Most common neurodegenerative dementia; insidious memory loss with cortical amyloid and tau pathology.
Also known as: AD, Alzheimer's disease, Alzheimer dementia
Overview
Progressive neurodegenerative disorder and the most common cause of dementia, defined pathologically by extracellular beta-amyloid plaques and intraneuronal hyperphosphorylated tau (neurofibrillary tangles), clinically presenting with insidious episodic memory loss and progressive impairment of multiple cognitive domains.
Epidemiology
Affects ~7.4 million Americans aged ≥65 (2026); accounts for 60-70% of dementia. Prevalence doubles every 5 years after age 65; reaches ~30% by age 85. Women > men (partly reflecting longer life expectancy).
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Question 1PsychiatryMedium
A 70-year-old man with moderate Alzheimer dementia is brought in by his daughter for 2 months of worsening agitation, evening wandering, and aggressive outbursts during personal care. He has no pain on examination, no fever, and no recent medication changes, and urinalysis is unremarkable. He is not an immediate danger to himself or others. Which of the following is the most appropriate initial management?
AVerbal correction and reasoning during outbursts
BStructured routine and environmental changes
CScheduled low-dose quetiapine at bedtime
DDonepezil dose increase for behavioral symptoms
EAs-needed lorazepam for agitation episodes
Reveal answer & full explanation
Correct answer: B — Structured routine and environmental changes
AVerbal correction and reasoning during outbursts
BStructured routine and environmental changes✓
CScheduled low-dose quetiapine at bedtime
DDonepezil dose increase for behavioral symptoms
EAs-needed lorazepam for agitation episodes
Why Structured routine and environmental changes is correct
Behavioral and psychological symptoms of dementia (BPSD) are managed with non-pharmacologic measures first per current guidance, including APA recommendations and the AGS Beers Criteria
A predictable daily routine, redirection, adequate daytime lighting, and caregiver education reduce agitation and wandering without drug-related harms
The stem excludes reversible triggers (no pain, fever, urinary infection, or medication change) and there is no imminent danger, so behavior-first management is appropriate
Why the others are wrong
Scheduled low-dose quetiapine at bedtime — antipsychotics carry a boxed warning for increased stroke and mortality in older adults with dementia and are reserved for severe, persistent symptoms after non-pharmacologic measures fail (right-treatment-wrong-step trap)
Donepezil dose increase for behavioral symptoms — cholinesterase inhibitors target cognition, with at best small and delayed effects on agitation, and titrating up adds bradycardia, syncope, and GI adverse effects without addressing the behavior now (right-drug-wrong-target trap)
As-needed lorazepam for agitation episodes — benzodiazepines worsen cognition and cause falls and paradoxical agitation in older adults with dementia; it tempts learners who buzzword-match agitation to an anxiolytic
Verbal correction and reasoning during outbursts — explaining and correcting can feel respectful and orienting, but a person with moderate dementia often cannot retain the correction, so arguing or reasoning during an outburst tends to escalate distress; caregivers are taught to stay calm, validate the emotion, and redirect, while the routine and environmental changes reduce triggers (reasoning-with-the-patient trap)
Question 2PsychiatryMedium
A 70-year-old man with moderate Alzheimer dementia who takes donepezil is seen in clinic with his daughter. Over the past 6 weeks, he has had frightening visual hallucinations and severe agitation at night, and he has struck his daughter twice. A consistent daily routine, daytime activity and light exposure, and caregiver redirection have not helped. On examination, he is calm and afebrile and shows no sign of pain; he is alert, his attention is at baseline, and there is no rigidity or tremor. A medication review finds no offending drug, and urinalysis, complete blood count, and basic metabolic panel are normal. His daughter asks about medication for the hallucinations and nighttime agitation. Which of the following medications is most appropriate?
ATrazodone
BDiphenhydramine
CQuetiapine
DHaloperidol
ELorazepam
Reveal answer & full explanation
Correct answer: C — Quetiapine
ATrazodone
BDiphenhydramine
CQuetiapine✓
DHaloperidol
ELorazepam
Why Quetiapine is correct
His hallucinations and agitation are dangerous, persist despite weeks of consistent nonpharmacologic measures, and occur without delirium or another reversible cause: the preconditions for an antipsychotic in dementia (APA 2016; AGS Beers 2023).
Because APA 2016 recommends against first-line haloperidol for nonemergency treatment without delirium, a low-dose second-generation antipsychotic is the choice among these options.
Quetiapine started low at bedtime (e.g., 12.5-25 mg) is sedating for nighttime symptoms and has minimal extrapyramidal effects; its low D2 affinity also makes it less likely than haloperidol to provoke neuroleptic sensitivity if Lewy body co-pathology underlies the visual hallucinations.
Its efficacy evidence is limited: APA 2016 found insufficient evidence for quetiapine and modest evidence for risperidone, olanzapine, and aripiprazole.
