Neurodegenerative Disorders

Alzheimer Disease

Core Definition and Epidemiology

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in older adults. Dementia is an acquired decline in cognition severe enough to impair independent function, with preserved consciousness. AD classically presents after age 65 years with insidious impairment of episodic memory, followed by language, visuospatial, executive, and behavioral dysfunction. Age is the strongest risk factor; prevalence approximately doubles every 5 years after age 65. Early-onset familial AD accounts for <5% of cases.

Molecular Pathogenesis

AD is defined pathologically by extracellular amyloid-β plaques and intracellular neurofibrillary tangles, causing synaptic dysfunction, neuronal loss, cortical atrophy, and neurotransmitter deficits, especially reduced acetylcholine from degeneration of the nucleus basalis of Meynert.

Pathologic Feature	Composition	Mechanism	High-Yield Association
Neuritic plaques	Extracellular Aβ-amyloid, especially Aβ42	Abnormal processing of amyloid precursor protein by β- and γ-secretases	Congo red positive; apple-green birefringence
Neurofibrillary tangles	Intracellular hyperphosphorylated tau	Microtubule destabilization and impaired axonal transport	Correlate strongly with clinical severity
Cerebral amyloid angiopathy	Aβ deposition in vessel walls	Vascular fragility	Lobar intracerebral hemorrhage in older adults

Amyloid precursor protein (APP) is located on chromosome 21; this explains the high risk of early AD pathology in Down syndrome, often with amyloid deposition by age 40. Familial early-onset AD is associated with mutations in APP, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1. Presenilins are components of γ-secretase and increase production of aggregation-prone Aβ42. The strongest genetic risk factor for late-onset sporadic AD is APOE ε4; APOE ε2 is relatively protective. APOE ε4 impairs amyloid clearance and increases deposition.

Neuroanatomy and Gross Pathology

AD begins prominently in the hippocampus and entorhinal cortex, explaining early inability to form new memories. Grossly, there is diffuse cortical atrophy with narrowed gyri, widened sulci, and enlarged ventricles due to ex vacuo dilation. The temporal and parietal association cortices are classically involved; primary sensory and motor cortices are relatively spared until late disease.

Clinical Features and Staging

The typical course is gradual and progressive over 8–10 years. Early disease features short-term memory loss, repetition, misplacing objects, and getting lost. As disease advances, patients develop aphasia, apraxia, agnosia, visuospatial impairment, personality changes, hallucinations, delusions, and loss of activities of daily living. Late disease includes incontinence, dysphagia, immobility, and increased infection risk.

Stage	Typical Findings	Approximate MMSE
Mild	Short-term memory loss, impaired complex tasks, preserved basic activities	21–26
Moderate	Disorientation, language impairment, loss of instrumental activities	10–20
Severe	Dependent for basic activities, minimal speech, incontinence, dysphagia	<10

The Mini-Mental State Examination is scored from 0–30; scores <24 suggest cognitive impairment, though education and language affect interpretation. The MoCA is also scored from 0–30; a common abnormal cutoff is <26 and it is more sensitive for mild cognitive impairment.

Diagnosis and Biomarkers

On Step 1, AD is primarily a clinical-pathologic diagnosis. Laboratory evaluation in real patients excludes reversible causes of cognitive impairment, especially TSH abnormalities and vitamin B12 deficiency. Neuroimaging may show hippocampal and cortical atrophy. Cerebrospinal fluid typically shows decreased Aβ42 with increased total tau and phosphorylated tau. Amyloid PET demonstrates amyloid deposition but is not required for classic exam diagnosis.

Pharmacology

Treatment is symptomatic and does not cure established AD. Cholinesterase inhibitors increase synaptic acetylcholine and may modestly improve cognition or slow decline. Adverse effects reflect muscarinic excess: nausea, vomiting, diarrhea, bradycardia, syncope, bronchospasm, and increased gastric acid secretion.

