schedule a dedicated cognitive visit with the patient and an informant — don't try to diagnose during a 15-minute acute care slot; bill prolonged services or cognitive assessment/care plan codes (G0505/99483).

Presentation Patterns and Key History

— Earliest deficit: short-term episodic memory — forgetting recent conversations, misplacing items, repeating questions within minutes

— Word-finding difficulty, mild executive dysfunction follow

— Preserved social graces and remote memory early, which delays recognition

— Posterior cortical atrophy — visuospatial deficits, difficulty reading, dressing apraxia

— Logopenic primary progressive aphasia — word-finding pauses, impaired repetition

— Frontal/dysexecutive variant — apathy, planning failures

— Mild (MCI → mild dementia): IADL impairment, preserved basic ADLs, intact orientation to self

— Moderate: behavioral symptoms (agitation, wandering, sundowning, delusions of theft), needs cueing for ADLs, gets lost

— Severe: mute or near-mute, incontinent, bedbound, dysphagia → aspiration pneumonia (terminal event)

— AD8 informant tool (8 questions, ≥2 = concern) or Functional Activities Questionnaire (FAQ)

— Time course: gradual progression (AD) vs stepwise (vascular) vs fluctuating (DLB) vs subacute weeks-months (prion, autoimmune, NPH)

— Medication review: anticholinergics (diphenhydramine, oxybutynin, TCAs), benzodiazepines, opioids, PPIs — reversible contributors

— Alcohol use, sleep (OSA), depression screen (PHQ-9), thyroid symptoms

Classic amnestic AD (most common phenotype):

Atypical AD phenotypes (younger patients, age 50s–60s):

Stage-based trajectory (typical 8–10 year course):

Key history questions:

Key distinction: Delirium is acute/fluctuating with attention deficit; MCI has cognitive complaints with intact function; dementia requires functional impairment. Never diagnose dementia during an episode of delirium — reassess after resolution.

Board pearl: Visual hallucinations early + parkinsonism + REM sleep behavior disorder → think Lewy body dementia, not AD. Early personality/behavior change with preserved memory → frontotemporal dementia.

Physical Exam Findings and Cognitive Assessment

— Absence of focal neuro signs, normal gait, normal cranial nerves

— Focal deficits, early gait disorder, or parkinsonism should prompt search for alternative diagnoses

— Gait: magnetic/apractic gait → NPH; shuffling/festinating → PD/DLB; spastic or asymmetric → vascular/structural

— Tone and tremor: rigidity, bradykinesia, resting tremor → DLB or PD dementia

— Cranial nerves and lateralizing signs → think stroke, tumor, subdural

— Myoclonus, rapid progression → prion disease (CJD)

— Primitive reflexes (grasp, snout, palmomental) appear in moderate-advanced AD — nonspecific

— Mini-Cog (3-word recall + clock draw) — 3 minutes, ideal for primary care

— MoCA (/30, ≤25 abnormal) — more sensitive for MCI, tests executive function, preferred for educated patients

— MMSE (/30) — copyrighted, ceiling effect; <24 suggests dementia; useful for staging

— SLUMS — alternative validated tool

— Katz ADLs (bathing, dressing, toileting, transferring, continence, feeding)

— Lawton IADLs (finances, medications, transportation, shopping, cooking, housekeeping, phone, laundry)

— Driving safety: ask about near-misses, getting lost; consider formal driving evaluation

— Orthostatic vitals — orthostasis suggests DLB or autonomic neuropathy

— BP control matters: midlife HTN is a modifiable AD risk factor

General exam in early AD is typically normal — this is a key feature

Targeted neuro exam:

Cognitive screening tools (office-based):

Functional assessment:

Hemodynamic/vital signs:

Step 3 management: Document baseline MoCA/MMSE score and functional status at diagnosis — these anchor future progression assessments and qualify the patient for dementia care planning codes and disease-modifying therapy eligibility.

Board pearl: Normal exam + abnormal cognitive screen + functional decline + informant corroboration = AD until proven otherwise.

Diagnostic Workup — Initial Labs and Imaging

— CBC, CMP (Na, Ca, glucose, BUN/Cr, LFTs)

— TSH — hypothyroidism

— Vitamin B12 (± methylmalonic acid if borderline) — deficiency mimics dementia

— Consider: HIV (risk factors), RPR/treponemal testing (neurosyphilis if exposure or atypical features), Lyme (endemic areas), heavy metals only if exposure history

— Depression screen (PHQ-9) — pseudodementia

— Non-contrast MRI brain preferred — assesses medial temporal/hippocampal atrophy (AD signature), white matter disease (vascular), strategic infarcts, NPH ventriculomegaly, subdural hematoma, tumors

— Non-contrast CT acceptable if MRI contraindicated (pacemaker, claustrophobia)

— Atrophy is supportive but not specific; normal imaging does not exclude AD

— Hypothyroidism, B12 deficiency, neurosyphilis, HIV, NPH (gait + cognition + incontinence + ventriculomegaly), chronic subdural (falls, anticoagulation), OSA, depression, polypharmacy

— Medication audit using Beers criteria — discontinue anticholinergics, sedatives, sleep aids

AD remains a clinical diagnosis; initial workup is aimed at excluding reversible causes of cognitive impairment (~10% of dementia evaluations reveal contributing factors)

Recommended initial labs (AAN guideline):

Structural neuroimaging is indicated in all new dementia evaluations:

Reversible/contributory conditions to exclude:

CCS pearl: Order in the office setting: Mini-Cog or MoCA → CBC, CMP, TSH, B12 → MRI brain without contrast → review medication list → schedule informant interview/follow-up in 4–6 weeks. Don't order PET or CSF biomarkers first-line.

