Alzheimer's and Other Dementias

Neurodegenerative (irreversible) causes

• Alzheimer's disease: amyloid-β and tau proteinopathy; the great majority are sporadic late-onset. Autosomal dominant early-onset AD arises from APP, presenilin-1, or presenilin-2 mutations — all increase Aβ42 production.
• Lewy body disease and Parkinson disease dementia: α-synuclein aggregation.
• Frontotemporal lobar degeneration: tau or TDP-43 inclusions; often familial (MAPT, GRN, C9orf72 — the last also causes ALS).
• Prion disease (Creutzfeldt–Jakob): misfolded PrP^Sc, producing dementia over weeks to months rather than years.

Vascular and structural causes

• Vascular cognitive impairment: large-vessel infarcts, lacunes, and chronic small-vessel ischemia; cerebral amyloid angiopathy contributes lobar microbleeds.
• Chronic subdural hematoma, normal pressure hydrocephalus, tumor — structural mimics that imaging must exclude.

Potentially reversible contributors examiners plant in stems

• Vitamin B12 deficiency, hypothyroidism, neurosyphilis, HIV, hepatic or uremic encephalopathy, and depression ("pseudodementia").
• Medications: anticholinergics (oxybutynin, diphenhydramine), benzodiazepines, opioids, sedating antihistamines — listed as potentially inappropriate in older adults by the AGS Beers Criteria.

Non-modifiable risk factors

• Age — the dominant risk factor; incidence rises steeply after 65.
• APOE ε4 (dose-dependent risk; ε2 appears protective), family history, and female sex for AD.
• Down syndrome: trisomy 21 carries an extra (third) copy of APP, increasing Aβ production; essentially all patients develop AD neuropathology by roughly age 40–50.

• Midlife hypertension, diabetes, obesity, dyslipidemia, smoking, physical inactivity, excess alcohol.
• Hearing loss, low educational attainment/limited cognitive reserve, social isolation, depression, traumatic brain injury, and air pollution.
• Blood pressure and vascular risk control carry the strongest randomized evidence (SPRINT MIND reduced incident MCI, with probable dementia alone a non-significant secondary endpoint). The Lancet Commission attributes roughly 40–45% of dementia risk to this cluster of modifiable factors collectively; evidence for individual interventions such as hearing aids and multidomain lifestyle programs is still evolving.

Alzheimer's Disease

• Amyloid-beta (Aβ) accumulation: Aβ42 is cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase; accumulates extracellularly as amyloid plaques; triggers neuroinflammation and microglial activation; believed to initiate pathologic cascade
• Tau hyperphosphorylation: Intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein; tau normally stabilizes microtubules; phosphorylation causes destabilization, cytoskeletal collapse, and neuronal death; spreads transneuronally in predictable patterns
• Neurodegeneration: Amyloid and tau together cause synaptic dysfunction, mitochondrial dysfunction, oxidative stress, and neuronal death; earliest changes occur in entorhinal cortex and hippocampus, progressively affecting neocortical regions
• Apolipoprotein E4 (APOE4): Genetic risk factor strongly associated with late-onset AD; homozygosity carries ~8-fold increased risk; role in amyloid clearance and neuroinflammation

Vascular Dementia

• Multi-infarct dementia from multiple lacunar infarcts in white matter and basal ganglia secondary to chronic hypertension and atherosclerotic disease
• Cerebral amyloid angiopathy (CAA) causes microhemorrhages and ischemic changes

Lewy Body Dementia

• Alpha-synuclein accumulation in intracellular Lewy bodies and Lewy neurites
• Affects cortex (cortical LBD) and substantia nigra; causes neuronal loss in basal forebrain cholinergic systems
• Can overlap with AD pathology (mixed pathology common)

Frontotemporal Dementia (FTD)

• Tau or TDP-43 (TAR DNA-binding protein 43) accumulation causing frontotemporal atrophy
• Behavioral variant involves orbitofrontal and anterior temporal regions; language variants (primary progressive aphasia) involve perisylvian regions

Normal Pressure Hydrocephalus (NPH)

• Impaired CSF absorption leading to ventricular enlargement without increased intracranial pressure
• Gait disturbance, urinary incontinence, and cognitive decline from disrupted periventricular white matter and corticospinal tract compression

Alzheimer's Disease

• Memory loss (earliest symptom): Initially short-term memory affected; patient may repeat questions, misplace objects, forget recent conversations; long-term memory preserved early
• Cognitive decline: Slowly progressive over years; involves executive function, language, visuospatial abilities; patients often lack awareness (anosognosia)
• Behavioral changes: Personality shifts, apathy, depression, anxiety; sundowning (increased confusion/agitation in evenings)
• Later stages: Mutism, inability to recognize family members, incontinence, myoclonus, rigidity, seizures in advanced disease

Vascular Dementia

• Stepwise progression: Abrupt cognitive decline following stroke events, contrasting with gradual AD decline
• Focal neurologic deficits: Hemiparesis, hemianopsia, dysarthria reflecting specific vascular territories
• Subcortical vascular dementia: Gait disturbance ("marching"), pseudobulbar palsy, emotional incontinence from white matter disease

