A Research Guide for
Facing Frontotemporal Dementia

LANDMARK DISCOVERY In 2011, DeJesus-Hernandez et al. and Renton et al. simultaneously reported that a GGGGCC hexanucleotide repeat expansion in C9orf72 causes familial ALS and FTD. Before this, one-third of familial FTD had no known genetic cause. The discovery explained 25–40% of familial FTD and 40–50% of familial ALS, revealed the two conditions as a biological continuum, and established C9orf72 as the field’s primary therapeutic target. Every gene-targeted therapy now in development for C9orf72-related FTD traces directly to this discovery.

FUNDAMENTAL DISCOVERY Neumann et al. (Science, 2006) identified TDP-43 as the primary pathological protein in most non-tau FTD and ALS. TDP-43 normally functions as a nuclear RNA-binding protein; in FTD and ALS it mislocalizes to cytoplasmic aggregates, depleting the nucleus of its regulatory function. TDP-43 pathology accounts for ~60% of all FTD across four subtypes: Type A (GRN mutations, bvFTD/nfvPPA), Type B (C9orf72, FTD-ALS), Type C (svPPA, sporadic), and Type D (VCP mutations, rare).

ACTIVE THERAPEUTIC TARGET GRN haploinsufficiency causes FTD by reducing progranulin to ~50% of normal. Therapeutic approaches include: anti-sortilin antibody latozinemab (AL001, INFRONT-3 NCT04374136 — missed clinical endpoint October 2025, met progranulin biomarker endpoint; development future uncertain); AAV9 gene therapy PR006/Prevail/Lilly (NCT04408625, Phase 1/2 safety and progranulin-raising data evaluating); and AAV GRN gene therapies PBFT02 (Passage Bio, upliFT-D NCT04747431) and AVB-101 (AviadoBio, ASPIRE-FTD NCT06064890). Despite INFRONT-3’s negative clinical result, gene therapy approaches remain active as potentially more durable restoration strategies.

MAJOR DIAGNOSTIC ADVANCE Ultrasensitive immunoassays now enable blood-based measurement of disease-relevant proteins. Plasma NfL: elevated in FTD across all variants; correlates with atrophy rate; rises 5–10 years before symptom onset in presymptomatic carriers (GENFI data); used as trial endpoint. Plasma pTau181/pTau217: lower in FTD vs Alzheimer’s disease — low result argues against AD pathology, supporting FTD diagnosis. ALZpath pTau217 shows AUC ~0.96 for AD vs non-AD discrimination. Plasma progranulin: ~50% of normal in GRN mutation carriers; practical first-line screen before formal genetic testing. Important caveat: lvPPA often has Alzheimer’s pathology and may show elevated pTau — always interpret in clinical context.

PLATFORM STUDY The Genetic Frontotemporal dementia Initiative (GENFI), founded by Dr. Jonathan Rohrer at UCL, has enrolled over 700 C9orf72, GRN, and MAPT mutation carriers and their non-carrier family members at 30+ centers. Key findings: brain atrophy begins 10–20 years before expected symptom onset; NfL rises ~5–10 years before symptoms; subtle cognitive and behavioral changes detectable 2–5 years before clinical diagnosis. GENFI data have powered more than 100 publications and are the scientific backbone for all genetic FTD prevention trial designs.

CONCEPTUAL ADVANCE FTD and ALS share underlying biology — both mediated by TDP-43 pathology and united by C9orf72 genetics. ~10–15% of FTD patients develop ALS symptoms; ~50% of ALS patients show frontal cognitive/behavioral changes. The same C9orf72 mutation can produce ALS in one family member, FTD in another, and FTD-ALS in a third. ALS centers should screen for cognitive/behavioral changes; FTD centers should screen for motor neuron signs. Therapies targeting C9orf72 may be relevant to both conditions.

THERAPEUTIC DEVELOPMENT PSP and CBD have become important disease models for developing tauopathy treatments because they progress faster than typical FTD-MAPT, enabling clinical trial readouts within 12–18 months. Multiple anti-tau antibody trials have been conducted in PSP. Although Phase 2 results have been disappointing, the PSP community has advanced trial design, biomarkers, and outcome measures benefiting the broader tauopathy field. CurePSP (curepsp.org, 1-800-457-4777) is the primary advocacy organization for PSP and CBD patients and families.

bvFTD is defined by early, progressive, and pervasive changes in personality, behavior, and executive function with relative preservation of memory and visuospatial skills in early stages. It is the most commonly misdiagnosed type of FTD, frequently mistaken for depression, bipolar disorder, midlife crisis, or Alzheimer’s disease.

Rascovsky 2011 Consensus Criteria — Probable bvFTD requires 3 of these 6 features:

Genetic Associations

• C9orf72: Most common genetic cause; bvFTD with psychosis, hallucinations, paranoid delusions more common than in other genetic FTD
• GRN: Can produce bvFTD with asymmetric atrophy; plasma progranulin low
• MAPT: Variable; some produce classic bvFTD; others parkinsonism-predominant
• Sporadic (~70% of cases): TDP-43 type A or B pathology most common at autopsy

nfvPPA is characterized by progressive breakdown in the motor production of speech and grammatical construction. Speech becomes slow, effortful, and halting. Comprehension of individual words is largely preserved early on.

Core Features

• Effortful, halting speech: Patients grope for words, produce distorted sounds, and make multiple attempts at a target word
• Agrammatism: Grammatically simplified speech — omitting small function words, simplified sentence structures, errors in verb tenses. May produce telegraphic speech: “John...go...store...yesterday.”
• Apraxia of speech: Motor planning of speech movements is impaired — inconsistent sound errors, characteristic groping movements. Distinct from dysarthria.
• Preserved word comprehension (early)

Pathology

Tau pathology (4-repeat, often CBD or PSP-like) in the majority of cases; GRN mutations can produce nfvPPA. Brain regions: left inferior frontal cortex (Broca’s area) and left anterior insula.

svPPA (formerly called semantic dementia) presents with progressive inability to understand the meaning of words and objects. Speech remains fluent, well-articulated, and grammatically intact — but the semantic content empties out.

• Progressive loss of word meaning: Patients lose the ability to understand what words refer to. Early: uncommon words. Later: common words and names of familiar objects.
• Object agnosia: Parallel loss of visual object recognition
• Fluent, effortless speech production with circumlocution (“that thing you put food in” for “bowl”)
• Relatively preserved episodic memory (early): Can remember what happened yesterday but not what a fork is — opposite of Alzheimer’s
• Face recognition impairment when atrophy extends to right anterior temporal lobe (prosopagnosia)

Pathology: TDP-43 type C is dominant in svPPA — characterized by long dystrophic neurites in the temporal lobe. Usually sporadic; genetic causes uncommon. Brain: predominantly left anterior temporal lobe (fusiform, perirhinal cortex, amygdala).

lvPPA is characterized by impaired single-word retrieval in spontaneous speech and impaired repetition of sentences. It is the only PPA variant where the underlying pathology is usually Alzheimer’s disease (amyloid plaques and tau tangles), not FTLD pathology.

• Frequent pauses while speaking, searching for words — tip-of-tongue hesitations
• Impaired sentence repetition due to phonological working memory deficits
• No agrammatism (grammar preserved), no semantic knowledge loss

FTD-MND occurs when a patient meets criteria for both behavioral-variant FTD and ALS simultaneously or in close temporal succession. This combination has the worst prognosis of any FTD variant, with median survival of only 2–3 years from symptom onset.

• Behavioral changes of bvFTD: Personality change, disinhibition, apathy, loss of empathy, compulsive behaviors
• Upper and lower motor neuron signs: Weakness, fasciculations, muscle wasting, hyperreflexia, dysarthria from motor neuron dysfunction
• Bulbar symptoms: Swallowing difficulty and speech changes from brainstem involvement often occur early
• Respiratory compromise: Diaphragm weakness leads to breathing difficulties — primary cause of death

Genetics: C9orf72 expansion is by far the most common genetic cause. TDP-43 type B pathology essentially universal at autopsy.

PSP is a 4-repeat tauopathy closely related to FTD. It shares tau pathology, genetic risk factors (MAPT H1 haplotype), and overlapping clinical features. Prevalence is approximately 6 per 100,000, similar to ALS.

PSP Subtypes (MDS Criteria 2017)

• PSP-Richardson syndrome (PSP-RS): Early postural instability with backward falls, supranuclear vertical gaze palsy (difficulty looking down), dysarthria, dysphagia, frontal cognitive decline. Most commonly recognized subtype.
• PSP-Parkinsonism (PSP-P): Resembles Parkinson’s at onset; gaze palsy and falls develop later
• PSP-frontal (PSP-F): Prominent frontal behavioral features resembling bvFTD
• PSP-SL (speech/language): Prominent progressive apraxia of speech overlapping nfvPPA

Key Distinguishing Features from Parkinson’s Disease

Management priorities: Fall prevention (most important safety issue); levodopa trial; prism glasses for downward gaze palsy; dysphagia management; CurePSP (curepsp.org, 1-800-457-4777).

CBS (clinical syndrome) vs CBD (pathological diagnosis confirmed at autopsy). ~50% of CBS cases do NOT have CBD at autopsy — they have PSP, Alzheimer’s, or other pathologies. This makes CBS one of the most pathologically heterogeneous FTD-spectrum syndromes.