Board pearl: A patient on chronic diphenhydramine for sleep with memory complaints — stop the drug and reassess in 4–6 weeks before labeling as AD. Anticholinergic burden is the most overlooked reversible contributor.

Advanced and Confirmatory Studies

— Young-onset dementia (<65)

— Atypical presentations

— Diagnostic uncertainty after standard workup

— Eligibility determination for anti-amyloid therapy

— Detailed cognitive profiling across domains (memory, executive, language, visuospatial, attention)

— Useful to distinguish MCI from normal aging, AD from FTD, and to establish baselines in high-functioning patients

— ↓ Aβ42 (or ↓ Aβ42/Aβ40 ratio), ↑ total tau, ↑ phospho-tau-181

— Pattern is sensitive and specific for AD pathology

— Detects fibrillar amyloid plaques; covered by Medicare when anti-amyloid therapy is being considered

— Positive scan supports AD; negative scan effectively rules out AD as cause

— Not for diagnosis; required before lecanemab/donanemab to risk-stratify for ARIA (homozygotes have highest risk)

— Counseling needed — implications for relatives

Advanced testing is not required for typical late-onset amnestic AD but is increasingly used for:

Neuropsychological testing:

CSF biomarkers (lumbar puncture):

Amyloid PET imaging (florbetapir, florbetaben, flutemetamol):

Tau PET (flortaucipir) — confirms tau pathology and stages disease; emerging clinical role

FDG-PET: temporoparietal hypometabolism in AD; frontotemporal hypometabolism in FTD — useful when MRI ambiguous

Plasma biomarkers (emerging): p-tau 217, Aβ42/40 ratio — increasingly available, may become first-line screening

APOE genotyping:

Key distinction: A negative amyloid PET or CSF Aβ profile essentially rules out AD; reconsider FTD, vascular, DLB, or non-degenerative causes.

Board pearl: Order LP/PET only when results will change management — typically when considering disease-modifying therapy or in atypical/young-onset cases. Routine elderly amnestic dementia does not require biomarker confirmation for symptomatic management.

Risk Stratification and Management Framework

— MCI due to AD: cognitive complaints + objective deficit on testing + preserved function → monitor, optimize vascular risk, consider disease-modifying therapy if amyloid-positive

— Mild dementia: IADL impairment → start cholinesterase inhibitor, advance care planning, driving evaluation, caregiver education

— Moderate dementia: ADL dependence, behavioral symptoms → add memantine, address BPSD, home safety, caregiver support

— Severe dementia: total care → palliative focus, deprescribe, hospice eligibility (FAST stage 7c)

— BP control (target <130 systolic in midlife reduces dementia)

— Diabetes control, lipid management

— Smoking cessation, moderate alcohol

— Hearing aids if hearing loss (largest single modifiable factor in late life)

— Physical activity ≥150 min/week, Mediterranean/MIND diet, social engagement, cognitive stimulation

— Treat depression, optimize sleep (screen for OSA)

— Structured routine, environmental cues, music therapy, reminiscence therapy, exercise programs

— Caregiver training reduces BPSD and delays institutionalization

— Patient still has capacity to articulate preferences

— Advance directive, healthcare proxy, POLST/MOLST, financial/legal planning, long-term care planning

Stage-based management is the Step 3 framework:

Modifiable risk factor optimization (Lancet Commission identifies ~40% of dementia risk as modifiable):

Non-pharmacologic interventions are first-line for behavioral symptoms:

Goals-of-care discussion at diagnosis:

Step 3 management: The mild-stage outpatient visit checklist — (1) confirm diagnosis and stage, (2) start cholinesterase inhibitor, (3) optimize vascular risk, (4) driving and home safety assessment, (5) advance care planning, (6) caregiver resources (Alzheimer's Association 24/7 helpline 800-272-3900), (7) follow-up in 3 months.

Board pearl: The single most evidence-based intervention for the caregiver — and indirectly for the patient — is structured caregiver education and support, which reduces nursing home placement.