Drug	Mechanism	Typical Dose Range	Half-Life	Key Toxicities
Donepezil	Reversible acetylcholinesterase inhibitor	5–10 mg orally nightly; severe AD up to 23 mg/day	~70 h	GI upset, bradycardia, insomnia
Rivastigmine	Acetylcholinesterase and butyrylcholinesterase inhibitor	1.5–6 mg orally twice daily or transdermal patch 4.6–13.3 mg/24 h	~1.5 h	GI upset, weight loss
Galantamine	Acetylcholinesterase inhibitor; nicotinic receptor modulation	8–24 mg/day orally	~7 h	GI upset, dizziness
Memantine	NMDA receptor antagonist; reduces excitotoxic glutamate signaling	5–20 mg/day orally	~60–80 h	Dizziness, confusion, constipation

Memantine is generally used in moderate-to-severe disease, often with a cholinesterase inhibitor. Anti-amyloid monoclonal antibodies, such as lecanemab, target aggregated amyloid and are relevant to current practice but less central for Step 1. In the phase 3 CLARITY-AD trial, lecanemab slowed decline on the Clinical Dementia Rating–Sum of Boxes by about 27% over 18 months in early AD, but can cause amyloid-related imaging abnormalities, including edema and hemorrhage, especially in APOE ε4 carriers.

High-Yield Differentiation

• Alzheimer disease: early episodic memory loss; hippocampal atrophy; plaques and tangles.
• Vascular dementia: stepwise decline after infarcts; focal neurologic deficits; vascular risk factors.
• Dementia with Lewy bodies: fluctuating cognition, visual hallucinations, parkinsonism, REM sleep behavior disorder.
• Frontotemporal dementia: early personality, disinhibition, apathy, or language-predominant deficits with relative early memory sparing.

Parkinson Disease

Core Pathology and Epidemiology

Parkinson disease (PD) is a progressive neurodegenerative movement disorder caused by loss of dopaminergic neurons in the substantia nigra pars compacta, which project to the striatum. Clinically apparent parkinsonism usually requires approximately 50–70% loss of nigral neurons and about 80% depletion of striatal dopamine. PD affects about 1% of individuals older than 60 years, with mean onset near age 60; earlier onset suggests a genetic cause.

The classic gross finding is depigmentation of the substantia nigra. The classic microscopic finding is the Lewy body: an intracytoplasmic eosinophilic inclusion composed mainly of misfolded α-synuclein and ubiquitin. α-Synuclein accumulation also explains overlap with dementia with Lewy bodies and some autonomic/nonmotor manifestations.

Basal Ganglia Mechanism

The basal ganglia regulate movement through two major pathways. Dopamine from the substantia nigra normally facilitates movement by stimulating D1 receptors in the direct pathway and inhibiting D2 receptors in the indirect pathway.

• Direct pathway: cortex → striatum → inhibits GPi/SNr → disinhibits thalamus → increases cortical motor activity.
• Indirect pathway: cortex → striatum → inhibits GPe → disinhibits subthalamic nucleus → excites GPi/SNr → inhibits thalamus → decreases cortical motor activity.
• In PD: dopamine loss decreases direct pathway activity and increases indirect pathway activity, producing excessive thalamic inhibition and bradykinesia.

Environmental and toxic associations include MPTP, a contaminant of illicit meperidine analogs. MPTP is converted by MAO-B to MPP+, taken up by dopaminergic neurons, and inhibits mitochondrial complex I, causing parkinsonism.

Clinical Features

The motor syndrome is classically remembered as TRAP: Tremor, Rigidity, Akinesia/bradykinesia, and Postural instability. Diagnosis is clinical; a key feature is bradykinesia plus rest tremor or rigidity, typically beginning asymmetrically.

• Resting tremor: “pill-rolling,” usually 4–6 Hz, decreases with voluntary movement.
• Rigidity: “cogwheel” rigidity from tremor superimposed on increased tone.
• Bradykinesia: slowness and decrement in amplitude of repetitive movements; often most disabling.
• Gait: shuffling gait, reduced arm swing, difficulty initiating movement, festination.
• Postural instability: tends to occur later and increases fall risk.

Nonmotor features are high yield: anosmia, constipation, REM sleep behavior disorder, depression, autonomic dysfunction, orthostatic hypotension, urinary symptoms, erectile dysfunction, and later cognitive impairment. Psychosis and visual hallucinations may reflect advanced disease or dopaminergic therapy.