Core Clinical Features

• Alien limb phenomenon: One arm seems to move on its own, independently of the patient’s intention. Patients describe “a limb that has a mind of its own.”
• Asymmetric motor involvement: Begins unilaterally; one hand becomes progressively stiff, dystonic, apraxic, and clumsy
• Cortical sensory loss: Impaired two-point discrimination and graphesthesia in the more affected limb
• Apraxia: Inability to perform learned skilled movements despite intact motor power
• Myoclonus: Brief shock-like jerks in the affected limb, often provoked by movement or touch

Underlying pathologies: ~50% CBD (4R tau), ~25% PSP, ~15% Alzheimer’s disease, ~10% FTLD-TDP or other. Amyloid PET is strongly recommended for all CBS patients — the ~15% with Alzheimer’s pathology may be candidates for anti-amyloid therapy.

The 3.6-year average delay to an FTD diagnosis is not inevitable, and understanding why it happens helps families shorten it. The delay has three main causes: the first symptoms are behavioral or language changes rather than memory loss, so they are mistaken for depression or stress; routine office cognitive tests (like the common “remember three words” screens) are often normal early in FTD and falsely reassure; and the person affected frequently does not recognize that anything is wrong, so unless someone who knows them well speaks up, the changes go unreported.

There are concrete things you can do to move faster. Bring a written timeline of the specific changes you have noticed — what changed, when, and how it differs from the person's lifelong character — because this informant history is the single most valuable piece of information a specialist receives, and it is exactly what a brief office visit tends to miss. Ask directly for a referral to a behavioral neurologist or a cognitive disorders / memory clinic, ideally at an academic center, rather than accepting a psychiatric explanation that does not fit a progressive, worsening course. If imaging has been called “normal,” ask whether an FDG-PET scan has been done, since it can show FTD changes that a standard MRI misses. And if there is any family history of dementia, ALS, or early-onset cognitive change, mention it explicitly — it raises the suspicion for FTD and may point toward genetic testing.

Advocating in this way is not being difficult; it is often what finally gets a years-long puzzle solved, and an accurate diagnosis opens the door to the right treatment, the right support, and clinical-trial options.

FTD history must be gathered primarily from an informant who has known the patient for years. Anosognosia (lack of insight) is a core feature of bvFTD, and PPA patients may not be able to give a reliable history.

Essential History Elements

• Timeline: When did changes first appear? Over what period?
• Behavioral changes: New inappropriate social behavior; apathy; loss of empathy; compulsive/repetitive behaviors; eating changes; hygiene changes; financial mismanagement; legal problems
• Language changes: Word-finding difficulties; speech fluency changes; comprehension problems; writing changes
• Motor symptoms: Falls (note direction); tremor; walking changes; swallowing difficulties; muscle weakness or wasting; fasciculations
• Cognitive profile: Memory, orientation, visuospatial abilities, executive function — in early bvFTD, memory and spatial skills are often preserved
• Family history: Full 3-generation pedigree — any family member with dementia, ALS, Parkinson’s-like syndrome, psychiatric illness with late onset, or early neurological death

Standardized Informant Assessments

• FBI (Frontal Behavioral Inventory): 24-item caregiver-completed questionnaire validated for FTD vs AD vs normal
• NPI (Neuropsychiatric Inventory): 12-domain behavioral assessment with caregiver distress rating for each domain
• CDR+NACC FTLD-SB: Modified Clinical Dementia Rating scale with FTD-relevant domains; used in clinical trials as primary clinical outcome measure

The classic FTD neuropsychological pattern: executive dysfunction and behavioral dysregulation with relatively preserved memory and visuospatial function.

MRI cannot identify the specific pathological protein or reliably distinguish FTD from Alzheimer’s in all cases. A normal MRI does not rule out very early FTD.

FDG-PET

Measures glucose metabolism as a proxy for neuronal activity. More sensitive than MRI for early diagnosis. FTD shows frontal and anterior temporal hypometabolism; Alzheimer’s shows posterior parietal and posterior cingulate hypometabolism — a clearly different pattern useful for AD vs FTD differentiation when clinical and MRI findings are ambiguous.

Amyloid PET

Directly detects amyloid plaque deposition. Primary role in FTD evaluation: ruling out Alzheimer’s pathology. A negative amyloid PET in a patient with dementia is strong evidence against AD and supports a non-AD diagnosis such as FTD. Positive amyloid PET in atypical dementia raises possibility of lvPPA (often AD pathology) or co-existing AD/FTLD (in older patients). CMS/Medicare covers amyloid PET in patients enrolled in approved registries.

Tau PET

First-generation tracer flortaucipir (Tauvid, FDA-approved) binds primarily to Alzheimer’s-type tau — not specific for FTD-type tau; may show non-specific off-target binding in PSP/CBD. Second-generation tracers (PI-2620, MK-6240) have improved selectivity for 4R tauopathies including PSP and CBD but are not yet FDA-approved for routine use; available at academic research centers.

Blood Biomarker Pathway for FTD Evaluation

1. Plasma pTau217 + Aβ42/40 ratio: If positive for AD pattern, reconsider FTD diagnosis; evaluate for lvPPA; consider anti-amyloid therapy eligibility
2. Plasma NfL: Elevated confirms active neurodegeneration; provides prognostic information
3. Plasma progranulin: If low (~50% of normal), order GRN gene sequencing
4. C9orf72 repeat-primed PCR: For all patients with family history or motor neuron features
5. CSF if blood biomarkers are ambiguous or borderline
6. Amyloid PET if biomarkers are ambiguous and management depends on AD vs non-AD status
7. FDG-PET if MRI and biomarkers do not clarify the clinical picture

Key CSF Biomarker Interpretations

• Aβ42 / Aβ42:40 ratio: Low in Alzheimer’s; normal/high in FTD — supports non-AD diagnosis
• pTau181: Elevated in Alzheimer’s; normal or low in FTD (including MAPT-FTD and PSP) — most useful CSF differentiator
• NfL: Elevated in FTD and other neurodegenerative conditions; confirms active neurodegeneration; non-specific for FTD subtype

The most common error: psychiatric misdiagnosis. Studies show FTD patients receive an average of 2.3 incorrect diagnoses before the correct one. Most common incorrect diagnoses: major depressive disorder, bipolar disorder, OCD, personality disorder, late-onset schizophrenia (especially in C9orf72 carriers with psychosis).

1. What specific type of FTD do I have, and how certain are you?
2. Have you ruled out Alzheimer’s disease? Was amyloid PET, CSF, or a blood pTau test performed?
3. Should I have genetic testing, and if so, which genes?
4. Do my family members need to know about genetic risk? Should I see a genetic counselor?
5. What did the brain MRI show, and which regions are most affected?
6. What is the expected progression for my specific variant?
7. Are there clinical trials I should be aware of?
8. Should I see a speech-language pathologist now, even if my speech is only mildly affected?
9. Can you refer me to an FTD specialty center?
10. What medications should I avoid? (Specifically: are cholinesterase inhibitors or memantine planned, and why are they inappropriate for most FTD variants?)
11. When should I stop driving?
12. What is the AFTD, and how can it help my family? (theaftd.org, 866-507-7222)

Found in 25–40% of familial FTD and 40–50% of familial ALS. Also present in 5–10% of apparently sporadic FTD and ALS. The GGGGCC repeat expansion causes disease through three simultaneous mechanisms: (1) loss of C9orf72 protein function, impairing lysosomal/autophagy pathways; (2) toxic RNA foci that sequester RNA-binding proteins; and (3) five dipeptide repeat (DPR) proteins (poly-GA, GP, GR, PA, PR) produced by RAN translation, with poly-GR and poly-PR particularly toxic to neurons.

Clinical Features Specific to C9orf72

• Most commonly presents as bvFTD; can cause nfvPPA, ALS alone, or mixed FTD-ALS
• Psychiatric symptoms distinctively common: Psychosis, paranoid delusions, hallucinations at much higher rates than other genetic FTD — may be misdiagnosed as late-onset schizophrenia or bipolar disorder for years
• Variable penetrance within families; age of onset varies widely (some affected in 40s, others reach 70s without symptoms)

Testing

Requires repeat-primed PCR — standard PCR and whole-exome sequencing will MISS this expansion. Most commercial FTD gene panels (Athena/LabCorp, GeneDx, Invitae) include C9orf72 RP-PCR. Ordering must specifically request C9orf72 testing.

Therapeutic Programs

• WVE-004 (Wave Life Sciences): antisense oligonucleotide targeting the toxic repeat-containing C9orf72 transcript; the Phase 1b/2a FOCUS-C9 trial (NCT04931862) lowered the poly-GP biomarker but did not show a clinical benefit, and the program was discontinued.
• Earlier C9orf72 ASO (BIIB078, Biogen) was also discontinued after failing to show benefit. As of 2026 no C9orf72-targeted therapy is in a pivotal trial — this remains an active research area.

GRN mutations cause FTD by haploinsufficiency — one mutated copy produces a truncated, rapidly degraded protein, leaving cells with only ~50% of normal progranulin. More than 70 pathogenic loss-of-function variants are catalogued. Progranulin deficiency impairs lysosomal function, reduces autophagy, dysregulates microglial inflammation, and leads downstream to TDP-43 pathology.

Identifying GRN Carriers — Plasma Progranulin Screening Test

A simple plasma progranulin measurement identifies carriers: levels consistently below ~60 ng/mL (typically 40–60 ng/mL) vs ~80–120 ng/mL in non-carriers. Order as first-line screen before proceeding to full genetic sequencing.