Pharmacotherapy — Symptomatic Therapy First-Line

— Donepezil 5 mg daily × 4–6 weeks → 10 mg daily (max 23 mg in moderate-severe); once-daily dosing favors adherence

— Rivastigmine oral or transdermal patch (4.6 → 9.5 → 13.3 mg/24h); patch reduces GI side effects, useful in dysphagia

— Galantamine ER 8 → 16 → 24 mg daily

— Mechanism: inhibit acetylcholinesterase → increase synaptic ACh in cortex/hippocampus

— Modest benefit (~2–4 point MMSE improvement, delay decline 6–12 months); does not modify underlying disease

— GI: nausea, vomiting, diarrhea, anorexia, weight loss — most common, titrate slowly with food

— Bradycardia, syncope, AV block — check baseline HR/ECG; caution with beta-blockers, digoxin

— Vivid dreams, insomnia (give donepezil in morning if disturbed)

— Urinary frequency, muscle cramps, increased seizure threshold

— NMDA receptor antagonist, blocks glutamate excitotoxicity

— Start 5 mg daily, titrate weekly to 10 mg BID (or 28 mg ER daily)

— Well tolerated; main side effects dizziness, confusion, headache

— Can combine with ChEI in moderate-severe disease — modest additive benefit

— Renal dose adjustment required (CrCl <30: max 5 mg BID)

— Anticholinergics (diphenhydramine, oxybutynin, TCAs) — directly oppose ChEI mechanism, worsen cognition

— Benzodiazepines, Z-drugs, opioids — increase falls and delirium

— Antipsychotics — black box warning for increased mortality in dementia

Cholinesterase inhibitors (ChEIs) — first-line for mild to moderate AD:

Side effects (cholinergic):

Memantine — moderate to severe AD (MMSE <15–18):

Avoid/use cautiously:

CCS pearl: Start donepezil 5 mg HS, recheck in 4–6 weeks for tolerance and HR, uptitrate to 10 mg. Document baseline MMSE/MoCA; reassess every 6 months. Continue ChEI through moderate-severe disease; stop only when no clear benefit, intolerable side effects, or FAST stage 7.

Board pearl: New syncope or bradycardia on donepezil → ECG, hold drug; don't reflexively pace — withdraw the offending agent first.

Disease-Modifying Therapy and Emerging Treatments

— Lecanemab (Leqembi) — FDA approved 2023 for MCI and mild AD dementia with confirmed amyloid pathology; IV every 2 weeks

— Donanemab (Kisunla) — FDA approved 2024, similar indication; IV every 4 weeks

— Mechanism: clear β-amyloid plaques; slow clinical decline by ~25–35% over 18 months (modest, not reversal)

— Confirmed amyloid pathology (amyloid PET or CSF)

— MCI or mild dementia stage (MMSE typically ≥22)

— APOE genotyping required before initiation

— Baseline MRI to exclude microhemorrhages, superficial siderosis, prior macrohemorrhage

— Not on therapeutic anticoagulation (relative contraindication due to ARIA-H bleeding risk)

— ARIA-E: vasogenic edema; ARIA-H: microhemorrhages/superficial siderosis

— Highest risk in APOE ε4 homozygotes (~30–40%)

— Most asymptomatic; severe cases → headache, confusion, seizures, rarely fatal

— Surveillance MRI before infusions 5, 7, 14 (lecanemab schedule)

— Manage by holding/discontinuing therapy based on severity

— Brexpiprazole — only FDA-approved antipsychotic for dementia-related agitation (still carries black box mortality warning)

— Citalopram ≤20 mg (off-label) — evidence for agitation; QT caution

— Trazodone for sleep disturbance

— Avoid haloperidol/atypicals chronically unless severe psychosis or danger

Anti-amyloid monoclonal antibodies — new class targeting AD pathology:

Eligibility requirements:

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

Aducanumab — withdrawn from market 2024 due to limited evidence/uptake

Symptomatic adjuncts for behavioral and psychological symptoms (BPSD):

Step 3 management: Refer eligible MCI/mild-AD patients to a memory clinic or neurology for anti-amyloid therapy evaluation — this is now a standard-of-care referral, not optional, when patient/family interested and eligible.

Board pearl: APOE ε4/ε4 homozygote + lecanemab + warfarin = highest ARIA risk constellation — typically defer therapy. Always check genotype and review anticoagulation before recommending.

Special Populations — Elderly and Renal/Hepatic Impairment

— ChEIs still indicated but expect more GI and cardiac side effects

— Start low, titrate slow; consider transdermal rivastigmine to bypass GI issues

— Reassess goals — symptomatic benefit may not outweigh burden in advanced frailty or limited life expectancy (<6–12 months)

— Apply Beers Criteria and STOPP/START: deprescribe anticholinergics, benzodiazepines, sedative-hypnotics, long-acting sulfonylureas, PPIs without indication

— Anticholinergic burden scales — cumulative load worsens cognition; even "minor" agents (cetirizine, ranitidine, paroxetine) add up

— Simplify regimens — once-daily dosing, blister packs, pill organizers, caregiver-administered

— Memantine: max 5 mg BID if CrCl <30

— Donepezil, rivastigmine, galantamine — predominantly hepatic metabolism, no renal adjustment

— Galantamine: avoid if severe hepatic or renal impairment (CrCl <9)

— Galantamine and rivastigmine require dose adjustment in moderate hepatic impairment; avoid in severe

