Dig Deeper Into Dementia: Clinical Trials Explore Genetic Component of FTD

Although frontotemporal dementia is the leading cause of the disease for those under 65 years of age, far fewer people are familiar with it than with Alzheimer disease.

The number of people diagnosed with dementia is continuing to climb. Worldwide, clinicians identify roughly 10 million new cases every year, adding to the 50 million people already diagnosed.1 Among this population, as many as 60,000 Americans may have a specific group of disorders called frontotemporal dementia (FTD), which primarily affects younger adults.2

FTD—also referred to as frontotemporal degeneration and formerly called Pick disease—typically manifests in patients in their 50s or 60s, but it can occur much earlier or later in life.3 Although it's the leading cause of dementia for those under 65 years of age, far fewer people are familiar with it than with Alzheimer disease.

The Association for Frontotemporal Degeneration calls it “the cruelest disease you've never heard of,” and describes its marked changes in patients' personality, behavior, language, and movement caused by the loss of nerve cells in the brain's frontal or temporal lobes.4

The debilitating and life-threatening condition tends to progress rapidly, with an average survival time of 8 years after symptom onset.5 This relatively swift progression, coupled with the early age of onset, makes it critical to identify patients with FTD as quickly as possible to achieve the best outcomes.

However, FTD often is misdiagnosed as Alzheimer disease, a psychiatric disorder, vascular dementia, or Parkinson disease.6 For some affected individuals, genetic screening can help achieve a more accurate diagnosis and lead to more precise interventions.

Role of genetics in diagnosis and research

FTD is a group of disorders, each of which may present with similar but distinct impairments in behavior, language, memory, or thought processes. Some forms of FTD highly affect behavior, for example, whereas others predominantly result in language deficits.

Research suggests that approximately30% of all FTD is hereditary, although the genetic cause for disease in many families is still unknown.7 When the genetic cause for an FTD diagnosis is known, it most commonly involves a disease-causing variant in the progranulin (GRN), C9orf72, or MAPT genes—all of which can be screened through genetic testing.

Although no approved disease-modifying therapies currently exist for FTD, confirmation of a genetic variant underlying the diagnosis is crucial for 3 reasons:

  1. It allows clinicians to intervene sooner with a more defined treatment approach for the patient's specific form of FTD. For example, confirming that the underlying disease is FTD—as opposed to depression or Alzheimer disease, for instance—may lead the prescribing physician to choose different medications.
  1. It may open the door to participation in clinical trials.
  2. It allows for accurate risk assessment for family members who may wish to consider pre-symptomatic genetic testing (testing before symptoms appear), which is especially important given that family history is one of the few known risk factors for FTD.

Genetic testing can be very useful in helping health care providers pinpoint the root cause of an individual's disease, which may, in turn, help identify drugs and other therapies with the highest potential to improve the patient’s quality of life. In addition, patients may have the option to participate in clinical trials if their FTD diagnosis is confirmed through genetic testing. The Association for FTD (AFTD) explains various options for patients to participate in clinical research.8

For example, a phase 1/2 clinical trial is currently being initiated to study PBFT02, an adeno-associated virus (AAV)-delivery gene therapy for the treatment of patients with FTD with progranulin (GRN) variant.9

This represents approximately 5% to 10% of individuals with FTD—roughly 3000 to 6000 Americans—where the disease occurs because of disease-causing variants in the GRN gene that cause a deficiency of the important protein progranluin.10

In addition, 2 ongoing programs in the United States currently seek to identify people at risk for or with FTD caused by a progranulin gene mutation.11 In conjunction with the trials, both of the sponsor companies have partnered with a genetics services organization and a genetic testing lab to provide no-cost genetic counseling and testing for adults diagnosed with FTD.12

The goal is 2-fold:

  1. To identify whether there is an inherited genetic variant causing the disease in patients diagnosed with FTD.
  2. To increase awareness of clinical trials and inform families of possible research participation opportunities for which they may be eligible.

Through the programs, genetic counselors highly trained in hereditary neurological conditions discuss the genetics of FTD, genetic testing options, and potential implications of genetic testing with patients and their family members over the phone. Should a patient elect to proceed with genetic testing, the counselor coordinates the test order and sample collection. The counselor then follows up with the patient to discuss test results, including information about any potential treatments and/or available clinical trial options for which they may be eligible.

Greater awareness for the FTD community

FTD can be a debilitating diagnosis. There is much hope that the clinical research programs underway will help close the gap that many people now face in understanding their own or a loved one's diagnosis. The collaborative effort can serve as a valuable resource for the FTD community, allowing for greater awareness, earlier and more precise disease management, and potential participation in clinical trials aimed at finding innovative treatment options.


  1. World Health Organization. Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia. Accessed 22 July 2021.
  2. The Association for Frontotemporal Degeneration. Fast Facts about Frontotemporal Degeneration. https://www.theaftd.org/wp-content/uploads/2009/05/Fast-Facts-Final-11-12.pdf. Accessed 22 July 2021.
  3. Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/frontotemporal-dementia. Accessed 22 July 2021.
  4. The Association for Frontotemporal Degeneration. https://www.theaftd.org/60minutes/?gclid=CjwKCAjwwqaGBhBKEiwAMk-FtIYECLv4u62K0ISRGXNxQNjJeQ8edf4AmpJhjObaLDYafwuhP_A6TBoC27UQAvD_BwE. Accessed 22 July 2021.
  5. J R Hodges, R Davies, J Xuereb, J Kril, G Halliday. Survival in frontotemporal dementia. Neurology 2003 Aug 12;61(3):349-54. https://pubmed.ncbi.nlm.nih.gov/12913196/. Accessed 22 July 2021.
  6. University of California San Francisco Weill Institute for Neurosciences Memory and Aging Center. Frontotemporal Dementia versus Alzheimer’s Disease. https://memory.ucsf.edu/dementia/ftd/ftd-misdiagnosis. Accessed 22 July 2021.
  7. Alzheimer’s Society. Frontotemporal dementia and genes. https://www.alzheimers.org.uk/about-dementia/risk-factors-and-prevention/frontotemporal-dementia-and-genes. Accessed 22 July 2021.
  8. The Association for Frontotemporal Degeneration. Clinical Trials. https://www.theaftd.org/research-clinical-trials/ways-to-participate/clinical-trials/. Accessed 22 July 2021.
  9. National Institutes of Health U.S. National Library of Medicine. A Study of PBFT02 in Patients With Frontotemporal Dementia and Progranulin Mutations (FTD-GRN) (upliFT-D). https://clinicaltrials.gov/ct2/show/NCT04747431. Accessed 22 July 2021.
  10. Leonel T. Takada. The Genetics of Monogenic Frontotemporal Dementia. Dement Neuropsychol. 2015 Jul-Sep; 9(3): 219–229. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619362/. Accessed 22 July 2021.
  11. InformedDNA. Progranulin Gene Frontotemporal Dementia (PG FTD): Genetic counseling and testing for progranulin gene-related FTD. https://informeddna.com/alector/. Accessed 22 July 2021.No-Cost Genetic Counseling and Genetic Testing for Frontotemporal Dementia (FTD). https://informeddna.com/passagebio-ftd/. Accessed 22 July 2021.
  12. No-Cost Genetic Counseling and Genetic Testing for Frontotemporal Dementia (FTD). https://informeddna.com/passagebio-ftd/. Accessed 22 July 2021.