Clinical Features

• Typically presents as bvFTD or nonfluent PPA
• Highly variable age of onset, even within the same family (40s to early 80s)
• Often shows asymmetric parietal involvement on MRI in addition to frontal/temporal atrophy; parkinsonism common

Therapeutic Pipeline

Mutations in MAPT (chromosome 17q21) cause FTD by producing abnormal tau protein that misfolds and aggregates. More than 50 pathogenic MAPT mutations are catalogued; all are autosomal dominant. Accounts for ~10–20% of familial FTD cases. Key mutations include P301L (most common worldwide; autosomal dominant FTD with parkinsonism; 4R tau), IVS10+16 (splice-site mutation altering 3R:4R ratio; PSP/CBD-like syndrome), V337M, and R406W (late-onset FTD resembling AD clinically).

Therapeutic Programs

• Tau-lowering antisense oligonucleotides: NIO752 (Novartis), an intrathecal tau-lowering ASO, is in a Phase 1 program (NCT04539041) in progressive supranuclear palsy (PSP) — a tauopathy in the FTLD-tau spectrum. BIIB080 (Ionis/Biogen), another tau-lowering ASO, is being studied primarily in Alzheimer’s disease; dedicated MAPT-FTD ASO trials are still being developed.

• TARDBP (TDP-43 gene): Mutations primarily cause familial ALS; rare FTD cases; TDP-43 pathology
• FUS: Mutations cause early-onset ALS; rare FTD. Sporadic FUS-FTD is a distinct neuropathological subtype in young patients with bvFTD.
• VCP: Mutations cause multisystem proteinopathy — inclusion body myopathy, Paget’s disease of bone, and FTD in variable combinations; rare but clinically important
• TBK1: Loss-of-function mutations cause ALS and FTD-ALS overlap; important in autophagy-inflammation pathways; increasingly identified on clinical sequencing panels
• CHMP2B: Extremely rare; identified in Danish and Belgian families; ubiquitin-positive, FUS/TDP-43-negative inclusions

Who Should Have Genetic Testing?

• Any FTD patient with family history of FTD, ALS, or early-onset dementia in a first-degree relative
• Any FTD patient with a first-degree relative with ALS
• FTD patients under age 60 as a general recommendation
• FTD patients evaluated for clinical trial eligibility
• First-degree relatives of confirmed mutation carriers requesting testing

Presymptomatic Testing Principles

• Testing must be voluntary: The right not to know is as valid as the right to know
• Pre-test counseling required: Genetic counselor must discuss implications before testing, including insurance implications (GINA protects health insurance and employment but NOT life, long-term care, or disability insurance)
• Result disclosure: In person with support present; not by letter or phone
• Family planning: Autosomal dominant inheritance means each child has 50% risk. Preimplantation genetic testing (PGT) can prevent transmission to future generations — discuss with all carriers of reproductive age
• Research participation: GENFI and ALLFTD actively enroll presymptomatic carriers. Enrollment builds the evidence base for prevention trials.

Living as a Presymptomatic Carrier

• Complete healthcare directives and financial power of attorney while fully competent
• Secure life, disability, and long-term care insurance before testing if possible (GINA does not protect these)
• Enroll in GENFI or ALLFTD longitudinal study for annual biomarker monitoring (earliest possible detection of disease onset)
• Direct-to-consumer testing (23andMe, AncestryDNA) does NOT include C9orf72 RP-PCR, MAPT sequencing, or comprehensive GRN analysis. Negative consumer tests do not exclude FTD mutations.

• Should I have genetic testing given my family history and specific FTD diagnosis?
• Which genes should be tested? Does your lab use repeat-primed PCR for C9orf72?
• What is my plasma progranulin level?
• Can you refer me to a certified genetic counselor with neurodegenerative disease experience?
• If I have a mutation, should my children and siblings be told and offered counseling?
• How will genetic testing results affect my eligibility for clinical trials?
• Are there research studies that follow presymptomatic mutation carriers longitudinally?
• Should I establish advance care planning documents now, before any possible cognitive decline?
• Does my genetic result have implications for life or disability insurance I should address now?

If a parent has a known FTD-causing gene change (most commonly C9orf72, GRN, or MAPT), each child has a 50% chance of inheriting it. If you are at risk yourself and are thinking about having children, several paths exist:

• Natural pregnancy, with or without first finding out whether you carry the family's gene change.
• IVF with embryo testing (PGT-M): eggs and sperm are combined in a lab, the resulting embryos are tested for the family's specific gene change, and only embryos without it are used. This can prevent passing the condition to your child.
• Testing during pregnancy (chorionic villus sampling or amniocentesis), which can tell you whether the baby has inherited the gene change.

One option that surprises many families: embryo testing can sometimes be done without you having to learn your own status (through what are called “non-disclosure” or “exclusion” approaches). This means you can avoid passing on the gene change while still choosing not to find out whether you yourself carry it — a humane option, because deciding whether to learn your own genetic future is one of the hardest choices a person can face.

Deciding whether to be tested when you have no symptoms (called predictive testing) is entirely your choice, and many people at risk choose not to know. If you do pursue it, it should always be done with a genetic counselor through a careful, step-by-step process — the same approach used for Huntington's disease — with support before and after the result. The result carries real-world weight beyond your own peace of mind: it can affect life, disability, and long-term-care insurance (which, unlike health insurance, is not protected by U.S. law), so it is wise to address insurance before testing. The upside of knowing can include eligibility for prevention research studies and the ability to plan your life and finances while fully well. There is no wrong choice here — only the one that is right for you and your family.

Less commonly, a woman who already has early-onset FTD may become pregnant. This situation needs a coordinated team — her neurologist together with a high-risk pregnancy (maternal-fetal medicine) specialist. The main issues are practical and medical: some medications used for FTD symptoms are safer in pregnancy than others (certain antidepressants are reasonably well studied, while some mood-stabilizing and anti-seizure drugs can seriously harm a developing baby and are avoided), and the family will need to plan realistically for the demands of caring for a newborn alongside the changes FTD brings. Decisions about medications during breastfeeding are made the same careful way, weighing benefits and risks together with the care team.

The behaviors that come with FTD — saying hurtful things, acting on impulse, rigid routines, apathy, loss of empathy — can be the hardest part of the illness to live with, in part because they feel deliberate. The most important shift in mindset is to recognize that they are symptoms of brain damage, not choices or personal attacks. The parts of the brain that control social behavior, judgment, and empathy are being injured by the disease. This reframing does not make the behaviors easier to witness, but it changes how you respond — from arguing or taking it personally toward managing the situation.

A few principles work across most situations. Don't argue or try to reason the person out of a belief or behavior — the brain regions needed to update beliefs from evidence are damaged, so confrontation only escalates distress without changing anything. Instead, redirect: acknowledge the feeling without agreeing, then offer a different activity and, ideally, change the physical setting — a walk, a snack, moving to another room — because movement breaks a behavioral loop more reliably than words. Look for triggers and patterns: many difficult behaviors are set off by predictable things (hunger, fatigue, overstimulation, a disrupted routine), and removing the trigger prevents the behavior more effectively than reacting to it. Lean on routine, since predictability reduces anxiety and channels compulsive tendencies into harmless habits.

Finally, protect against the high-stakes consequences of disinhibition early — securing finances, credit cards, car keys, and access to alcohol or hazards — rather than waiting for a crisis. These steps are not about taking away dignity; they are the practical scaffolding that keeps everyone safer while preserving as much independence as is safe.

Structured Environment and Daily Routine

The bvFTD brain has lost its capacity for flexible adaptation to novelty. Unpredicted changes and unstructured time reliably trigger agitation. A predictable daily structure is the single most effective behavioral intervention: consistent wake time, mealtimes, activity times, and bedtime; simple pre-planned activities; minimize surprises; inform the patient of schedule changes in advance using simple, concrete language.

Environmental Modifications for Safety

• Finances: Remove checkbooks and credit cards; set up automatic bill pay; establish a limited cash account; consider representative payee status if judgment is severely impaired
• Driving: Formal evaluation required early — executive dysfunction and impulsivity impair driving before the patient has any awareness of the problem (see Driving section below)
• Weapons: Remove all firearms if impulsivity or aggression are present
• Toxic substances: Lock up medications, cleaning products, alcohol, and yard chemicals; patients with hyperorality may ingest non-food items
• Wandering prevention: GPS tracking devices worn as watches; door alarms; fenced yard; medical ID bracelet with diagnosis and emergency contact; enroll in Safe Return program

Redirection — The Core Behavioral Technique

Arguing does not work. The frontal circuits responsible for reasoning and updating beliefs based on evidence are directly damaged. Confrontation escalates agitation without changing behavior. Redirection means: (1) acknowledge without agreeing; (2) offer an alternative activity immediately; (3) move the body — a change of room, a walk, or a snack breaks a behavioral loop more effectively than verbal intervention; (4) keep your voice calm and slow.

Music Therapy — Validated Evidence in bvFTD

Music engages deep limbic circuits and subcortical structures relatively preserved in FTD even when the frontal cortex is severely atrophied. Structured music therapy reduces agitation and improves mood. Personalized playlists of music meaningful to the patient in earlier life are more effective than generic approaches. Active music-making (clapping, simple percussion) is more engaging than passive listening. Predictable musical cues can signal daily routine transitions.