— Donepezil — use with caution

— CHF/bradyarrhythmia: ChEIs can worsen bradycardia, AV block — baseline ECG; avoid if symptomatic sick sinus or 2nd/3rd degree block without pacer

— COPD/asthma: ChEIs can theoretically increase bronchial secretions — monitor but not contraindicated

— PUD/GIB history: increased ulcer risk with ChEIs; consider PPI cover if high risk

— Seizure disorder: ChEIs lower threshold — caution

— Dementia patients fall 2–3× more often

— Annual falls screen, vitamin D supplementation, home safety eval, PT for gait/balance, deprescribe sedatives

Very elderly (≥85) and frail patients:

Polypharmacy considerations:

Renal impairment:

Hepatic impairment:

Comorbidity interactions:

Falls risk:

Step 3 management: At every visit, perform a medication reconciliation with the goal of removing one drug — deprescribing is an active intervention in dementia care, not passive monitoring.

Board pearl: A frail nursing home patient with advanced AD, weight loss, and recurrent aspiration — discontinuing the ChEI is appropriate and evidence-based, not abandonment.

Special Populations — Younger-Onset and Genetic Forms

— Often presents with atypical phenotypes: posterior cortical atrophy, logopenic aphasia, frontal/dysexecutive variant

— More likely to have genetic etiology and to be initially misdiagnosed as depression, stress, or perimenopause

— Workup mandatory: MRI, neuropsych testing, CSF or amyloid PET biomarkers, genetic counseling referral

— APP (chr 21), PSEN1 (chr 14, most common), PSEN2 (chr 1)

— Onset typically 30s–50s; near-100% penetrance

— Cascading family history of early dementia → refer to genetic counseling before testing

— Children have 50% risk; predictive testing requires extensive counseling

— Triplication of APP gene → universal AD pathology by age 40, clinical dementia by 50s–60s

— Baseline cognitive assessment at age 35–40, then annual screening

— Behavioral change or new seizures may be earliest signs; use adapted tools (DSDS, NTG-EDSD)

— ChEIs reasonable but evidence weaker; lecanemab/donanemab not studied

— One copy: ~3× risk; two copies: ~10–15× risk

— Not recommended for routine population screening (psychological harm, no preventive benefit historically)

— Now relevant pre-anti-amyloid therapy decisions

— Social Security Disability Insurance — YOAD on Compassionate Allowances list (faster approval)

— FMLA, ADA accommodations, transition planning

— Pediatric-aged children at home — psychosocial support critical

Young-onset AD (YOAD): symptom onset <65 years; ~5–10% of all AD

Autosomal dominant AD (<1% of all AD, but ~10–15% of YOAD):

Down syndrome (trisomy 21):

APOE ε4 — risk factor, not deterministic:

Pregnancy: not applicable (AD presents post-reproductive age); rare YOAD in reproductive years requires individualized counseling — no AD medications are pregnancy-tested

Workplace/disability considerations for YOAD:

Board pearl: A 52-year-old with progressive word-finding difficulty, impaired repetition, MRI showing left temporoparietal atrophy → logopenic PPA, an atypical AD variant — order amyloid biomarkers, not just standard dementia workup.

Step 3 management: All suspected young-onset dementia → refer to specialty memory clinic with access to biomarkers, genetic counseling, and clinical trials.

Complications and Adverse Outcomes

— Agitation, aggression (verbal or physical)

— Psychosis: delusions (theft, infidelity, "phantom boarder," Capgras), visual hallucinations

— Depression, anxiety, apathy (apathy is most common, often confused with depression)

— Sleep-wake reversal, sundowning (worse confusion late afternoon/evening)

— Wandering, exit-seeking

— Disinhibition, sexual inappropriateness, hoarding

— Delirium from infection (UTI, pneumonia), pain, constipation, urinary retention, dehydration, medication change

— Environmental: overstimulation, unfamiliar setting, caregiver burnout

— Unmet needs: hunger, thirst, toileting, social isolation

— Falls and hip fractures — 2–3× increased; consider DEXA, vitamin D, gait training

— Aspiration pneumonia — leading cause of death; swallow evaluation in moderate-severe disease

— Malnutrition, weight loss, dysphagia

— Pressure injuries in bedbound stages

— Incontinence — urinary then fecal; rule out UTI, fecal impaction; avoid anticholinergic bladder agents

— Recurrent hospitalizations with iatrogenic harm — each hospitalization accelerates decline

— Caregiver burden, depression, financial strain, employment loss

— Screen caregivers at every visit (Zarit Burden Interview)

— Respite care, adult day programs, support groups reduce burnout

— Median survival from diagnosis 4–8 years (variable); from severe stage 1–3 years

— Direct causes of death: pneumonia, sepsis (often urinary), cachexia, cardiovascular events

Behavioral and psychological symptoms of dementia (BPSD) — affect >90% over disease course:

Triggers — always screen first before pharmacotherapy:

Medical complications:

Caregiver outcomes:

Mortality:

Step 3 management: New agitation in a moderate-AD patient → rule out delirium first (UA, CBC, BMP, exam for fecal impaction, urinary retention, pain, medication review) before prescribing antipsychotics or sedatives. Reflexive pharmacologic management is a Step 3 trap.