Genetics and Classification

Gene/Factor	Inheritance/Association	High-yield mechanism
SNCA	Autosomal dominant	α-Synuclein overproduction/misfolding; Lewy body formation
LRRK2	Autosomal dominant	Kinase mutation; common familial PD cause
PARK2/parkin, PINK1, DJ-1	Autosomal recessive	Early-onset PD; impaired mitochondrial quality control/proteostasis
GBA	Risk factor	Lysosomal dysfunction; increased PD and Lewy body risk

Staging and Scoring

The Hoehn and Yahr scale is a simple clinical staging system: stage 1 is unilateral disease; stage 2 is bilateral disease without balance impairment; stage 3 includes postural instability but preserved independence; stage 4 is severe disability but able to stand/walk; stage 5 is wheelchair-bound or bedridden unless aided. The Unified Parkinson Disease Rating Scale (UPDRS) quantifies mentation, activities of daily living, motor examination, and treatment complications; it is commonly used in trials.

Pharmacology

Therapy is symptomatic and aims to restore dopaminergic signaling or rebalance dopamine-acetylcholine tone. It does not clearly stop neurodegeneration. Current guideline-based practice generally favors levodopa as the most effective initial motor therapy, especially in older patients or those with significant functional impairment.

Drug/Class	Typical dosing facts	Mechanism	Important adverse effects
Carbidopa/levodopa	Common start: 25/100 mg orally 3 times daily; levodopa half-life about 1–2 hours	Levodopa crosses BBB and is converted to dopamine; carbidopa inhibits peripheral dopa decarboxylase	Nausea, orthostatic hypotension, hallucinations, dyskinesias, “wearing-off”
Dopamine agonists: pramipexole, ropinirole, rotigotine	Pramipexole often starts 0.125 mg TID; ropinirole 0.25 mg TID	Directly stimulate dopamine receptors	Sleep attacks, edema, hallucinations, impulse-control disorders
MAO-B inhibitors: selegiline, rasagiline, safinamide	Selegiline commonly 5 mg twice daily	Decrease dopamine breakdown in CNS	Insomnia, serotonin syndrome risk with serotonergic drugs
COMT inhibitors: entacapone, tolcapone, opicapone	Entacapone 200 mg with each levodopa dose	Prolong levodopa effect by inhibiting peripheral catechol-O-methyltransferase	Diarrhea, orange urine; tolcapone can cause hepatotoxicity
Amantadine	Often 100 mg twice daily	Increases dopamine release; NMDA receptor antagonism	Livedo reticularis, ankle edema, confusion
Antimuscarinics: benztropine, trihexyphenidyl	Benztropine often 0.5–1 mg daily to BID	Reduce relative cholinergic excess in striatum	Dry mouth, urinary retention, constipation, confusion; best for tremor in younger patients

Deep brain stimulation of the subthalamic nucleus or globus pallidus interna can improve motor fluctuations and tremor in selected patients, but Step 1 emphasis is the circuit: reducing overactivity of inhibitory basal ganglia output improves thalamocortical motor drive.

Huntington Disease

Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder classically characterized by chorea, psychiatric disturbance, and cognitive decline. It is a prototypical trinucleotide repeat expansion disorder and a high-yield example of anticipation, in which disease occurs earlier and often more severely in successive generations.

Genetics and Molecular Pathogenesis

HD is caused by expansion of a CAG trinucleotide repeat in the HTT gene on chromosome 4p16.3. CAG encodes glutamine, so expansion produces an abnormal polyglutamine tract in the huntingtin protein. The mutant protein has a toxic gain-of-function, leading to misfolding, impaired proteostasis, mitochondrial dysfunction, transcriptional dysregulation, excitotoxicity, and neuronal death. Pathologically, neurons show ubiquitinated intranuclear inclusions.

