Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 25 peer-reviewed journal articles Updated
Neurology

The Biology of FTD: Proteins, Genes, and Diagnostic Tools

At a Glance

Frontotemporal dementia (FTD) is driven by misfolding proteins like TDP-43 and Tau, which damage the brain's frontal and temporal lobes. While most cases are sporadic, up to 40% are genetic. Doctors use MRI, PET scans, and biomarkers to confirm a diagnosis and rule out Alzheimer's disease.

While the symptoms of frontotemporal dementia (FTD) involve behavior and language, the “engine” driving the disease is a biological process occurring deep within the brain’s cells. Understanding these biological and genetic markers is key to moving from a “suspected” diagnosis to a confirmed one.

The Misbehaving Proteins

In a healthy brain, proteins perform vital tasks like maintaining cell structure and moving nutrients. In FTD, specific proteins begin to misfold, clump together, and become toxic, eventually causing brain cells to die [1][2].

There are three main protein “culprits” in FTD:

  • TDP-43: Found in about 50% of cases, this protein normally helps process genetic instructions. When it fails, it clumps in the brain, often leading to the behavioral variant of FTD or FTD-ALS [3][4].
  • Tau: In many other cases, a protein called tau—which normally stabilizes the “skeletons” of brain cells—forms tangled filaments that disrupt cell function [5][6].
  • FUS: This is a rarer protein involved in FTD, often associated with an earlier age of onset and specific behavioral symptoms [7].

The Role of Genetics

For about 60-70% of people, FTD is “sporadic,” meaning there is no known family history [8]. However, for the remaining 30-40%, FTD is familial, meaning it is passed down through genes [9].

The three most common genetic mutations are:

  1. C9orf72: The most frequent genetic cause, linked to both FTD and ALS. It often causes shrinkage in the thalamus and cerebellum early in the disease [10][11].
  2. MAPT: This mutation causes the tau protein to malfunction, leading to cell death primarily in the temporal lobes [12][13].
  3. GRN (Progranulin): This mutation causes a deficiency in a protein that helps keep brain cells healthy and “clean.” It often leads to TDP-43 clumping and highly asymmetric brain shrinkage [14][15].

A Note on Genetic Testing: Because FTD has a strong genetic component, discovering a familial mutation carries profound psychological implications for the entire family, including adult children who may wish to know their own risk. It is strongly recommended that anyone considering genetic testing consult with a certified genetic counselor prior to testing to fully understand these implications [9].

Confirming the Diagnosis: Scans and Biomarkers

Because FTD symptoms can look like other conditions, doctors use several tools to confirm what is happening biologically:

Brain Imaging

  • MRI (Structural): Doctors look for atrophy (shrinkage) in the frontal and temporal lobes. In advanced cases, the brain tissue undergoes severe shrinkage (often described in medical reports as “knife-edge” atrophy, a term that can be alarming to read but simply describes advanced tissue loss) [16][17].
  • PET Scans: FDG-PET shows where the brain is using less energy (glucose), while Amyloid-PET is used to “rule out” Alzheimer’s. A negative amyloid scan means the symptoms are likely not caused by Alzheimer’s pathology [18][19][20].

Blood and Fluid Biomarkers

  • p-tau181: High levels of this protein in the blood strongly suggest Alzheimer’s disease. Low levels, combined with dementia symptoms, point toward FTD [21][22].
  • Neurofilament Light Chain (NfL): This is a general marker of brain cell damage. While it doesn’t tell us which dementia a person has, very high levels can help distinguish a neurodegenerative disease like FTD from a primary psychiatric disorder like depression [23][24].

By combining genetic history, protein-specific blood tests, and advanced imaging, your care team can create a biological map of the disease, allowing for more precise management and a clearer outlook for the future [9][25].