Board pearl: Acute behavioral change in dementia = delirium until proven otherwise; the most common occult cause in the elderly woman is UTI or constipation.

When to Escalate Care — Consults and Triage

— Young-onset (<65) or atypical presentation

— Rapid progression (<1–2 years) → consider prion disease, autoimmune encephalitis

— Diagnostic uncertainty or atypical imaging

— Eligibility evaluation for anti-amyloid therapy

— Family history suggestive of autosomal dominant disease → genetic counseling

— Refractory BPSD not responsive to first-line interventions

— Severe psychosis, aggression, or self-harm

— Polypharmacy with neuropsychiatric meds

— Suicidal ideation, treatment-resistant depression

— Acute delirium without identifiable outpatient cause

— Acute medical illness requiring IV therapy not manageable at home

— Safety crisis (caregiver collapse, abuse, severe BPSD) without alternative

— Often not aligned with patient's prior preferences — review advance directives, POLST/MOLST, healthcare proxy at admission

— Aggressive interventions (intubation, dialysis, central lines, PEG tubes) frequently inconsistent with goals in advanced dementia

— PEG tubes do not prolong survival or prevent aspiration in advanced AD — counsel family against placement

— Hospice eligibility: FAST stage 7c + complication (aspiration pneumonia, recurrent UTI, sepsis, pressure ulcer stage 3–4, weight loss >10% in 6 months, dysphagia)

— Early palliative consult improves symptom control and family satisfaction

— Comfort feeding by hand replaces tube feeding in end-stage

— Mild dementia → formal driving evaluation

— Moderate dementia → cease driving; many states have mandatory physician reporting of impaired drivers

Referral to specialist (neurology, geriatrics, memory clinic) indications:

Geriatric psychiatry consult:

Hospitalization indications (use sparingly — admission worsens dementia trajectory):

ICU-level care considerations:

Palliative care and hospice:

Driving cessation:

CCS pearl: Hospitalized dementia patient — order delirium prevention bundle: avoid restraints/Foley, mobilize daily, sleep hygiene (no overnight vitals if stable), reorientation, hearing aids/glasses on, family at bedside, scheduled (not PRN) analgesia, hold sedatives.

Board pearl: PEG tube in advanced AD is the classic "don't do it" question — favor comfort feeding and hospice.

Key Differentials — Other Dementia Types

— Stepwise decline correlating with vascular events; prominent executive dysfunction, gait apraxia, urinary urgency early

— MRI: cortical/lacunar infarcts, extensive white matter hyperintensities, microbleeds

— Often coexists with AD (mixed dementia — most common in elderly)

— Management: aggressive vascular risk factor control; ChEIs/memantine modest benefit

— Core features: fluctuating cognition (alertness/attention), recurrent well-formed visual hallucinations, REM sleep behavior disorder, spontaneous parkinsonism

— Severe neuroleptic sensitivity — avoid antipsychotics (use quetiapine if absolutely required)

— DaT scan: reduced striatal dopamine uptake

— Treat with ChEIs (especially rivastigmine — best evidence in DLB); cautious carbidopa/levodopa for motor symptoms

— Established PD (motor symptoms ≥1 year) before cognitive decline

— Otherwise overlaps with DLB clinically — 1-year rule separates them

— Onset 50s–60s, often younger than AD

— Behavioral variant: disinhibition, apathy, loss of empathy, hyperorality, compulsions, preserved memory early

— Primary progressive aphasia variants: nonfluent/agrammatic, semantic

— MRI: frontal/anterior temporal atrophy; AD biomarkers negative

— ChEIs may worsen symptoms; SSRIs for behavioral symptoms

— Memory-first, gradual, normal early exam → AD

— Visual hallucinations + RBD + parkinsonism → DLB

— Stepwise + focal signs + vascular MRI → vascular

— Behavior-first or aphasia-first in 50s–60s → FTD

Vascular dementia / vascular cognitive impairment:

Dementia with Lewy bodies (DLB):

Parkinson disease dementia (PDD):

Frontotemporal dementia (FTD):

Mixed dementia: AD + vascular pathology coexist in 30–50% of cases; treat both

Key distinction:

Board pearl: A 72-year-old with new visual hallucinations of children in the house, REM sleep behavior disorder (acts out dreams), and mild parkinsonism — diagnose DLB, prescribe rivastigmine, and avoid haloperidol at all costs.