CAG Repeat Number	Interpretation	Clinical Significance
≤26	Normal	No HD; stable transmission
27-35	Intermediate / mutable normal	Unaffected individual, but repeat may expand in offspring
36-39	Reduced penetrance	May or may not develop HD
≥40	Full penetrance	Expected to develop HD with normal lifespan
>60	Large expansion	Often juvenile-onset HD

Anticipation is especially associated with paternal transmission, because CAG repeats are more likely to expand during spermatogenesis. Thus, an affected father may have a child with earlier-onset disease. Each child of an affected heterozygous parent has a 50% risk of inheriting the pathogenic allele.

Neuroanatomy and Basal Ganglia Mechanism

The earliest and most prominent degeneration occurs in the striatum, especially the caudate nucleus and putamen. The most vulnerable neurons are GABAergic medium spiny neurons of the indirect pathway, particularly those containing enkephalin.

To understand chorea, recall that the basal ganglia regulate movement through direct and indirect pathways. The direct pathway facilitates movement, whereas the indirect pathway suppresses unwanted movement. In early HD, loss of striatal GABAergic neurons in the indirect pathway decreases inhibition of movement. This leads to excessive thalamocortical activation and produces hyperkinetic choreiform movements. Later, more widespread striatal degeneration may produce rigidity, dystonia, and bradykinesia, especially in juvenile disease.

Gross pathology shows caudate atrophy with secondary enlargement of the frontal horns of the lateral ventricles, sometimes described as “boxcar ventricles.” MRI or CT may demonstrate marked caudate volume loss.

Clinical Features

Typical adult-onset HD presents between ages 30 and 50 years. The classic triad is:

• Motor: chorea, motor impersistence, abnormal saccades, dysarthria, dysphagia, gait instability, and later dystonia or parkinsonism.
• Psychiatric: depression, irritability, impulsivity, aggression, obsessive-compulsive symptoms, psychosis, and increased suicide risk. Psychiatric symptoms may precede motor findings.
• Cognitive: progressive subcortical dementia with impaired executive function, slowed processing, poor attention, and impaired planning; memory encoding is less severely affected early than in Alzheimer disease.

Juvenile Huntington disease, often associated with very large paternal expansions, presents before age 20 years. It more commonly causes rigidity, bradykinesia, seizures, dystonia, and cognitive decline rather than prominent chorea. This is sometimes called the Westphal variant.

Diagnosis and Staging

The diagnosis is confirmed by molecular genetic testing showing an expanded CAG repeat in HTT. Testing is highly sensitive and specific when repeat sizing is performed. Neuroimaging is supportive but not required. Predictive testing of asymptomatic adults requires careful counseling because there is no curative therapy; testing of minors is generally avoided unless symptoms are present.

Assessment Tool	Use	Key Point
Unified Huntington Disease Rating Scale	Motor, cognitive, behavioral, and functional assessment	Commonly used in clinical trials and longitudinal monitoring
Total Functional Capacity score	Functional staging	Ranges from 13 normal function to 0 complete dependence
Shoulson-Fahn stages	Disease stage classification	Stage I: TFC 11-13; Stage V: TFC 0-1

Pharmacology and Symptomatic Treatment

There is currently no disease-modifying therapy for HD. Treatment is symptomatic and focuses on chorea, psychiatric disease, sleep, nutrition, swallowing safety, and caregiver support. For Step 1, the highest-yield pharmacology is inhibition of monoamine packaging to reduce hyperkinetic movements.

Drug	Mechanism	Typical Dose Range	Key Adverse Effects
Tetrabenazine	VMAT2 inhibitor; depletes presynaptic dopamine, serotonin, norepinephrine	Start 12.5 mg daily; titrate weekly; usual 25-75 mg/day; maximum 100 mg/day	Depression, suicidality, parkinsonism, akathisia, sedation, QT prolongation
Deutetrabenazine	Deuterated VMAT2 inhibitor with longer exposure	Start 6 mg daily; titrate weekly; maximum 48 mg/day	Similar to tetrabenazine; may have smoother pharmacokinetics
Antipsychotics, e.g., risperidone or olanzapine	Dopamine D2 receptor antagonism	Agent-specific; low-dose initiation is typical	Extrapyramidal symptoms, metabolic syndrome, sedation

Tetrabenazine is metabolized partly by CYP2D6; if doses exceed 50 mg/day, CYP2D6 genotyping is recommended in prescribing information. Poor metabolizers or patients taking strong CYP2D6 inhibitors generally should not exceed 50 mg/day. VMAT2 inhibitors are avoided or used cautiously in patients with active untreated depression or suicidality.