Lewy Body Dementia

• Visual hallucinations (highly characteristic): Early, recurrent, often vivid and well-formed (people, animals); patient often maintains insight
• Parkinsonism: Bradykinesia, rigidity, postural instability (resting tremor less common than typical PD)
• Cognitive fluctuations: Pronounced variations in alertness/cognition throughout day
• REM sleep behavior disorder: Acts out dreams, often precedes cognitive symptoms by years
• Extreme neuroleptic sensitivity: Severe reactions to antipsychotics due to dopamine receptor supersensitivity

Frontotemporal Dementia

• Behavioral variant (bvFTD): Profound personality change, inappropriate behavior, disinhibition, poor judgment, loss of empathy, compulsive behaviors; memory relatively preserved early
• Primary progressive aphasia (PPA): Fluent (Wernicke-like) or non-fluent (Broca-like) language decline; semantic dementia variant involves loss of word meaning with preserved syntax
• Earlier onset: Typically 45-65 years (younger than typical AD); family history common

Normal Pressure Hydrocephalus

• Classic triad (Hakim and Adams): (1) Cognitive decline/dementia, (2) Gait disturbance ("magnetic gait"—shuffling, wide-based, feet feel stuck to floor), (3) Urinary incontinence
• Progressive presentation; responds to ventriculoperitoneal shunt in subset of patients

Important Clinical Pearls

• Distinguish dementia (irreversible, progressive) from delirium (acute, reversible, fluctuating) and depression/"pseudodementia" (subacute, mood-prominent)
• Mild cognitive impairment (MCI) is intermediate state between normal aging and dementia; 10-15% progress to dementia annually

Clinical Assessment

• Detailed history from patient and informant regarding timeline (acute vs. insidious), pattern (progressive, stepwise), specific cognitive domains affected, behavioral changes, functional decline
• Cognitive testing: Mini-Cog (3-minute screening combining clock draw and recall), Montreal Cognitive Assessment (MoCA), or Mini-Mental State Exam (MMSE) as bedside tools; neuropsychological battery provides detailed assessment across domains
• Functional status: Activities of daily living (ADLs) and instrumental ADLs (IADLs); dementia requires functional impairment

Imaging

• MRI brain (preferred): Assess for atrophy patterns (hippocampal atrophy in AD, frontal-temporal in FTD, diffuse in LBD); rule out other pathology; medial temporal lobe atrophy supports AD diagnosis
• CT brain: Rapid assessment if acute presentation or contraindications to MRI; may show normal pressure hydrocephalus (ventricular enlargement with minimal sulcal enlargement)
• PET imaging (not routine but helpful in specialist settings): Amyloid-PET and tau-PET show AD pathology; hypometabolism patterns vary by dementia type

Biomarker Testing

• Cerebrospinal fluid (CSF): Decreased Aβ42, elevated phosphorylated tau (p-tau) and total tau support AD pathology; obtained via lumbar puncture
• Blood biomarkers (increasingly important): Phosphorylated tau (p-tau181, p-tau217), phosphorylated tau/Aβ ratio, neurofilament light (NfL); non-invasive, correlate with PET findings; FDA-approved blood tests now available
• Amyloid-PET and tau-PET: Research use and specialized clinics; shows anatomic distribution of pathology

Diagnostic Criteria

• AD: Insidious onset, gradual progression, objective cognitive decline in memory ± other domains (language, visuospatial, executive, or social cognition); functional decline; supportive biomarkers (amyloid and tau) increasingly used
• Vascular dementia: Dementia with neuroimaging evidence of stroke(s) or subcortical white matter disease; temporal relationship to vascular events
• Lewy Body Dementia: Parkinsonism, hallucinations, or REM sleep behavior disorder with cognitive decline; fluctuating course
• FTD: Behavioral disin

Step 1 — exclude and treat reversible contributors

• Check TSH and vitamin B12, review the medication list, and deprescribe anticholinergics, benzodiazepines, and sedative-hypnotics (AGS Beers Criteria). Treat depression, sleep apnea, and sensory impairment.
• Superimposed delirium must be identified and worked up before attributing acute change to dementia.

Step 2 — non-pharmacologic care as the foundation

• Structured routines, caregiver education and respite, advance care planning, driving and firearm safety assessment, exercise, and management of vascular risk factors (AHA/ASA).

Symptomatic pharmacotherapy (AAN practice guidance)

• Acetylcholinesterase inhibitors — e.g., donepezil (also rivastigmine, galantamine): offset degeneration of basal forebrain cholinergic neurons; modest benefit in mild-to-moderate AD, and particularly useful in Lewy body dementia, where the cholinergic deficit is severe.
• NMDA receptor antagonist — memantine: blunts glutamatergic excitotoxicity; used in moderate-to-severe AD, alone or added to a cholinesterase inhibitor. It is not first-line in mild disease.