Key Differentials — Non-Degenerative Mimics

— Acute (hours to days), fluctuating, inattention is the hallmark, altered consciousness

— Always rule out before diagnosing dementia; can occur on top of dementia

— Causes: infection, medications, metabolic, hypoxia, withdrawal, pain

— Subacute, prominent psychomotor slowing, "I don't know" answers, mood-congruent

— Treat with SSRI; cognition often improves

— Note: depression in elderly may also be prodromal AD — reassess after treatment

— Wet, wobbly, wacky — urinary incontinence, gait apraxia (magnetic gait), cognitive impairment

— MRI: ventriculomegaly out of proportion to atrophy

— Large-volume LP (tap test) — gait improvement supports diagnosis → VP shunt

— Subacute combined degeneration: posterior column + lateral CST + cognition

— Check B12; supplement IM or high-dose oral

— Argyll Robertson pupils, tabes dorsalis, personality change, dementia

— RPR/treponemal serology; CSF VDRL; IV penicillin

— Subcortical pattern; check HIV if risk factors

— Elderly fall, anticoagulation, gradual cognitive decline ± headache

— CT/MRI diagnostic; neurosurgery for evacuation

— Alcohol use, thiamine deficiency; confabulation, anterograde amnesia

— Treat with IV thiamine before glucose

— Subacute (weeks-months), psychiatric features, seizures, faciobrachial dystonic seizures (LGI1)

— Treat with immunotherapy

— Rapidly progressive (weeks-months) dementia + myoclonus + ataxia

— MRI DWI: cortical ribboning, basal ganglia hyperintensity; EEG periodic sharp waves; CSF RT-QuIC

Delirium:

Depression ("pseudodementia"):

Normal pressure hydrocephalus (NPH):

Vitamin B12 deficiency:

Hypothyroidism: TSH; treat with levothyroxine

Neurosyphilis:

HIV-associated neurocognitive disorder (HAND):

Chronic subdural hematoma:

Wernicke-Korsakoff syndrome:

Autoimmune/limbic encephalitis (anti-NMDA, anti-LGI1, paraneoplastic):

Creutzfeldt-Jakob disease (CJD):

Step 3 management: "Rapidly progressive dementia" (<1 year) — never assume AD; full workup including autoimmune panel, CSF, MRI with DWI, EEG, and consider prion testing. Refer urgently.

Board pearl: Cognitive impairment + gait disorder + incontinence + large ventricles = NPH; tap test → shunt is potentially reversible — don't miss it.

Long-Term Plan and Care Coordination

— Cognitive assessment, functional assessment, safety evaluation

— Caregiver assessment and education

— Medication review and reconciliation

— Advance care planning documentation

— Referral plan and community resources

— Required at diagnosis and updated annually

— Mild: cholinesterase inhibitor ± anti-amyloid (if eligible)

— Moderate: ChEI + memantine combination

— Severe: continue or deprescribe based on benefit; focus on comfort

— BPSD: non-pharmacologic first; brexpiprazole, citalopram, or SSRIs as targeted; avoid benzos

— BP <130/80 (avoid aggressive lowering in frail/orthostatic)

— LDL/diabetes per guidelines, but deintensify in advanced dementia and limited life expectancy

— Smoking cessation, alcohol moderation, exercise as tolerated, MIND diet

— Hearing aids, vision correction

— Influenza annually, COVID per current guidance, pneumococcal (PCV20 or PCV15+PPSV23), RSV ≥60, shingles, Tdap

— Remove firearms (mandatory conversation), lock medications, stove safety devices, GPS tracking, MedicAlert + Safe Return, grab bars, adequate lighting, simplify environment

— Driving cessation at appropriate stage

— Alzheimer's Association (800-272-3900), local chapters

— Adult day care, respite care, home health

— Eventual placement planning: assisted living → memory care unit → skilled nursing

— Durable power of attorney, healthcare proxy, will, long-term care insurance review

— Medicaid planning if assets limited

Comprehensive care plan (Medicare-reimbursable as G0505 or 99483):

Disease-stage medication management:

Vascular risk factor optimization (lifelong):

Vaccinations:

Home safety:

Caregiver support:

Financial/legal:

Step 3 management: Build a dementia care team — primary care quarterback, geriatrics or neurology, social work, pharmacy, home health, palliative care. Coordinated care reduces hospitalizations 20–30%.

Board pearl: Annual Wellness Visit cognitive assessment is mandatory under Medicare — failing to document it is both a quality and billing issue.

Follow-Up, Monitoring, and Rehab/Counseling

— Initial diagnosis: 4–6 weeks to check medication tolerance, titrate

— Stable: every 3–6 months office visits

— Annual: comprehensive reassessment with cognitive testing, functional status, caregiver status

— Acute changes (new behavior, decline, falls): urgent visit, evaluate for delirium

— Cognition: MoCA or MMSE annually (or every 6 months in early disease) — track trajectory

— Function: ADL/IADL scales; specific items (driving, finances, cooking, medications)

— Behavior: Neuropsychiatric Inventory (NPI-Q); ask about agitation, hallucinations, sleep, mood

— Weight: monthly to quarterly — unintentional loss signals decline

— Safety: falls, wandering, near-misses

— Medications: check HR with ChEI, BP, renal function, anticholinergic burden

— Caregiver: Zarit Burden Interview, depression screen, respite needs

— Cognitive stimulation therapy — group structured activities, modest benefit

— Physical therapy — gait, balance, fall prevention

— Occupational therapy — home safety, ADL adaptation, caregiver training

— Speech therapy — for swallowing evaluation, communication strategies in PPA

— Music therapy, reminiscence therapy, pet therapy — useful for BPSD

— Exercise — strongest non-pharmacologic intervention for mood, sleep, function

— Patient: stage-appropriate education, goals of care

— Family/caregiver: disease trajectory, what to expect, when to call, respite, self-care, support groups