All antipsychotics, typical and atypical, carry an FDA boxed warning of 1.6-1.7x increased mortality from CV events and pneumonia in elderly patients with dementia; obtain informed consent, use the lowest effective dose, reassess regularly, and use the shortest course possible (taper off if there is no response after a 4-week trial; if he responds, attempt a taper within 4 months, per APA 2016).
Why the others are wrong
Lorazepam — benzodiazepines increase fall risk, worsen cognitive impairment, and cause paradoxical agitation in elderly patients with dementia, and they do not treat hallucinations; AGS Beers 2023 advises avoiding them in older adults and in dementia.
Haloperidol — the "hallucinations plus severe agitation" reflex fits hyperactive delirium or an acute emergency, where short-term low-dose haloperidol can be appropriate, but for nonemergency treatment without delirium APA 2016 recommends against it as a first-line agent. The boxed warning is shared but the risk is not: it causes more extrapyramidal effects and falls, carries excess mortality at least as high as any atypical studied and about twice quetiapine's (Maust, JAMA Psychiatry 2015), and can provoke severe neuroleptic sensitivity if Lewy body pathology is present.
Diphenhydramine — a first-generation antihistamine with strong anticholinergic effects; causes confusion, urinary retention, and worsened cognitive impairment in elderly patients, and directly opposes his donepezil; listed on the AGS Beers Criteria as potentially inappropriate (avoid).
Trazodone — a sedating antidepressant often used off-label for sleep and sundowning in dementia, but it has no antipsychotic effect on his frightening hallucinations, its evidence even for sleep in dementia is limited, and its orthostatic hypotension adds to fall risk.
Additional high-yield points
The FDA-approved drugs for agitation associated with Alzheimer dementia are brexpiprazole (2023) and dextromethorphan-bupropion (2026); both are approved for agitation, not psychosis.
Pimavanserin (Nuplazid) is FDA-approved (2016) only for hallucinations and delusions of Parkinson disease psychosis; FDA declined the dementia-related psychosis (2021) and Alzheimer disease psychosis (2022) indications.
For irregular sleep-wake rhythm in dementia, AASM 2015 suggests light therapy, suggests avoiding melatonin, and recommends against sleep-promoting drugs; Cochrane 2020 found no benefit from melatonin in Alzheimer dementia and only limited evidence for low-dose trazodone or suvorexant.
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Traumatic brain injury, hearing loss, social isolation, depression
Pathophysiology
Imbalanced production and clearance of amyloid-beta (Abeta42) → extracellular plaques. Tau becomes hyperphosphorylated and aggregates into intraneuronal neurofibrillary tangles, beginning in the entorhinal cortex and hippocampus (medial temporal) and spreading to neocortex (Braak staging). Synaptic loss, neuronal death, and cholinergic deficit (degeneration of the nucleus basalis of Meynert) produce the cognitive phenotype. Cerebral amyloid angiopathy frequently coexists.
Functional decline in IADLs (finances, medications, driving, cooking) then basic ADLs
Classic findings
Profound short-term memory loss with relatively preserved older memories and intact remote procedural memory; hippocampal/medial temporal atrophy on MRI.
Differential diagnosis
Vascular dementia — Stepwise decline, focal neurologic findings, vascular risk factors, white matter disease and infarcts on imaging; often coexists with AD ('mixed')
Lewy body dementia — Fluctuating cognition, visual hallucinations, parkinsonism (within 1 yr of dementia), REM sleep behavior disorder, neuroleptic sensitivity
Frontotemporal dementia — Behavioral/personality change (bvFTD) or progressive aphasia (primary progressive aphasia) in younger patients (50-70); memory relatively preserved early
Normal pressure hydrocephalus — 'Wet, wacky, wobbly' — urinary incontinence, cognitive impairment, magnetic gait; ventriculomegaly out of proportion to atrophy; CSF tap test responsive
Pseudodementia (depression) — Subacute, 'I don't know' answers, lack of effort, prior psychiatric history; improves with treatment of depression
Mild cognitive impairment (MCI) — Cognitive decline beyond age-expected but ADLs intact; ~10-15% per year progress to dementia
Creutzfeldt-Jakob disease — Rapidly progressive dementia, myoclonus, ataxia, periodic sharp waves on EEG, cortical ribboning on DWI
Diagnostic workup
Diagnostic criteria
NIA-AA: probable AD dementia = insidious onset, progressive cognitive decline, predominant memory or non-amnestic syndrome, exclusion of other causes. Biomarker-supported (CSF or imaging) AD if available.