High-Yield Differentiation

HD should be distinguished from other causes of chorea. Sydenham chorea follows group A streptococcal infection and is associated with rheumatic fever. Wilson disease may cause movement disorders in younger patients and involves ATP7B mutation, low ceruloplasmin, hepatic disease, and Kayser-Fleischer rings. Drug-induced chorea can occur with levodopa, stimulants, and some antipsychotic-related tardive syndromes. The combination of autosomal dominant inheritance, adult-onset chorea, psychiatric symptoms, caudate atrophy, and CAG expansion on chromosome 4 is classic for Huntington disease.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper motor neurons (UMNs) and lower motor neurons (LMNs). The name is descriptive: a- “no,” myo “muscle,” and trophic “nourishment” refers to denervation-related muscle wasting; lateral sclerosis refers to gliosis and degeneration of the lateral corticospinal tracts. ALS is high-yield because it produces combined UMN and LMN signs with preserved sensation.

Pathophysiology and Neuropathology

ALS involves degeneration of motor neurons in the primary motor cortex, corticospinal tracts, anterior horn cells of the spinal cord, and motor nuclei of the brainstem, especially the hypoglossal nucleus and nucleus ambiguus. Sensory neurons, dorsal columns, extraocular motor neurons, and autonomic pathways are relatively spared, explaining the classic absence of sensory loss, ophthalmoplegia, and bowel/bladder dysfunction.

The central molecular lesion in most ALS is abnormal protein homeostasis with cytoplasmic inclusions. Most sporadic ALS and many familial cases show TDP-43 aggregation, a DNA/RNA-binding protein involved in RNA splicing and transport. Mislocalized TDP-43 causes toxic gain-of-function and loss of normal nuclear RNA processing. Other mechanisms include glutamate excitotoxicity, mitochondrial dysfunction, oxidative injury, impaired axonal transport, neuroinflammation via microglia/astrocytes, and defective autophagy-proteasome degradation.

ALS subtype/gene	Approximate association	Mechanistic concept	High-yield association
Sporadic ALS	~90% of cases	Usually TDP-43 proteinopathy	Most common form; no family history
Familial ALS	~5%–10% of cases	Often autosomal dominant	Earlier onset may occur
C9orf72 hexanucleotide repeat expansion	Most common inherited ALS cause	RNA toxicity, dipeptide repeat proteins	Strong link to frontotemporal dementia
SOD1	Classic familial ALS gene	Mutant superoxide dismutase causes oxidative/protein misfolding toxicity	TDP-43 inclusions often absent in SOD1 ALS
TARDBP, FUS	Less common familial causes	RNA-binding protein dysfunction	Protein aggregation disorders

Clinical Features

ALS usually begins between ages 55 and 75 years. Incidence is approximately 1–2 per 100,000 persons/year, with prevalence around 5 per 100,000. Median survival is 3–5 years after symptom onset, most commonly due to respiratory failure from diaphragmatic and intercostal muscle weakness.

The classic presentation is asymmetric limb weakness that progresses regionally. LMN degeneration causes flaccid weakness, muscle atrophy, fasciculations, and cramps. UMN degeneration causes spasticity, hyperreflexia, clonus, and Babinski sign. Bulbar involvement produces dysarthria, dysphagia, tongue atrophy, tongue fasciculations, and aspiration risk. Pseudobulbar affect—uncontrolled laughing or crying—can occur due to corticobulbar tract involvement.

• UMN signs: increased tone, brisk reflexes, Babinski sign, spastic gait.
• LMN signs: fasciculations, fibrillations on EMG, decreased tone, atrophy, weakness.
• Typically spared: sensation, cognition early in most cases, eye movements, sphincter function.
• Important exception: ALS overlaps with frontotemporal dementia, especially in C9orf72 disease.