Eating Behavior and Hyperorality Management

• Scheduled meals and snacks at fixed times reduces constant food-seeking
• Pre-portioned meals; serve one plate at a time; do not leave serving dishes on the table
• Locked pantry and refrigerator using childproof cabinet locks or refrigerator locking devices
• Provide healthy sweet substitutes (fruit, sugar-free alternatives) for continuous snacking urge
• Track weight; significant weight gain is recognized in bvFTD
• SSRIs (especially sertraline and fluvoxamine) and trazodone (Lebert 2004 RCT) show benefit for eating disturbances

Driving Assessment and Cessation

• Formal behind-the-wheel evaluation by an occupational therapist certified as a Driver Rehabilitation Specialist (CDRS) is the gold standard
• Some US states mandate physician reporting of dementia diagnoses to the DMV (California, Oregon, Delaware, Nevada, New Jersey, others)
• When the patient refuses to stop driving despite safety concerns, families may need to take practical steps: hide car keys, disable the vehicle, contact the DMV directly
• Identify alternative transportation before cessation to reduce resistance

SSRIs — First-Line Pharmacotherapy

Allow 4–6 weeks at adequate dose before assessing response. Do not discontinue prematurely.

Trazodone — Best-Evidenced Drug for bvFTD Agitation

The Lebert et al. 2004 double-blind RCT is the best evidence for any FTD behavioral medication. Trazodone 150–300 mg/day significantly improved NPI total score, with specific benefit for irritability, agitation, and eating behavior disturbances vs placebo.

• Starting dose: 50 mg at bedtime; increase by 50 mg every 1–2 weeks; typical range 100–300 mg/day
• Can split: 50–100 mg daytime for behavioral effects + 100–200 mg at bedtime for sleep
• Orthostatic hypotension: Check standing blood pressure. Particularly dangerous in PSP (fall risk). Start with patient seated/reclined after dose.
• Priapism (rare, ~1:6,000 male patients): Urologic emergency. Counsel all male patients: seek emergency care immediately if erection persists >2–4 hours.

Compulsive Behavior — Channel, Don’t Always Suppress

When compulsive behaviors are harmless, channeling them is often better than suppression: provide materials for sorting and organizing; use repetitive walking as physical activity; designate a safe collection space. When behaviors are harmful (hoarding fire hazards, compulsive spending, hypersexuality, aggression), SSRIs are the first pharmacologic step. Fluvoxamine with its established OCD-spectrum role is a reasonable choice for prominent compulsive behaviors.

• Which specific behaviors are causing the most safety risk or caregiver burden right now?
• What non-medication strategies do you recommend for the behaviors we are struggling with most?
• Is an SSRI appropriate? Which one, and what dose should we target?
• Should we try trazodone? Is fall risk too high to use it?
• What medications should we absolutely avoid? (Specifically: donepezil, memantine, typical antipsychotics)
• When, if ever, is an antipsychotic appropriate for this patient?
• Is driving still safe? When should we pursue a formal CDRS evaluation?
• What should we do in a behavioral crisis — severe agitation, aggression, or wandering?
• Can you refer us to a behavioral neurologist, geriatric psychiatrist, or FTD-specialized social worker?
• Are there FTD-specific caregiver training programs in our area or online?

FDA-APPROVED FOR PSEUDOBULBAR AFFECT Nuedexta (dextromethorphan 20 mg / quinidine 10 mg) is FDA-approved for pseudobulbar affect (PBA) — episodes of involuntary, uncontrollable laughing or crying disconnected from the person’s actual emotional state. PBA is common in FTD-ALS overlap and can occur in other FTD variants. This is the only FDA-approved medication for any FTD-related indication.

• Dosing: One capsule once daily for 7 days, then twice daily
• Quinidine component prolongs QTc — contraindicated with other QTc-prolonging drugs; check interactions carefully if patient is on riluzole
• Contraindicated with MAOIs
• Distinguish PBA from depression: PBA episodes are brief, episodic, triggered by minor stimuli; depression is a persistent state

If an antipsychotic must be used (severe aggression creating immediate safety risk; psychosis causing danger; all other strategies failed): Quetiapine (Seroquel) at very low doses (12.5–50 mg) is the most commonly chosen because it is less likely to worsen motor symptoms. Use the lowest effective dose for the shortest possible time. Reassess at every visit. Document the specific indication and risks discussed. Haloperidol and other typical antipsychotics are particularly dangerous in FTD, especially in patients with PSP, CBS, or Lewy body overlap.

• Riluzole (Rilutek) 50 mg twice daily: FDA-approved for ALS; reduces glutamate excitotoxicity; extends median survival by approximately 2–3 months; requires liver function monitoring; continued in FTD-ALS until dysphagia prevents oral intake
• Edaravone (Radicava) 60 mg IV, oral suspension Radicava ORS also available: FDA-approved for ALS; free-radical scavenger; 28-day cycles (10 days on, 18 days off); 33% reduction in ALSFRS-R decline rate in predefined early, rapidly progressing subgroup
• Nuedexta for PBA (see above)
• Baclofen or tizanidine: For spasticity in ALS component
• Mexiletine 150–300 mg TID: For muscle cramps (common and painful in ALS)

• Levodopa/carbidopa trial: Most PSP-RS patients have little or no response, but a 1–3 month trial at adequate dose (up to 600–1000 mg levodopa/day) is recommended — PSP-Parkinsonism subtype may show transient 30–40% improvement; CBS has variable levodopa response
• Amantadine 100 mg BID: Mild dopaminergic and NMDA-antagonist effects; occasionally helpful for parkinsonism in PSP/CBS; low side-effect profile
• Botulinum toxin injections: For focal dystonia (arm posturing in CBS), drooling (injected into parotid/submandibular glands), blepharospasm; effects last 3–4 months; administered by movement disorder neurologist
• Bupropion 75–150 mg/day: Norepinephrine-dopamine reuptake inhibitor; anecdotal benefit for apathy in FTD; lowers seizure threshold — caution

• What is the specific target symptom for each medication you are prescribing? How will we measure whether it is working?
• Are there medications on my current list that might be worsening behavioral or cognitive symptoms?
• Is an SSRI the right first step? Which agent and dose?
• Should we add trazodone? Is my fall risk too high to use it? Has the priapism risk been discussed with male patients?
• Under what specific circumstances would you consider an antipsychotic, and which would you choose?
• If I have FTD-ALS, should I be on riluzole? Is edaravone appropriate for my disease stage?
• Is Nuedexta appropriate for the episodes of crying/laughing we are seeing?
• What over-the-counter medications or supplements should we avoid entirely?
• What is the plan for pain management as disease advances? (Acetaminophen is preferred analgesic in FTD)

Voice banking records a large sample of a person’s natural voice while speech is still fluent and intelligible, then builds a synthetic voice model that sounds like them for use in AAC devices. This is profoundly meaningful for identity and dignity.

Who should bank: Any nfvPPA patient with intelligible speech; any C9orf72-FTD patient who may develop ALS bulbar dysfunction; any FTD-ALS patient still fluent and intelligible. The window is narrow — once speech becomes severely dysarthric, banking is no longer effective. At the first PPA or FTD-ALS diagnosis, raise voice banking immediately.

• ModelTalker (modeltalker.org): Free service; records ~1,800 scripted sentences at home on a computer; resulting voice file usable with many AAC applications
• VocaliD (vocalid.ai): Commercial service; more natural-sounding personalized synthetic voice; longer recording corpus required
• Message Banking: Complementary approach — record frequently used phrases and expressions (“I love you,” “I need help”) in natural voice for playback buttons in AAC systems. Even if full voice banking is not done, message banking ensures key utterances remain in the patient’s own voice.

Low-Technology AAC

• Communication books/boards: Binders with photographs, symbols, and key words arranged thematically by topic (food/drink, medical needs, family, feelings)
• Alphabet boards: For patients with preserved literacy but impaired speech — allow spelling words. Can be combined with word prediction boards.
• PECS (Picture Exchange Communication System): Structured image-card system; patient selects and hands card to communication partner to initiate requests

High-Technology AAC

• iPad-based AAC apps: Proloquo2Go, TouchChat, Snap Core First, Grid 3 — symbol-based and text-based AAC; highly personalizable; voice output can use banked patient voice
• Dedicated speech-generating devices (SGDs): Accent series (PRC-Saltillo), Tobii Dynavox TD Snap — more durable; Medicare Part B covers SGDs when medical necessity is documented via SLP evaluation and prescription
• Eye-gaze systems (Tobii Dynavox, PCEye): Critical for FTD-ALS with severe limb weakness and PSP patients. Eye movement controls a computer screen for communication and environmental control (lights, TV). Must be set up while eye movement range is still adequate. PSP patients lose vertical gaze early — system setup must account for this. Life-changing for appropriate patients.

nfvPPA

• PROMPT Therapy: Tactile-kinesthetic approach using gentle touch on face and jaw to guide articulatory movements. For apraxia of speech. Requires PROMPT-certified SLP. Evidence for slowing apraxia progression when started early.
• Script Training: Identify 5–10 frequently needed scripts (“I’d like a coffee, please”; “My name is [name] and I have a language disorder”) and practice extensively until nearly automatic. Leverages preserved procedural memory.

svPPA

• Semantic therapy: Structured relearning of personally meaningful vocabulary using multi-modal encoding (seeing, touching, using, saying, reading, writing simultaneously). Item-specific learning possible but does not generalize.
• Environmental labeling: Label household objects and rooms with written words and pictures for continuous retrieval support

Caregiver Communication Training (All PPA Variants)

• Slow down; give extra time after asking a question; do not rush to fill silence
• Use yes/no questions: “Would you like tea or coffee?” instead of “What do you want to drink?”
• Use visual cues: show pictures or written words; gesture; point; draw
• Confirm understanding with yes/no verification
• Avoid correcting word errors — respond to the communicative intent, not the specific words used
• Reduce background noise during key conversations

Swallowing difficulty develops in all FTD variants as disease advances, but is especially early and severe in PSP (brainstem involvement) and FTD-ALS (bulbar ALS). Aspiration pneumonia is one of the leading causes of death in FTD and PSP.