Labs
Reversible-cause screen: CBC, BMP, calcium, LFTs, TSH, B12, folate; consider HIV, RPR, heavy metals if risk factors
Depression screen (PHQ-9 or GDS)
CSF biomarkers (when diagnosis unclear): decreased Abeta42, increased total and phosphorylated tau
Plasma biomarkers (p-tau217, Abeta42/40 ratio): the first FDA-cleared blood test (2025, plasma p-tau217/Abeta42 ratio) aids diagnosis in symptomatic adults ≥55 in specialty care; not a screening or stand-alone test
Imaging
MRI brain (or CT if MRI contraindicated): generalized and disproportionate medial temporal/hippocampal atrophy; excludes vascular disease, NPH, masses, subdural
FDG-PET: temporoparietal hypometabolism
Amyloid PET (florbetapir, florbetaben, flutemetamol): positive cortical amyloid; amyloid confirmation by PET or CSF biomarkers is required before anti-amyloid therapy
Tau PET (flortaucipir): research and selected clinical use
Diagnostic algorithm
flowchart TD
A[Cognitive complaint<br/>± informant concern] --> B[Cognitive screen<br/>MoCA / MMSE / Mini-Cog]
B --> C{Impairment<br/>+ functional decline?}
C -->|No, screen normal| D[Reassure, recheck<br/>in 6-12 mo]
C -->|Cognitive but ADLs intact| E[Mild Cognitive<br/>Impairment]
C -->|Yes| F[Dementia syndrome]
F --> G[Reversible-cause<br/>workup + MRI]
G --> H{Vascular,<br/>NPH, mass?}
H -->|Yes| I[Treat underlying cause]
H -->|No| J{Pattern}
J -->|Insidious memory + temporoparietal atrophy| K[Probable AD]
J -->|Fluctuating + hallucinations + parkinsonism| L[DLB]
J -->|Behavioral / aphasic, age <70| M[FTD]
K --> N[Cholinesterase inhibitor<br/>± memantine]
K --> O[Anti-amyloid mAb<br/>if early AD + amyloid+]
Diagnostic approach to suspected Alzheimer disease.
Treatment
First-line
Cholinesterase inhibitor (AChE inhibitor) — donepezil, rivastigmine (oral or transdermal patch), galantamine; modest symptomatic benefit for mild-to-moderate AD; oral rivastigmine and galantamine IR are dosed BID (rivastigmine patch and galantamine ER are once daily); side effects include nausea, diarrhea, anorexia, bradycardia, vivid dreams, urinary urgency
NMDA receptor antagonist — memantine; for moderate-to-severe AD (MMSE ≤17), may add to AChE inhibitor
Anti-amyloid monoclonal antibody therapy — lecanemab and donanemab (FDA-approved 2023-2024) for early symptomatic AD with confirmed amyloid; modestly slows cognitive decline; significant risk of amyloid-related imaging abnormalities (ARIA-E edema, ARIA-H hemorrhage), especially in APOE4 homozygotes; requires MRI monitoring
Aggressive cardiovascular risk factor control (BP, glucose, lipids); physical activity, social and cognitive engagement
Second-line / adjunct
Behavioral and psychological symptoms (BPSD): nonpharmacologic first (structured environment, redirection, music, exercise, treat pain and infection); reserve antipsychotics for severe agitation/aggression with risk of harm — black-box warning for increased mortality in elderly dementia patients (preferred: low-dose risperidone, quetiapine, or aripiprazole; avoid in DLB); brexpiprazole FDA-approved for agitation in AD
Depression: SSRIs (citalopram up to 20 mg/day in elderly due to QT, sertraline, escitalopram)
Sleep: avoid benzodiazepines and Z-drugs (delirium, falls); consider trazodone, melatonin
Caregiver support, advance care planning, driving safety assessment, capacity evaluation
Power-of-attorney, MOLST/POLST, palliative care, hospice in late stage
Complications
Progressive functional dependence and institutionalization
Wandering, falls, fractures
Aspiration pneumonia (often terminal)
Pressure ulcers, malnutrition, weight loss
Caregiver burden and depression
Polypharmacy and adverse drug events
Driving and firearm safety concerns
PANCE pearls
Memory loss alone does not equal dementia — must impair daily function. Memory loss with preserved function = mild cognitive impairment (MCI).
Hallmark of AD memory loss is impaired storage (no benefit from cues), distinguishing it from subcortical or depression-related retrieval failure (which improves with cues).
Always screen for reversible causes (TSH, B12, depression) and review medication list for anticholinergics.
APOE4 testing is NOT recommended for routine diagnosis or risk prediction; it does inform ARIA risk before starting anti-amyloid therapy.
Avoid restraints and antipsychotics for delirium superimposed on dementia when possible — address underlying medical cause first.
Late-onset visual hallucinations without dementia in elderly with vision loss may be Charles Bonnet syndrome, not Alzheimer or DLB.
References
Alzheimer's Association 2024 — Revised Criteria for Diagnosis and Staging of Alzheimer's Disease: Alzheimer's Association Workgroup (Jack et al., Alzheimers Dement 2024;20:5143-5169)
NIA-AA 2011/2018 — Diagnostic Guidelines for Alzheimer's Disease (McKhann et al., Alzheimers Dement 2011; Jack et al., 2018 Research Framework)
CLARITY-AD Trial — Lecanemab in Early Alzheimer's Disease (van Dyck et al., NEJM 2023)
TRAILBLAZER-ALZ 2 — Donanemab in Early Symptomatic Alzheimer Disease (Sims et al., JAMA 2023)
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