— End-of-life preparation as disease advances — hospice timing, comfort feeding, deprescribing

Follow-up cadence:

Monitoring parameters:

On anti-amyloid therapy: surveillance MRI per protocol for ARIA; infusion reaction monitoring

Non-pharmacologic interventions and "rehab":

Counseling topics at each visit:

Step 3 management: A 6-month follow-up showing >3-point MMSE drop warrants reassessment — check for new medication issues, delirium, depression, vascular events — don't assume "just AD progression."

Board pearl: Stable cognition + worsening behavior = look for delirium/medical cause; stable behavior + steadily declining cognition = expected AD trajectory.

Ethical, Legal, and Patient Safety Considerations

— Capacity is decision-specific (medical, financial, driving, voting) and time-specific

— Patients with mild-moderate AD often retain capacity for some decisions

— Assess: understanding, appreciation, reasoning, expressing a choice

— Document carefully; involve psychiatry or ethics for complex cases

— Establish capacity before every major decision (surgery, anti-amyloid therapy, research enrollment)

— If incapacitated, defer to healthcare proxy or surrogate hierarchy per state law

— Anti-amyloid therapy — ensure patient (when capacitated) understands modest benefit, ARIA risks, infusion burden, MRI requirements; document shared decision-making

— Best done early while patient has capacity

— Discuss artificial nutrition (PEG tubes — generally not recommended in advanced AD), hospitalization preferences, CPR, intubation, dialysis

— Complete healthcare proxy, living will, POLST/MOLST

— Mild dementia → formal evaluation

— Moderate dementia → cease driving

— State-mandated reporting of unsafe drivers varies — know your state law

— Document conversation; provide written recommendations

— Physicians are mandatory reporters in all 50 states

— Suspect when bruises, malnutrition, dehydration, financial exploitation, neglect, caregiver hostility

— Report to Adult Protective Services; do not require patient consent

— Universal counseling — remove or secure firearms in homes of dementia patients

— Patient safety + caregiver safety + risk of suicide/homicide

— Surrogate consent processes vary by IRB and state; require careful capacity assessment and clear benefit-risk

— Hospital discharge is high-risk — medication reconciliation, follow-up scheduled within 7 days, clear written instructions for caregiver (low health literacy assumption), home safety eval

— Avoid new anticholinergics or benzodiazepines started in hospital from being continued at home — explicitly stop

Capacity assessment:

Informed consent:

Advance care planning:

Driving safety:

Mandatory elder abuse reporting:

Firearm safety:

Research and clinical trials:

Transitions of care:

Step 3 management: A patient with moderate AD presents with unexplained bruises and weight loss; the daughter (sole caregiver) appears overwhelmed and hostile — you must file an APS report even without definitive proof of abuse; suspicion is the threshold, not certainty.

Board pearl: Capacity to drive ≠ capacity to manage finances ≠ capacity to consent to surgery — assess each separately.

High-Yield Associations and Rapid-Fire Facts

— β-amyloid plaques (extracellular, from APP cleavage by β- and γ-secretases)

— Neurofibrillary tangles (intracellular hyperphosphorylated tau)

— Hippocampal and temporoparietal atrophy on MRI

— Cholinergic deficit (nucleus basalis of Meynert) — basis for ChEI therapy

— APP (chr 21), PSEN1 (chr 14), PSEN2 (chr 1) — autosomal dominant early-onset

— APOE ε4 — risk factor (sporadic late-onset)

— APOE ε2 — protective

— Down syndrome — universal AD pathology by age 40

— Donepezil — once-daily ChEI, GI side effects, bradycardia, vivid dreams

— Rivastigmine patch — bypasses GI, useful in dysphagia

— Galantamine — also allosterically modulates nicotinic receptors

— Memantine — NMDA antagonist, moderate-severe AD, renal adjustment

— Lecanemab/donanemab — anti-amyloid mAbs, MCI/mild AD, ARIA risk, APOE genotyping required

— Brexpiprazole — only FDA-approved antipsychotic for dementia agitation

— Anticholinergics (diphenhydramine, TCAs, oxybutynin, scopolamine)

— Benzodiazepines and Z-drugs

— Conventional antipsychotics chronically (black box mortality)

— First-generation antihistamines, muscle relaxants (Beers list)

— Drugs, Emotional (depression), Metabolic (B12, thyroid), Eyes/ears, Nutritional, Tumor/trauma (SDH), Infection (neurosyphilis, HIV), Alcohol/atherosclerosis, Subdural/sleep apnea/seizures

— Less education, hearing loss, HTN, smoking, obesity, depression, physical inactivity, diabetes, social isolation, alcohol, head injury, air pollution, vision loss

Pathology buzzwords:

Genetics:

Drugs and key facts:

Avoid in dementia (pharmacologic):

Reversible mimics mnemonic — DEMENTIAS:

Risk modifiers (Lancet Commission) — ~40% of dementia risk modifiable:

Hospice criteria: FAST 7c + complication (aspiration pneumonia, UTI, pressure ulcer stage 3–4, weight loss >10%, dysphagia, sepsis)

Board pearl: "Don't do" list in AD — PEG tubes in advanced disease, restraints, Foley catheters for convenience, chronic antipsychotics without indication, anticholinergics, benzodiazepines for sleep.