Swallowing Assessment Options

• Videofluoroscopic swallow study (VFSS) / Modified barium swallow: Gold standard; X-ray fluoroscopy records the swallowing mechanism in real time; identifies exactly where breakdown occurs
• FEES (Fiberoptic endoscopic evaluation of swallowing): Flexible endoscope through the nose; done at bedside; no radiation; direct visualization of aspiration and residue

Safe Swallowing Strategies

• Sit upright at 90 degrees for all meals; maintain upright for 30 minutes after eating
• Small bites and small sips; no rushing
• Chin tuck posture can reduce aspiration in some patients
• Avoid mixed-texture foods (soup with chunks) which are particularly difficult to control
• IDDSI-standardized texture modification: thickened liquids (Levels 1–4) and modified food textures (Levels 4–7) prescribed based on formal swallowing assessment

PEG Feeding Tube — Evidence and Decision-Making

Evidence in Alzheimer’s dementia shows PEG tubes do not extend survival or reduce aspiration pneumonia (aspiration of oral secretions continues regardless). The same principles generally apply to FTD. Most FTD/palliative care guidelines do not recommend routine PEG placement in advanced FTD. Exception: in FTD-ALS, PEG placed before respiratory decline (FVC >50% predicted) may extend survival and quality of life because the primary driver of death is respiratory failure. FTD-ALS patients should have ALS multidisciplinary team including nutrition and respiratory specialists guiding this decision. PEG discussions must happen proactively, early, while the patient can participate — not in a crisis.

• Should we be referred to an SLP specifically experienced with PPA or FTD? Where is the nearest specialist?
• Should we start AAC planning now, even though speech is still functional?
• Has voice banking been discussed? Which programs do you recommend, and how much time do we have before speech quality is too impaired?
• How often should we see the SLP? Can therapy continue via telehealth?
• Is a formal swallowing study (VFSS or FEES) needed now, or should we monitor?
• What specific changes in eating or drinking should prompt an urgent SLP call?
• What are the signs that aspiration pneumonia may be developing?
• What is your recommendation about PEG feeding tube — should we discuss this now while the patient can participate?

Why PSP Falls Are Different from Parkinson’s Falls

• Axial rigidity prevents normal postural correction reflexes
• Retropulsion: center of gravity shifted posterior; falls backward
• Vertical gaze palsy: cannot see the ground in front of feet; stairs, curbs, and uneven surfaces are extremely dangerous
• Impaired fear of falling: many PSP patients continue attempting unsafe activities

Adaptive Equipment for PSP

• U-Step walker or weighted rollator: Standard wheeled walkers are unsafe for PSP — they can accelerate backward falls. The U-Step with its low wide base and reverse braking provides a stable counterbalance. Standard walkers should be avoided.
• High-back tilt-recline wheelchair: When ambulation becomes unsafe. Custom seating by a seating specialist is often required for PSP’s rigid, hyperextended neck posture (retrocollis).
• Prism glasses: Yoked prism glasses can optically shift the visual field downward, partially compensating for the inability to look down. Neuro-ophthalmology or optometry referral for fitting.
• Gait belt: Essential for all PSP transfers; worn around the waist to provide a secure handhold for caregivers
• Fall mats and low beds: Bedside floor mats reduce injury from bed falls
• Home hazard removal: Rugs, thresholds, extension cords. Grab bars in bathroom, raised toilet seat, walk-in shower or shower chair.

Monitoring Respiratory Function

• FVC (Forced Vital Capacity): Assessed at every ALS clinic visit (~every 3 months). NIV typically introduced when FVC falls to 50–70% predicted or earlier if symptoms present.
• SNIP (Sniff Nasal Inspiratory Pressure): More sensitive than FVC in patients with early bulbar weakness
• Nocturnal oximetry: Detects overnight desaturation from hypoventilation before daytime failure develops
• Symptoms to watch: Morning headaches (nocturnal CO2 retention), excessive daytime sleepiness, orthopnea, fatigue, recurrent respiratory infections

Noninvasive Ventilation (NIV/BiPAP)

Bourke et al. 2006 randomized trial showed NIV extended median survival by ~7 months in ALS without severe bulbar dysfunction, and improved sleep quality and quality of life. NIV initiated when FVC <50% predicted, SNIP <40 cmH2O, overnight SaO2 <90% for >5% of recording time, or symptoms of nocturnal hypoventilation. Multiple mask styles (nasal, full-face, nasal pillow) should be tried. Cognitive impairment from FTD may make mask tolerance challenging — behavioral management and family support are needed.

Mechanical Insufflation-Exsufflation (Cough Assist)

As expiratory muscle weakness develops, patients lose ability to generate effective cough. CoughAssist (Philips Respironics) provides controlled positive-then-negative pressure cycles to simulate cough and mobilize secretions. Significantly reduces pneumonia and respiratory crisis frequency. Prescribed and set up by respiratory therapy.

Invasive Ventilation — The Decision

Tracheostomy with mechanical ventilation (IMV) prolongs life but does not slow FTD or ALS progression. For FTD-ALS, cognitive impairment may make IMV extremely difficult to tolerate. Communication about discomfort or wishes to withdraw becomes impossible as FTD advances. This decision must be made in advance, documented, and revisited. It is a deeply personal decision; neither choosing IMV nor declining it is universally right.

• Levodopa trial: ~30–40% of CBS patients show transient motor improvement; worth attempting (titrate up to 600–1000 mg levodopa/day over 1–3 months)
• Botulinum toxin for focal dystonia: For arm posturing, fisted hand, foot dystonia — significantly reduces tone, pain, and hygiene difficulties; repeat every 3–4 months
• Alien limb management: Keep the affected hand occupied (holding an object) reduces alien limb behaviors; clonazepam low-dose PRN can reduce myoclonus if severe
• Cortical myoclonus: Clonazepam, sodium valproate, or levetiracetam; avoid phenytoin which can worsen cortical myoclonus

• In-home visit to identify fall hazards, recommend bathroom modifications, assess kitchen and stairway safety
• Systematic evaluation of activities of daily living and instrumental ADLs to identify support needed and appropriate adaptive equipment
• Adaptive equipment: button hooks and dressing aids, long-handled reachers, weighted utensils, non-slip mats, shower chairs, raised toilet seats
• Cognitive aids for patients with preserved insight: medication reminder apps, labeled storage, simplified task checklists
• Certified Driver Rehabilitation Specialist (CDRS) assessment for driving
• Energy conservation strategies for patients with fatigue (common in PSP and FTD-ALS)

• Is a levodopa trial worthwhile for my diagnosis? What dose and how long before concluding it is not helping?
• Should we be referred to a PT specifically experienced with PSP or atypical parkinsonism?
• Is an OT home evaluation appropriate? What hazards should we address?
• What walking aids are safe for PSP? Should we switch to a U-Step or weighted rollator?
• Are prism glasses worth trying for downward gaze difficulty?
• Is botulinum toxin injection appropriate for the arm posturing and pain in CBS?
• How often should FVC be checked, and at what level should we start discussing NIV?
• Should we see a respiratory therapist now, before NIV is needed?
• What is the protocol for respiratory crises at home?
• When should we start palliative care conversations, and how do we access those services?

Living with FTD while reading headlines about “breakthroughs” can be an emotional rollercoaster, so it helps to have a realistic frame. The honest summary in 2026 is twofold: there is still no treatment that slows or stops FTD, and the science has never been more promising. For the first time, knowing exactly which gene causes a person's FTD points to a specific experimental strategy — raising a missing protein in GRN-related FTD, lowering a harmful one in C9orf72- and tau-related FTD. That is a genuine scientific turning point, even though it has not yet produced an approved therapy.

The recent history of the GRN program shows both the promise and the difficulty. An antibody called latozinemab succeeded in raising the missing protein in patients but did not slow their decline in its large trial, and that program was stopped — a disappointment, but also a clarifying lesson that is now reshaping how the next treatments (including gene therapies that aim to restore the protein more completely) are designed and tested. Several gene-therapy and gene-silencing approaches remain in active trials.

What this means practically: if FTD in your family has a known genetic cause, ask specifically about trials for that gene — including prevention trials open to people who carry a gene change but have no symptoms yet, an option that does not exist for most diseases. Treat any single new result, good or bad, as one step in a long process rather than a final verdict, and weigh participation in research not only for the possible personal benefit but as a contribution that is genuinely moving the field toward the first effective treatments.

Latozinemab targets the sortilin receptor (SORT1), which normally degrades progranulin in lysosomes. By blocking sortilin, AL001 allows endogenous progranulin to accumulate — restoring progranulin levels without gene replacement. Phase 3 INFRONT-3 (NCT04374136) enrolls symptomatic GRN mutation carriers. Co-primary endpoints: CDR+NACC FTLD-SB (clinical) and plasma progranulin (biomarker). Phase 2 INFRONT-2 demonstrated robust progranulin restoration as proof-of-mechanism. Phase 3 met its biomarker endpoint but missed its clinical endpoint in October 2025. The field has learned that progranulin restoration may be necessary but insufficient by itself once clinical disease is established — earlier intervention, in presymptomatic carriers, may be needed. Development future uncertain; verify status at ClinicalTrials.gov.

PBFT02 is an adeno-associated virus (AAV1) gene therapy delivering a functional copy of the GRN gene to CNS neurons via intra-cisterna magna injection. Unlike latozinemab which boosts existing progranulin, gene therapy delivers a new working gene — potentially a one-time treatment that durably restores progranulin. The Phase 1/2 upliFT-D trial (NCT04747431) is evaluating safety and pharmacodynamics in symptomatic GRN mutation carriers. A separate AAV GRN gene-therapy program, AVB-101 (AviadoBio), is in the Phase 1/2 ASPIRE-FTD trial (NCT06064890). AAV gene therapy has established CNS precedent in spinal muscular atrophy (Zolgensma). If gene therapy achieves durable progranulin restoration from a single administration, it would represent a fundamentally different paradigm from periodic infusions.