Diagnosis, Classification, and Scoring

ALS is primarily a clinical diagnosis supported by electrodiagnostic testing. Electromyography (EMG) shows active and chronic denervation: fibrillation potentials, positive sharp waves, fasciculation potentials, and large-amplitude motor unit potentials from reinnervation. Nerve conduction studies are typically normal for sensory nerves, helping distinguish ALS from peripheral neuropathies. MRI and laboratory testing are used mainly to exclude mimics such as cervical myelopathy, multifocal motor neuropathy, myasthenia gravis, B12 deficiency, and structural lesions.

The revised El Escorial criteria classify ALS based on UMN and LMN involvement across body regions: bulbar, cervical, thoracic, and lumbosacral. The Awaji criteria increase sensitivity by allowing EMG fasciculations to count as evidence of active denervation in the correct context.

Tool	Key concept	Numerical feature
ALSFRS-R	Functional staging scale assessing speech, swallowing, handwriting, walking, dyspnea, orthopnea, respiratory insufficiency, and ADLs	12 items scored 0–4; total 0–48, with lower scores indicating worse function
Forced vital capacity (FVC)	Respiratory muscle strength marker	Decline predicts mortality; <50% predicted is a classic threshold for significant ventilatory impairment

Pharmacology and Disease-Modifying Therapy

There is no curative therapy, but several drugs modestly slow progression or target defined genetic subtypes. For Step 1, focus on mechanisms rather than detailed specialty management.

Drug	Dose	Mechanism	High-yield adverse effects/data
Riluzole	50 mg orally every 12 hours, taken 1 hour before or 2 hours after meals	Reduces glutamatergic transmission; inhibits presynaptic glutamate release and voltage-gated Na+ channels	Half-life ~12 hours; improves survival by about 2–3 months; monitor aminotransferases for hepatotoxicity
Edaravone	60 mg IV daily in treatment cycles; oral formulations also exist	Free-radical scavenger reducing oxidative stress	Half-life ~4.5–6 hours; trial in early ALS slowed ALSFRS-R decline over 24 weeks, approximately −5.0 vs −7.5 points
Tofersen	100 mg intrathecal loading doses followed by every-28-day maintenance	Antisense oligonucleotide reducing SOD1 mRNA/protein	For SOD1-mutant ALS; illustrates precision therapy targeting toxic gain-of-function protein

High-Yield Differentials

Disorder	Distinguishing feature from ALS
Myasthenia gravis	Fluctuating fatigable weakness, ocular involvement, normal reflexes/sensation, anti-AChR antibodies
Multiple sclerosis	CNS demyelination with sensory symptoms, optic neuritis, internuclear ophthalmoplegia
Cervical spondylotic myelopathy	Structural cord compression; may have sensory level or neck pain
Poliomyelitis or spinal muscular atrophy	Predominantly LMN findings without UMN signs

USMLE takeaway: ALS is the prototype of a motor neuron disease causing simultaneous UMN and LMN findings, with progressive weakness, fasciculations, atrophy, hyperreflexia, preserved sensation, and death from respiratory failure.

Frontotemporal Dementia

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders characterized by progressive degeneration of the frontal and/or anterior temporal lobes, producing early changes in personality, behavior, executive function, or language. It is a major cause of early-onset dementia, typically presenting between ages 45–65 years, and is often more rapidly progressive than Alzheimer disease. Unlike Alzheimer disease, early memory and visuospatial function may be relatively preserved.

Core Neuropathology and Mechanisms

The pathologic umbrella term is frontotemporal lobar degeneration (FTLD). Grossly, the brain may show marked, asymmetric frontal and temporal cortical atrophy, sometimes described as “knife-edge” atrophy due to severe narrowing of gyri. Microscopically, there is neuronal loss, gliosis, and protein aggregation. The major molecular subtypes are defined by the dominant misfolded protein.

FTLD subtype	Protein abnormality	High-yield associations
FTLD-tau	Hyperphosphorylated tau aggregates	Pick disease, corticobasal degeneration, progressive supranuclear palsy; MAPT mutations
FTLD-TDP	TDP-43 inclusions	Most common FTLD pathology; associated with GRN and C9orf72; overlaps with ALS
FTLD-FUS	FUS protein inclusions	Less common; often younger onset

Pick disease is a classic FTLD-tau disorder. Histology shows Pick bodies, which are round, intracytoplasmic, tau-positive inclusions, and Pick cells, which are swollen achromatic neurons. On Step 1, FTD is strongly associated with frontal disinhibition and personality change, while Alzheimer disease is associated with early episodic memory impairment, amyloid-β plaques, and neurofibrillary tangles.