Disease-modifying therapy

• Anti-amyloid monoclonal antibodies — lecanemab, donanemab: clear amyloid plaque; indicated only for MCI or mild AD dementia with biomarker-confirmed amyloid, per Alzheimer's Association/AAN appropriate-use recommendations. Require baseline and serial MRI for ARIA and APOE genotyping.
• Avoid or use with great caution with concurrent anticoagulation, multiple (>4) microhemorrhages, prior lobar hemorrhage or superficial siderosis, or ***APOE* ε4 homozygosity**; counsel explicitly about elevated ARIA risk before initiation.

Neuropsychiatric symptoms

• Behavioral approaches first. The APA practice guideline restricts antipsychotics to severe agitation or psychosis causing danger or distress, at the lowest dose, with documented risk–benefit discussion and periodic taper attempts; all carry a boxed warning for increased mortality in dementia. Brexpiprazole is FDA-approved for agitation in AD dementia.

Disease-specific management

• NPH: high-volume LP (tap test), then ventriculoperitoneal shunt in responders — gait improves first and most reliably.
• bvFTD: no cholinergic therapy; SSRIs or trazodone are the preferred symptomatic agents for disinhibition and compulsive behaviors.

Contraindicated / avoid

• Typical antipsychotics (haloperidol) in Lewy body dementia — may precipitate life-threatening neuroleptic sensitivity.
• Anticholinergics and routine benzodiazepines in all dementias.
• Cholinesterase inhibitors in FTD — avoid (not beneficial, may worsen behavior) rather than a true contraindication.

Complications of the disease

• Aspiration pneumonia: loss of swallowing coordination in advanced dementia; signals include coughing with meals, recurrent fevers, and right-lower-lobe infiltrate. This is the most common immediate cause of death and is an emergency when accompanied by hypoxia or sepsis.
• Delirium superimposed on dementia: acute inattention and fluctuating consciousness in a previously stable patient. Emergency — mandates a search for infection (especially UTI/pneumonia), metabolic derangement, retention, pain, or a new drug. Do not attribute abrupt change to "progression."
• Falls, hip fracture, and subdural hematoma: impaired gait, visuospatial dysfunction, and postural instability (prominent in LBD and vascular dementia); new focal deficit or headache after a fall demands non-contrast head CT.
• Malnutrition and weight loss from apraxia of feeding and appetite loss; pressure ulcers and incontinence-related infection in immobile patients.
• Wandering/elopement, unsafe driving, financial exploitation and elder abuse — safety issues examiners expect to be addressed proactively.
• Seizures and myoclonus in advanced AD; abrupt myoclonus with rapidly progressive dementia should raise Creutzfeldt–Jakob disease.
• Caregiver burnout and depression — screen the caregiver, not just the patient.

Complications of treatment

• ARIA with anti-amyloid antibodies: vasogenic edema (ARIA-E) or microhemorrhage/siderosis (ARIA-H) from perivascular amyloid clearance; usually asymptomatic and detected on surveillance MRI, but headache, confusion, visual change, or seizure is an emergency. Risk is highest in APOE ε4 homozygotes and with concurrent anticoagulation.
• Cholinesterase inhibitors: cholinergic excess — bradycardia, syncope, AV block, nausea, diarrhea, weight loss, vivid dreams. Syncope in a patient recently started on donepezil is a classic stem.
• Antipsychotics: increased mortality and stroke; in LBD, severe rigidity and neuroleptic malignant syndrome — an emergency.
• VP shunt: subdural hematoma from over-drainage, infection, obstruction.

• Acute change in a demented patient is delirium until proven otherwise. The single best next step is a search for a precipitant (urinalysis/culture, CXR, metabolic panel, medication review) — not a dementia drug.
• Every new dementia workup gets TSH and vitamin B12, plus structural imaging. This is the reversible-cause screen examiners reward.
• Wet, wacky, and wobbly = normal pressure hydrocephalus. Gait comes first and improves first after high-volume LP or shunting; ventriculomegaly out of proportion to sulcal atrophy on CT is the imaging clue.
• Visual hallucinations + fluctuating cognition + parkinsonism + REM sleep behavior disorder = Lewy body dementia. The tested association is neuroleptic sensitivity — giving haloperidol can cause severe rigidity or NMS. The "1-year rule" separates DLB (cognition within a year of parkinsonism) from Parkinson disease dementia.
• Down syndrome patients develop AD pathology early because trisomy 21 carries an extra copy of APP.
• Young patient with disinhibition, hyperorality, and loss of empathy but preserved memory = behavioral-variant FTD, not AD. Cholinesterase inhibitors are not helpful and may worsen behavior.
• Rapidly progressive dementia over weeks with startle myoclonus = Creutzfeldt–Jakob disease; supportive findings include periodic sharp wave complexes on EEG, cortical ribboning on DWI MRI, and CSF RT-QuIC/14-3-3.
• Syncope or bradycardia after starting donepezil is cholinergic excess — check an ECG for AV block.
• Common distractors: memantine is not first-line for mild AD; anti-amyloid antibodies are only for biomarker-confirmed MCI/mild AD, not moderate-severe disease; a depressed elder with prominent "I don't know" answers and rapid onset has pseudodementia — treat the depression before labeling neurodegeneration.