Tofersen is an antisense oligonucleotide FDA-approved in April 2023 for SOD1-ALS, based on NfL reduction as a biomarker endpoint (VALOR trial, Miller et al., NEJM 2022, PMID 36129998). This established regulatory precedent for intrathecal ASO therapy in neurodegeneration. Tofersen itself is specific to SOD1 and is NOT a C9orf72 therapy. C9orf72-specific ASO programs (WVE-004, BIIB078) targeted the toxic repeat RNA and DPR protein production but lowered biomarkers without clinical benefit and were discontinued; no C9orf72-targeted therapy is currently in a pivotal trial. The presymptomatic ATLAS trial for SOD1 ASO is testing whether intervention before symptom onset can delay or prevent disease — directly relevant to all genetic FTD presymptomatic program designs.

Tau-lowering antisense oligonucleotides reduce production of tau protein, decreasing substrate available for toxic aggregation. NIO752 (Novartis) is an intrathecal tau-lowering ASO with a Phase 1 program (NCT04539041) in progressive supranuclear palsy (PSP), a tauopathy in the FTLD-tau spectrum. BIIB080 (Ionis/Biogen), another tau-lowering ASO, is being studied primarily in Alzheimer’s disease and showed CSF tau reduction; a dedicated MAPT-FTD ASO trial has not yet been registered. These programs are the conceptual parallel to tofersen for SOD1-ALS but remain early for FTLD-tau.

Pepinemab blocks semaphorin 4D (SEMA4D), a signaling protein that activates microglial and astrocyte inflammatory responses and disrupts the blood-brain barrier. By blocking SEMA4D binding to its receptor PLXNB1, pepinemab aims to reduce neuroinflammation and preserve synaptic function. Neuroinflammation is a prominent feature of FTD pathology across all subtypes. Unlike the GRN, C9orf72, and MAPT programs, the RALLY trial is mutation-agnostic — enrolling bvFTD patients regardless of genetic cause, making it relevant to the majority of FTD patients who do not carry a known mutation. Vaccinex previously completed the SIGNAL-HD trial of pepinemab in early Huntington’s disease with signals of benefit in the most active disease subgroup. Verify current RALLY enrollment status at ClinicalTrials.gov.

TDP-43 proteinopathy accounts for ~60% of all FTD cases — the largest single pathological category — but has no approved therapy targeting it directly. Research directions include:

• STMN2 and UNC13A ASO programs: TDP-43 nuclear depletion causes aberrant splicing of STMN2 (stathmin-2, essential for axon regeneration) and UNC13A (synaptic vesicle release). ASOs correcting these splicing errors are in preclinical and early clinical development. Restoring STMN2 expression in neurons may restore axon repair capacity lost in ALS and FTD-TDP.
• Progranulin restoration as a broader TDP-43 FTD strategy: Emerging data suggest TDP-43 aggregation impairs progranulin processing even in patients without GRN mutations. This has prompted interest in progranulin restoration beyond GRN carriers.
• C9orf72 DPR clearance: Antibody and small molecule approaches targeting dipeptide repeat (DPR) protein clearance are in early development; CSF poly-GP is a validated pharmacodynamic biomarker for C9orf72 trials.

ALLFTD (Advancing Research and Treatment for Frontotemporal Lobar Degeneration) is the NINDS-funded multicenter longitudinal natural history consortium, merging the former ARTFL and LEFFTDS cohorts. It enrolls both symptomatic and presymptomatic FTD participants — especially C9orf72, GRN, and MAPT mutation carriers — with standardized clinical, imaging, and fluid biomarker data collected over time at 20+ US sites. ALLFTD is the infrastructure backbone for most US FTD trials. Enrollment information at allianceftd.org. Presymptomatic carriers who enroll receive annual biomarker monitoring (MRI, neuropsychology, blood NfL, progranulin) and are the first to be contacted when prevention trials open.

• UCSF Memory and Aging Center, San Francisco, CA, USA — Bruce Miller, Adam Boxer, Howie Rosen; world’s largest FTD clinical research program; 510-885-7290; memory.ucsf.edu. Hosts the FTD Disorders Registry (ftd-registry.org). Principal investigator site for INFRONT-3, upliFT-D, RALLY, and ALLFTD. A consultation here is appropriate for any patient with suspected FTD, regardless of geography.
• UCL Queen Square Institute of Neurology, London, UK — Jonathan Rohrer (FTD Research Group); +44 20 3448 8880. Co-founded the GENFI consortium; world-leading genetic counseling for FTD families; 18-site European natural history study.
• Northwestern Cognitive Neurology, Chicago, IL, USA — Emily Rogalski; 312-503-1249. Mesulam Center; world-leading primary progressive aphasia program; Northwestern PPA Research Program.
• Mayo Clinic, Rochester, MN, USA — Keith Josephs (FTD, PSP, CBS specialist); 507-538-3270. Comprehensive behavioral neurology; strong neuroimaging and neuropathology programs.
• MGH Frontotemporal Disorders Unit, Boston, MA, USA — Bradford Dickerson; 617-726-2000. Comprehensive FTD evaluation and research; ALLFTD site.
• Toronto Western Hospital, Canada — Mario Masellis; 416-603-5800. GENFI Canadian site; genetic counseling for GRN/MAPT/C9orf72 families.
• Erasmus MC, Rotterdam, Netherlands — John van Swieten; +31 10 704 4640. GENFI coordinator; GRN/MAPT specialist; European GRN mutation family registry.
• FRONTIER Research Group, UNSW Sydney, Australia — frontierresearch.org.au. World-leading bvFTD behavioral neuroscience; GENFI Australian site.

International patient organizations:

• AFTD (Association for FTD) — theaftd.org; 1-866-507-7222 (US)
• FTD Disorders Registry — ftd-registry.org (global)
• CurePSP — curepsp.org; 1-800-457-4777 (PSP/CBD/FTD overlap)
• Pick’s Disease Support Group (UK) — pdsg.org.uk
• FTD Connect (online peer community) — theaftd.org/ftdconnect

Donepezil (Aricept), rivastigmine, and galantamine are FDA-approved for Alzheimer’s disease and work by increasing acetylcholine. The cholinergic deficit that drives AD is not a feature of most FTD. Multiple studies, including the Mendez et al. 2007 placebo-controlled trial of galantamine, showed behavioral worsening in bvFTD patients. These drugs should not be prescribed for bvFTD. The only exception: lvPPA with confirmed Alzheimer’s pathology on amyloid PET or CSF biomarkers. If a person with suspected or diagnosed bvFTD is on donepezil and behaviors are worsening, this medication question should be raised urgently with an FTD neurologist.

Boxer et al. 2013 Lancet Neurology multicenter RCT specifically tested memantine in FTD and found no benefit on clinical measures of function or behavior, with a trend toward worsening cognitive performance on some measures. Memantine is not recommended for any FTD variant.

Semorinemab (Roche/Genentech) failed its primary endpoint in the LAURIET trial in Alzheimer’s disease in 2022. Zagotenemab (Lilly) also failed in AD trials. Tau pathology in MAPT-FTD is molecularly distinct from AD tau (different isoform compositions, different conformations), so results in AD cannot be assumed to predict results in MAPT-FTD. Dedicated trials in MAPT mutation carriers with tau-specific endpoints are being designed. Anti-tau antibodies designed for AD should not be assumed appropriate for FTD tau.

Expert consensus has moved away from antipsychotics as first-line behavioral management in FTD. SSRIs and trazodone are preferred first-line agents. When antipsychotics are used, low-dose quetiapine is generally preferred due to lower dopamine blockade. Haloperidol and other typical antipsychotics should be avoided entirely — particularly dangerous in PSP and CBS where they can cause severe and irreversible parkinsonism.

• Selegiline (MAO-B inhibitor): No clinical benefit in FTD-specific trials
• Riluzole alone (for non-ALS FTD): No disease modification demonstrated; not used outside of ALS/FTD overlap cases
• Nicotine patch: A small RCT showed no significant benefit over placebo in FTD; not recommended outside of trials
• Corticosteroids: No benefit; FTD is not an autoimmune inflammatory disease in the conventional sense
• Leucovorin supplementation: Small biomarker signal in GRN carriers; not replicated; no clinical benefit established; not recommended outside trials
• GLP-1 agonists (semaglutide, etc.): Considerable interest based on metabolic and cardiovascular data; no FTD-specific data as of 2026; trials underway in Parkinson’s; FTD investigation requires specific trial design; not recommended for FTD outside of controlled trials
• Anti-amyloid therapies (lecanemab, donanemab) in bvFTD: Amyloid is not the primary pathology in FTD; anti-amyloid drugs are not appropriate for bvFTD. Exception: lvPPA with confirmed amyloid pathology (see lvPPA section).

Caregivers in FTD carry a uniquely heavy load, and looking after your own wellbeing is not optional or selfish — it is what makes sustained caregiving possible. The grief of FTD is particular: you are often mourning the loss of the person's personality, affection, and partnership while they are still physically present and apparently well, a painful experience sometimes called “ambiguous loss.” Naming it for what it is can be a relief, and it is one reason that support tailored specifically to FTD — rather than general dementia support — tends to help most, because other FTD caregivers understand the loss of empathy and the behavioral challenges in a way that is hard to convey otherwise.