Common questions in this guide

Is frontotemporal dementia hereditary?
Most cases of FTD are sporadic, meaning there is no known family history. However, about 30 to 40 percent of cases are familial and passed down through genetics. The most common genetic mutations linked to FTD involve the C9orf72, MAPT, and GRN genes.
Should I get genetic testing for FTD?
Because FTD has a strong genetic component, testing can reveal hereditary risks for you and your family. However, it is strongly recommended that anyone considering genetic testing speak with a certified genetic counselor first to fully understand the psychological implications.
How do brain scans help diagnose FTD?
Doctors use structural MRIs to look for specific tissue shrinkage, or atrophy, in the frontal and temporal lobes of the brain. They may also use PET scans to see where the brain is using less energy or to rule out Alzheimer's disease.
What is a p-tau181 blood test used for?
The p-tau181 test helps differentiate between FTD and Alzheimer's disease. High levels of this protein in the blood strongly suggest Alzheimer's, while low levels combined with dementia symptoms point toward FTD.
What does an NfL blood test tell us about dementia?
Neurofilament Light Chain (NfL) is a general biomarker that indicates brain cell damage. Very high levels of NfL can help doctors confirm that symptoms are caused by a neurodegenerative disease like FTD rather than a primary psychiatric disorder like depression.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Have we ruled out Alzheimer’s disease using a plasma p-tau181 test or an amyloid-PET scan?
  2. 2.Does the MRI show specific shrinkage in the frontal and temporal lobes consistent with FTD?
  3. 3.Is our case considered 'sporadic' or 'familial,' and should we speak with a genetic counselor about testing for the C9orf72, MAPT, or GRN mutations?
  4. 4.What do the levels of Neurofilament Light Chain (NfL) in the blood or spinal fluid tell us about the speed of neurodegeneration?
  5. 5.If we suspect a genetic cause, how might that change our eligibility for upcoming clinical trials?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (25)
  1. 1

    Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations.

    Lashley T, Rohrer JD, Mead S, Revesz T

    Neuropathology and applied neurobiology 2015; (41(7)):858-81 doi:10.1111/nan.12250.

    PMID: 26041104
  2. 2

    Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants.

    Staffaroni AM, Goh SM, Cobigo Y, et al.

    JAMA network open 2020; (3(10)):e2022847 doi:10.1001/jamanetworkopen.2020.22847.

    PMID: 33112398
  3. 3

    TDP-43 binds and transports G-quadruplex-containing mRNAs into neurites for local translation.

    Ishiguro A, Kimura N, Watanabe Y, et al.

    Genes to cells : devoted to molecular & cellular mechanisms 2016; (21(5)):466-81 doi:10.1111/gtc.12352.

    PMID: 26915990
  4. 4

    Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.

    Zeng J, Luo C, Jiang Y, et al.

    Acta neuropathologica communications 2024; (12(1)):205 doi:10.1186/s40478-024-01914-9.

    PMID: 39736783
  5. 5

    The Genetics of Monogenic Frontotemporal Dementia.

    Takada LT

    Dementia & neuropsychologia 2015; (9(3)):219-229 doi:10.1590/1980-57642015DN93000003.

    PMID: 29213965
  6. 6

    Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

    Zhang L, Flagan TM, Häkkinen S, et al.

    Annals of neurology 2023; (94(4)):632-646 doi:10.1002/ana.26738.

    PMID: 37431188
  7. 7

    Young-onset frontotemporal dementia with FUS pathology.

    Gowell M, Baker I, Ansorge O, Husain M

    Practical neurology 2020; doi:10.1136/practneurol-2020-002730.

    PMID: 33310885
  8. 8

    Understanding Frontotemporal Disease Progression and Management Strategies.

    Mulkey M

    The Nursing clinics of North America 2019; (54(3)):437-448 doi:10.1016/j.cnur.2019.04.011.

    PMID: 31331629
  9. 9

    Predictors of survival in frontotemporal lobar degeneration syndromes.

    El-Wahsh S, Finger EC, Piguet O, et al.

    Journal of neurology, neurosurgery, and psychiatry 2021; doi:10.1136/jnnp-2020-324349.

    PMID: 33441385
  10. 10

    RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy.

    Burrows DJ, McGown A, Abduljabbar O, et al.

    Annals of neurology 2024; (96(6)):1058-1069 doi:10.1002/ana.27068.

    PMID: 39215697
  11. 11

    Presymptomatic grey matter alterations in ALS kindreds: a computational neuroimaging study of asymptomatic C9orf72 and SOD1 mutation carriers.

    Bede P, Lulé D, Müller HP, et al.

    Journal of neurology 2023; (270(9)):4235-4247 doi:10.1007/s00415-023-11764-5.