Board Question Stem Patterns

— 76-year-old with 18 months of progressive memory loss, repeating questions, missed bills; daughter reports decline; exam normal; MMSE 22/30; MRI shows medial temporal atrophy; B12, TSH, CMP normal

— Answer: Diagnose AD, start donepezil, advance care planning, caregiver support

— 78-year-old on diphenhydramine nightly for sleep + oxybutynin for OAB + paroxetine for depression; new "memory problems"

— Answer: Discontinue anticholinergics, reassess cognition in 4–6 weeks before diagnosing dementia

— 73-year-old with visual hallucinations, fluctuating attention, REM sleep behavior disorder, mild parkinsonism

— Answer: Dementia with Lewy bodies — start rivastigmine, avoid haloperidol (severe neuroleptic sensitivity)

— 75-year-old with progressive gait difficulty, urinary urgency, mild cognitive decline; MRI ventriculomegaly

— Answer: Large-volume LP (tap test) → if gait improves, VP shunt

— Nursing home patient with moderate AD, acutely worse confusion, agitation overnight

— Answer: Workup for delirium first — UA, CBC, BMP, exam for impaction/retention, medication review — not prescribe antipsychotic

— Daughter caring for father with AD presents with father's bruises, weight loss; daughter tearful, irritable

— Answer: Report to Adult Protective Services; arrange respite care and caregiver support

— Bedbound AD patient, FAST 7c, recurrent aspiration; family asks about feeding tube

— Answer: Recommend against PEG; offer comfort feeding by hand and hospice evaluation

— 68-year-old MCI with positive amyloid PET, APOE ε4/ε4 homozygote, on warfarin for AFib

— Answer: Defer lecanemab given high ARIA risk + anticoagulation

— Mild-moderate AD patient still driving, family reports near-misses

— Answer: Formal driving evaluation; if unsafe → cease driving; document and report per state law

— Patient with mild AD wants to refuse a recommended surgery; family disagrees

— Answer: Assess capacity for that specific decision; if capacitated, honor refusal; if not, defer to proxy

Pattern 1 — Classic amnestic AD:

Pattern 2 — Anticholinergic mimic:

Pattern 3 — DLB not AD:

Pattern 4 — NPH reversible cause:

Pattern 5 — Delirium superimposed on dementia:

Pattern 6 — Caregiver burnout/abuse:

Pattern 7 — Advanced AD, family wants PEG:

Pattern 8 — Anti-amyloid candidacy:

Pattern 9 — Driving safety:

Pattern 10 — Capacity question:

Board pearl: The Step 3 AD question almost always tests management priorities — what to do first, what to avoid, when to escalate, not just "what is the diagnosis."

One-Line Recap

Alzheimer disease is a clinical diagnosis of insidious, progressive amnestic dementia in older adults, confirmed by functional decline plus exclusion of reversible mimics (B12, TSH, depression, anticholinergics, NPH, subdural), managed with cholinesterase inhibitors in mild-to-moderate disease, memantine added in moderate-to-severe disease, anti-amyloid monoclonal antibodies in eligible MCI/mild dementia, and a longitudinal care plan emphasizing caregiver support, advance care planning, vascular risk reduction, and avoidance of harmful medications.

Diagnosis essentials: Informant-corroborated functional decline + cognitive screen (MoCA/MMSE) + MRI + labs (CBC, CMP, TSH, B12) — reserve PET/CSF/genetics for atypical, young-onset, or anti-amyloid candidacy

Treatment hierarchy: Mild → donepezil/rivastigmine/galantamine + optimize vascular risk + hearing aids + exercise + Mediterranean diet; Moderate → add memantine; Severe → deprescribe and pivot to comfort/hospice (FAST 7c + complication)

Avoid-at-all-costs list: Anticholinergics, benzodiazepines, chronic antipsychotics (black box mortality), PEG tubes in advanced disease, physical restraints, abrupt environment changes — every Step 3 stem rewards recognizing these

Step 3 priorities: Caregiver support (Alzheimer's Association 800-272-3900), advance care planning at diagnosis while capacity intact, driving cessation at moderate stage, firearm removal, APS reporting for suspected abuse, delirium workup before pharmacologic treatment of new behavioral change, and coordinated longitudinal care across primary care, neurology/geriatrics, social work, and palliative care

Board pearl: When in doubt on an AD question, choose the answer that addresses caregiver education, advance care planning, deprescribing, or delirium evaluation before reaching for a new drug — Step 3 rewards thoughtful longitudinal management over reflexive prescribing.