Practically, build a support structure before you reach the breaking point rather than after. The Association for Frontotemporal Degeneration (AFTD) runs a HelpLine (1-866-507-7222) and support groups created specifically for FTD families. Ask your care team early about respite care, adult day programs, social work, and counseling — using these is a sign of doing caregiving well, not of failing at it. Because FTD often strikes in mid-life, the practical stresses are different too: lost income, dependent children, and legal-financial exposure from a disinhibited partner make early advance-care, power-of-attorney, and financial planning especially important, and a social worker or elder-law attorney can be invaluable.

Watch for your own burnout, depression, and isolation, and treat them as real needs deserving care rather than weaknesses to push through. The single most protective step many caregivers report is simply not doing it alone — sharing the load with family, professionals, and others who have walked the same path.

• Behavioral symptoms before memory loss: FTD causes personality change and disinhibition before significant memory impairment. Families often struggle to get the diagnosis taken seriously because “they can still remember things.”
• Anosognosia: Most bvFTD patients have no awareness of their own behavioral changes. This is neurological — not stubbornness or denial — making it impossible to reason with the person about their behavior.
• Younger onset: Median age of FTD onset is 58. Many patients are diagnosed in their 50s or 40s — active employment, dependent children still at home, mortgages, college funding all disrupted. The financial consequences are categorically different from dementia in patients over 80.
• Legal and financial implications: Disinhibited FTD patients may make large impulsive purchases, give away money, or sign contracts inappropriately. Establishing durable power of attorney (POA) and financial POA early — while the patient still has legal capacity — is critical.
• Impact on marriage: The partner becomes a caregiver for a person who no longer shows affection, reciprocity, or empathy. Divorce, separation, and estrangement from family members are common in FTD.

• Durable Power of Attorney for Healthcare (HCPOA): Designate a healthcare proxy while the patient has legal capacity
• Financial Power of Attorney: Designate a trusted person to manage finances before financial capacity is lost; otherwise court-supervised guardianship may be required
• POLST (Physician Orders for Life-Sustaining Treatment): A physician-signed medical order specifying preferences for CPR, artificial nutrition, and hospitalization; more immediately actionable than an advance directive in an emergency
• FTD-ALS respiratory advance directives are critical: Decisions about NIV, tracheostomy, and feeding tube must be discussed with the neurology team and palliative care early — before respiratory symptoms begin. Many families who have not had this conversation make irrevocable decisions in a crisis.

• Social Security Disability Insurance (SSDI): FTD qualifies under the Compassionate Allowances program, which expedites approval for serious neurological conditions. Apply as early as possible; there is a 5-month waiting period before benefits begin.
• Family and Medical Leave Act (FMLA): Employed caregivers are entitled to up to 12 weeks of unpaid, job-protected leave per year to care for a spouse or parent with a serious health condition.
• Long-term disability insurance: If a policy exists, file promptly. Policies typically have elimination periods of 90–180 days. An experienced disability attorney can assist with denied claims.
• Long-term care insurance: If a policy exists, review its terms immediately. FTD-related cognitive impairment triggers most ADL and cognitive impairment benefit clauses. Notify the insurer early.
• AFTD financial resources: theaftd.org/living-with-ftd/resources — curated list of financial assistance programs, SSDI guidance, and insurance navigation for FTD families

• AFTD (Association for Frontotemporal Degeneration) — theaftd.org; 1-866-507-7222 (helpline, M–F business hours). Primary US patient and caregiver organization. Provides knowledgeable helpline staff, FTD Caregiver Support Center, caregiver handbook (free download), driving and FTD guide, legal and financial resources, and support group listings.
• FTD Connect — Online peer support community at theaftd.org/ftdconnect. Disease-specific discussion forums; connection with others at similar stages of the journey.
• CurePSP — curepsp.org; 1-800-457-4777. Primary organization for PSP and CBD patients and families. Families navigating PSP/CBS presentations should be in contact with CurePSP in addition to AFTD.
• FTD Disorders Registry — ftd-registry.org. Connects families with researchers and trials; particularly valuable for genetic mutation carriers. Registration is free.
• UCSF Memory and Aging Center Caregiver Resources — memory.ucsf.edu/caregivers. Free educational videos, caregiver guides, and webinars from the UCSF FTD team. Available to anyone, regardless of where the patient is cared for.
• Adult day programs: Programs experienced with behavioral dementia (not just memory-loss Alzheimer’s) can provide respite and meaningful stimulation. Ask specifically whether staff are trained in behavioral dementia management before enrolling.
• Memory care placement: When home care becomes unsafe or unsustainable, seek facilities with specific experience in behavioral dementia rather than primarily Alzheimer’s memory-loss care. Ask about staff training, medication philosophy (minimizing antipsychotics), and experience with younger-onset residents.

ALLFTD

Advancing Research and Treatment for Frontotemporal Lobar Degeneration — a NINDS-funded US multicenter consortium conducting natural history studies and serving as the infrastructure for clinical trials. Enrolls symptomatic and presymptomatic participants. allianceftd.org.

Anosognosia

Lack of awareness of one’s own deficits caused by the brain disease itself, not by psychological denial. Most bvFTD patients have anosognosia for their behavioral changes and genuinely do not perceive themselves as having a problem. This is neurological.

Antisense oligonucleotide (ASO)

A short synthetic DNA-like strand designed to bind to a specific RNA and either degrade it or block it from being translated into protein. Intrathecal ASOs (injected into spinal fluid) are the delivery vehicle for tau-lowering programs (e.g., NIO752, BIIB080) and C9orf72-targeted programs (e.g., WVE-004) studied across the FTD/FTLD spectrum.

Aphasia

Impairment of language ability caused by brain disease. In FTD, aphasia is a core feature of the PPA variants (nfvPPA and svPPA) — distinct from the behavioral symptoms that dominate bvFTD.

ASO

See Antisense oligonucleotide.

Atrophy

Brain tissue loss visible on MRI. In FTD, atrophy patterns are regionally specific: frontotemporal in bvFTD, left frontal/perisylvian in nfvPPA, left temporal in svPPA, and variable subcortical in PSP/CBS. The pattern of atrophy guides diagnosis.

bvFTD

Behavioral variant frontotemporal dementia. The most common FTD subtype, characterized by personality change, disinhibition, apathy, compulsive behaviors, changes in empathy, and dietary changes — with relative preservation of memory in early stages. Caused most often by TDP-43 or tau pathology.

C9orf72

A gene on chromosome 9. A hexanucleotide (GGGGCC) repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD worldwide, and causes a disease continuum that includes FTD, ALS, and FTD-ALS. The repeat generates toxic RNA and dipeptide repeat (DPR) proteins that impair cellular function.

CBS

Corticobasal syndrome. A motor and cognitive syndrome with FTD-spectrum features including alien limb phenomenon, apraxia, cortical sensory loss, rigidity, and myoclonus. Often associated with CBD (corticobasal degeneration) tau pathology, but can be caused by multiple underlying pathologies including PSP, AD, and FTLD-TDP.

CDR+NACC FTLD-SB

Clinical Dementia Rating scale plus the National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration Sum of Boxes. A standardized clinical outcome measure used as a primary endpoint in FTD clinical trials. Higher scores indicate more impairment.

Cognitive reserve

The brain’s capacity to tolerate pathological damage without clinical symptoms, built up through education, occupational complexity, and cognitive engagement. Higher cognitive reserve delays symptom onset but may compress the symptomatic phase.

DPR (dipeptide repeat protein)

Toxic proteins produced by an abnormal translation process from the C9orf72 repeat expansion. DPR proteins (poly-GA, poly-GP, poly-GR, etc.) are thought to impair protein quality control and nuclear-cytoplasmic transport. Poly-GP in CSF is being developed as a pharmacodynamic biomarker for C9orf72 trials.

FDG-PET

Fluorodeoxyglucose positron emission tomography. Measures brain glucose metabolism (a proxy for neuronal activity). In FTD, FDG-PET shows frontal and/or temporal hypometabolism; helps distinguish FTD from Alzheimer’s disease.

FKLD / FTLD

Frontotemporal lobar degeneration. The neuropathological term for the pattern of brain degeneration underlying the clinical FTD syndromes. The pathological subtypes (FTLD-TDP, FTLD-tau, FTLD-FUS) refer to the protein that accumulates, not to the clinical presentation.

FTD

Frontotemporal dementia. The clinical umbrella term for a group of neurodegenerative brain diseases that primarily affect the frontal and temporal lobes, causing behavioral changes, language impairment, and/or motor symptoms. Also called Pick’s disease (historically), frontotemporal lobar degeneration (the neuropathological term), or frontotemporal brain degeneration (the term preferred by some advocacy groups to reduce stigma around “dementia”).

FUS proteinopathy

An uncommon cause of FTLD involving inclusions of the FUS (fused in sarcoma) protein. Distinct from TDP-43 and tau pathologies. Often presents in younger patients, sometimes with behavioral symptoms and ALS overlap.

GENFI

Genetic Frontotemporal dementia Initiative. An 18-site European (and international) longitudinal study of genetic FTD mutation carriers, coordinated by Jonathan Rohrer at UCL. GENFI has established the natural history of presymptomatic and early symptomatic genetic FTD across GRN, MAPT, and C9orf72 mutations. Data from GENFI have defined most of what is known about disease timing, biomarker trajectories, and neuroimaging changes before symptom onset.