    PMID: 37178170
  12. 12

    In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

    Zhou XY, Lu JY, Liu FT, et al.

    Movement disorders : official journal of the Movement Disorder Society 2022; (37(3)):525-534 doi:10.1002/mds.28867.

    PMID: 34842301
  13. 13

    Differential early subcortical involvement in genetic FTD within the GENFI cohort.

    Bocchetta M, Todd EG, Peakman G, et al.

    NeuroImage. Clinical 2021; (30()):102646 doi:10.1016/j.nicl.2021.102646.

    PMID: 33895632
  14. 14

    Neuroimmune dysfunction in frontotemporal dementia: Insights from progranulin and C9orf72 deficiency.

    Hashimoto K, Jahan N, Miller ZA, Huang EJ

    Current opinion in neurobiology 2022; (76()):102599 doi:10.1016/j.conb.2022.102599.

    PMID: 35792478
  15. 15

    White-matter abnormalities in presymptomatic GRN and C9orf72 mutation carriers.

    Lee H, Mackenzie IRA, Beg MF, et al.

    Brain communications 2023; (5(1)):fcac333 doi:10.1093/braincomms/fcac333.

    PMID: 36632182
  16. 16

    Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology.

    Peet BT, Spina S, Mundada N, La Joie R

    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2021; (18(2)):728-752 doi:10.1007/s13311-021-01101-x.

    PMID: 34389969
  17. 17

    Bilateral post-traumatic hygromas in patient with frontotemporal dementia.

    Scalia G, Marrone S, Costanzo R, et al.

    Surgical neurology international 2022; (13()):597 doi:10.25259/SNI_1056_2022.

    PMID: 36761258
  18. 18

    Neuropsychiatric Aspects of Frontotemporal Dementia.

    Younes K, Miller BL

    The Psychiatric clinics of North America 2020; (43(2)):345-360 doi:10.1016/j.psc.2020.02.005.

    PMID: 32439026
  19. 19

    Amyloid Imaging: Poised for Integration into Medical Practice.

    Anand K, Sabbagh M

    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2017; (14(1)):54-61 doi:10.1007/s13311-016-0474-y.

    PMID: 27571940
  20. 20

    Diagnostic value of amyloid-PET and tau-PET: a head-to-head comparison.

    Altomare D, Caprioglio C, Assal F, et al.

    European journal of nuclear medicine and molecular imaging 2021; (48(7)):2200-2211 doi:10.1007/s00259-021-05246-x.

    PMID: 33638661
  21. 21

    Diagnostic performance of plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL along the continuum of Alzheimer's disease and non-AD dementias: An international multi-center study.

    Doecke JD, Bellomo G, Vermunt L, et al.

    Alzheimer's & dementia : the journal of the Alzheimer's Association 2025; (21(6)):e14573 doi:10.1002/alz.14573.

    PMID: 40551285
  22. 22

    Diagnostic value of plasma p-tau181, NfL, and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias.

    Baiardi S, Quadalti C, Mammana A, et al.

    Alzheimer's research & therapy 2022; (14(1)):153 doi:10.1186/s13195-022-01093-6.

    PMID: 36221099
  23. 23

    Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration.

    Ahmad S, Imtiaz MA, Mishra A, et al.

    Communications biology 2024; (7(1)):1103 doi:10.1038/s42003-024-06804-3.

    PMID: 39251807
  24. 24

    The role of neurofilament light chain in frontotemporal dementia: a meta-analysis.

    Karantali E, Kazis D, Chatzikonstantinou S, et al.

    Aging clinical and experimental research 2021; (33(4)):869-881 doi:10.1007/s40520-020-01554-8.

    PMID: 32306372
  25. 25

    Multimodal mechanisms of human socially reinforced learning across neurodegenerative diseases.

    Legaz A, Abrevaya S, Dottori M, et al.

    Brain : a journal of neurology 2022; (145(3)):1052-1068 doi:10.1093/brain/awab345.

    PMID: 34529034

This page is for educational purposes only and does not replace professional medical advice. Always consult your neurologist or a certified genetic counselor to discuss your specific diagnostic results and testing options.

Get notified when new evidence is published on Frontotemporal dementia.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.