Clinical Classification

FTD is classified clinically into behavioral and language-predominant syndromes. These clinical phenotypes do not perfectly predict the underlying protein pathology, but they are highly testable.

Variant	Primary deficit	Typical features
Behavioral variant FTD	Frontal executive and social cognition dysfunction	Disinhibition, apathy, loss of empathy, compulsive behaviors, hyperorality, poor judgment
Semantic variant primary progressive aphasia	Loss of word and object meaning	Fluent speech with impaired naming and single-word comprehension; anterior temporal atrophy
Nonfluent/agrammatic primary progressive aphasia	Speech production and grammar	Effortful, halting speech, agrammatism, apraxia of speech; often left frontal-insular atrophy

The Rascovsky criteria for possible behavioral variant FTD require progressive deterioration plus at least 3 of 6 early features: behavioral disinhibition, apathy/inertia, loss of sympathy or empathy, perseverative or compulsive behavior, hyperorality/dietary change, and executive dysfunction with relative sparing of memory and visuospatial skills.

Genetics and ALS Overlap

Approximately 30–40% of FTD cases have a family history, and about 10–15% are autosomal dominant. Key genes include MAPT on chromosome 17, encoding tau; GRN, encoding progranulin; and C9orf72, a hexanucleotide repeat expansion that can cause both FTD and amyotrophic lateral sclerosis (ALS). This explains why some patients develop combined cognitive-behavioral decline and upper/lower motor neuron signs. TDP-43 pathology is a major mechanistic bridge between FTD and ALS.

Diagnosis and Step 1 Differentiation

Diagnosis is clinical, supported by neuropsychological testing and neuroimaging. MRI often shows focal frontal and/or anterior temporal atrophy; FDG-PET may show frontal or temporal hypometabolism. Alzheimer biomarkers, such as low CSF amyloid-β42 with elevated phosphorylated tau, are more typical of Alzheimer disease than FTD. Standard cognitive screens such as the MMSE may be falsely reassuring early because memory and orientation can be preserved. The Montreal Cognitive Assessment (MoCA), scored out of 30 with scores below 26 often considered abnormal, is more sensitive to executive dysfunction but is not specific for FTD.

Feature	FTD	Alzheimer disease
Typical onset	45–65 years	Usually >65 years
Early symptoms	Personality, disinhibition, apathy, language	Episodic memory loss
Primary regions	Frontal/anterior temporal lobes	Hippocampus, temporoparietal cortex
Classic pathology	Tau, TDP-43, or FUS inclusions; Pick bodies in Pick disease	Amyloid plaques and tau neurofibrillary tangles

Management Principles and Pharmacology

No disease-modifying therapy is approved for FTD. Management is supportive: safety supervision, caregiver education, speech-language therapy for aphasic variants, and treatment of behavioral symptoms. Cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine are not routinely recommended because FTD is not primarily a cholinergic-deficiency disorder and symptoms may worsen. Memantine, an NMDA receptor antagonist used in Alzheimer disease, has not shown clear benefit in FTD.

Medication class	Use in FTD	Typical adult dose range
SSRIs	May reduce disinhibition, compulsions, irritability, or hyperorality	Sertraline 25–200 mg/day; citalopram 10–20 mg/day in older adults due to QT risk
Trazodone	May help agitation, sleep disturbance, or behavioral symptoms	Often 25–100 mg at bedtime or divided dosing
Atypical antipsychotics	Reserved for severe dangerous agitation or psychosis	Use lowest effective dose; increased mortality warning in dementia-related psychosis

High-yield exam clue: a middle-aged patient with progressive personality change, socially inappropriate behavior, loss of empathy, compulsive eating, and frontal/anterior temporal atrophy most strongly suggests frontotemporal dementia, not Alzheimer disease or primary psychiatric illness.