GRN

The progranulin gene. Heterozygous loss-of-function mutations in GRN reduce brain progranulin levels by approximately 50%, causing TDP-43 type A accumulation in neurons. GRN-FTD is the second most common genetic cause of FTD. The protein product (progranulin) is a lysosomal growth factor important for neuronal survival and microglial function.

Hexanucleotide repeat expansion

The molecular change in C9orf72 FTD/ALS: a six-nucleotide sequence (GGGGCC) that is repeated hundreds or thousands of times in affected individuals (compared to fewer than 30 in unaffected individuals). This expansion generates toxic RNA foci and DPR proteins.

MAPT

The microtubule-associated protein tau gene. Mutations in MAPT cause production of tau protein with abnormal structure or abnormal isoform ratios, leading to tau aggregation in neurons. MAPT-FTD is predominantly a tauopathy; different mutations cause different clinical presentations including bvFTD, nfvPPA, PSP-like syndrome, and CBS-like syndrome. Autosomal dominant; each child of a carrier has a 50% chance of inheriting the mutation.

Memory

Explicit episodic memory (memory for events, like Alzheimer’s disease) is relatively preserved in early bvFTD and PPA variants. This is a critical distinguishing feature: “they can still remember things” is common family feedback that often delays FTD diagnosis. Semantic memory (knowledge of word meanings) is specifically impaired in svPPA.

MRI (magnetic resonance imaging)

Structural brain imaging that reveals atrophy patterns. FTD produces frontotemporal atrophy on MRI; specific subtype patterns guide diagnosis. MRI also helps rule out structural causes of symptoms (tumor, stroke, hydrocephalus).

NfL (neurofilament light chain)

A structural protein released from damaged neurons into blood and CSF. Elevated in all neurodegenerative diseases. In FTD, plasma NfL is elevated, rises with disease progression, and is being validated as a pharmacodynamic biomarker (falling NfL = less neuronal damage) in clinical trials including INFRONT-3. NfL does not distinguish FTD from ALS, AD, or other neurodegenerative diseases — but its trajectory within a known FTD patient provides a useful signal.

nfvPPA

Non-fluent/agrammatic variant primary progressive aphasia. A PPA subtype characterized by effortful, halting speech (apraxia of speech), grammatical errors, and impaired sentence comprehension with preserved word knowledge. Associated with FTLD-tau (CBD or PSP pathology) or FTLD-TDP type A. The most common PPA variant to progress to a CBS or PSP motor syndrome.

Neuropathology

The microscopic examination of brain tissue at autopsy. Currently the only definitive way to confirm FTD diagnosis and identify the underlying protein pathology (TDP-43 type, tau subtype, FUS). Autopsy studies have repeatedly revealed that clinical diagnoses are correct in approximately 70% of cases — and misdiagnosed as Alzheimer’s or PSP in up to 30%. Brain donation programs at UCSF, Mayo, Northwestern, and other centers provide definitive diagnoses for families and advance research. Contact your FTD center to learn about brain donation options before death.

PET (positron emission tomography)

Nuclear medicine imaging that can measure brain metabolism (FDG-PET), amyloid deposits (amyloid-PET), or tau deposits (tau-PET). FDG-PET shows reduced metabolism in frontal and temporal lobes in FTD. Amyloid-PET is used to rule out Alzheimer’s pathology. Tau-PET is used in research settings but not yet standard clinical care for FTD.

Pick bodies

Tau protein inclusions found in neurons in Pick’s disease, a specific FTLD-tau subtype associated with 3-repeat (3R) tau accumulation. Not present in all tauopathies. When neuropathologists identify Pick bodies at autopsy, this distinguishes Pick’s disease from other tau subtypes.

PPA (primary progressive aphasia)

An FTD-spectrum syndrome in which language impairment is the dominant early symptom for at least two years, with other cognitive and behavioral functions relatively preserved. Three main variants: nfvPPA (non-fluent/agrammatic), svPPA (semantic variant), and lvPPA (logopenic variant, often Alzheimer’s-related).

Progranulin

A lysosomal growth factor encoded by the GRN gene. Progranulin is essential for lysosomal function, neuronal survival, and regulation of neuroinflammation. Reduced progranulin (from GRN loss-of-function mutations) leads to lysosomal dysfunction and TDP-43 accumulation. Progranulin restoration is the mechanistic rationale for latozinemab and AAV9 gene therapy trials in GRN-FTD.

PSP (progressive supranuclear palsy)

A tau FTD-spectrum syndrome causing falls, vertical gaze palsy (inability to look up or down voluntarily), parkinsonian features, and behavioral/cognitive changes. PSP-Richardson syndrome is the classic presentation; PSP-bvFTD and PSP-nfvPPA are behavioral and language phenotypes. Caused by 4-repeat (4R) tau accumulation in specific brain regions. Cholinesterase inhibitors and typical antipsychotics can cause severe worsening in PSP and should be avoided.

Semantic memory

Knowledge of word meanings, concepts, and facts about the world (as opposed to memory for personal events). Semantic memory is specifically degraded in svPPA — patients lose knowledge of what words mean and what familiar objects are, while episodic memory may be relatively preserved.

Sortilin (SORT1)

A receptor that binds progranulin and traffics it to lysosomes for degradation. Blocking sortilin with an antibody (latozinemab/AL001) prevents progranulin degradation, raising tissue progranulin levels. This is the mechanism of action for latozinemab in GRN-FTD trials.

svPPA

Semantic variant primary progressive aphasia (also called semantic dementia). Characterized by progressive loss of word meaning (anomia, surface dyslexia, loss of object knowledge), with fluent but empty speech. Associated with TDP-43 type C pathology and left anterior temporal lobe atrophy. When right-predominant, behavioral symptoms are prominent.

TDP-43

TAR DNA-binding protein 43. Normally a nuclear protein; in FTD and ALS, TDP-43 misfolds, leaves the nucleus, and forms cytoplasmic inclusions. TDP-43 proteinopathy is the most common pathological subtype of FTD, accounting for approximately 60% of cases. Subtypes (A, B, C, D) are defined by inclusion morphology and distribution; each type is associated with distinct clinical presentations and genetic causes.

Tau

A microtubule-stabilizing protein encoded by the MAPT gene. In tauopathies (including MAPT-FTD, PSP, CBD, Pick’s disease, and Alzheimer’s disease), tau becomes hyperphosphorylated and forms intracellular aggregates. Different FTD tauopathies are characterized by different tau isoform compositions (3R, 4R, or mixed 3R/4R tau).

• Rascovsky K, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(9):2456–2477. PMID 21810890. (The consensus bvFTD diagnostic criteria.)
• Gorno-Tempini ML, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006–1014. PMID 21325651. (PPA variant criteria.)
• Litvan I, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies. Arch Neurol. 1998;55(7):969–978. (PSP/CBS overlap reference.)
• Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386(10004):1672–1682. PMID 26595641. (Comprehensive clinical review.)
• American Academy of Neurology (AAN) Quality of Care and Practice Advisory Committee. AAN guidance documents available at aan.com/Guidelines.

• DeJesus-Hernandez M, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–256. PMID 21944778. (C9orf72 discovery.)
• Baker M, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442(7105):916–919. PMID 16862116. (GRN discovery.)
• Hutton M, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686):702–705. PMID 9641683. (MAPT discovery.)
• Rohrer JD, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study. Lancet Neurol. 2015;14(3):253–262. PMID 25662776. (GENFI presymptomatic cohort.)
• Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol. 2019;266(8):2075–2086. PMID 31119452. (GENFI summary.)

• ClinicalTrials.gov NCT04374136 — INFRONT-3 (latozinemab in GRN-FTD). Results reported October 2025; verify current status.
• ClinicalTrials.gov NCT04747431 — upliFT-D (PBFT02 AAV1 GRN gene therapy, Passage Bio). Phase 1/2. (AVB-101/ASPIRE-FTD, NCT06064890, is a second GRN gene-therapy program.)
• ClinicalTrials.gov NCT04539041 — NIO752 (Novartis tau-lowering ASO) in PSP, a FTLD-tau-spectrum tauopathy. Phase 1.
• ClinicalTrials.gov NCT04931862 — FOCUS-C9 (WVE-004 C9orf72 ASO, Wave). Phase 1b/2a; discontinued after no clinical benefit.
• Miller TM, et al. Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. NEJM. 2020;383(2):109–119. PMID 32640130. (Tofersen precedent trial.)
• Boxer AL, et al. Memantine in patients with frontotemporal lobar degeneration. Lancet Neurol. 2013;12(2):149–156. PMID 23290598. (Negative memantine RCT in FTD.)

• Association for Frontotemporal Degeneration (AFTD) — theaftd.org; 1-866-507-7222
• CurePSP (PSP and CBS) — curepsp.org; 1-800-457-4777
• FTD Disorders Registry — ftd-registry.org
• ALLFTD Consortium — allianceftd.org
• UCSF Memory and Aging Center Patient Resources — memory.ucsf.edu
• Pick’s Disease Support Group (UK) — pdsg.org.uk
• Social Security Administration Compassionate Allowances for FTD — ssa.gov/compassionateallowances
• Alzheimer’s Association (broader dementia support) — alz.org; 1-800-272-3900
• National Institute on Aging (NIA) — nia.nih.gov; NIA Alzheimer’s and Related Dementias Education and Referral Center: 1-800-438-4380

Based on: Rascovsky 2011 bvFTD consensus criteria; Gorno-Tempini 2011 PPA criteria; GENFI natural history study; ALLFTD consortium data; INFRONT-3/upliFT-D/RALLY/ALLFTD and related trial registrations; AFTD clinical and caregiver guidance; CurePSP clinical guidance; AAN guidelines for dementia evaluation.