The Role of Genetics in FTD: An Overview


Partners in FTD Care, Winter 2022
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Frontotemporal degeneration (FTD) is a group of disorders caused by the degeneration of the frontal and/or temporal lobes of the brain, bringing progressive changes to behavior, personality, language, and/or movement. The FTD disorders occur when specific proteins accumulate and clump together in a person’s neurons. Three such proteins have been identified: tau, TDP-43, and FUS. The accumulation of any of these proteins in the neurons interferes with brain cell function and longevity, eventually leading to the symptoms of FTD.

What Causes FTD?
For most people with FTD, the accumulation of tau, TDP-43, or FUS protein in their neurons happens for unknown reasons. These individuals have no family history of FTD; their condition occurs as a random-chance, or sporadic, event.

Sporadic cases of FTD have a multifactorial etiology (meaning they are caused by a combination of multiple different factors). These factors have yet to be clearly established, but likely include aging, lifestyle/environment, and susceptibility genes that make us more (or less) vulnerable to developing sporadic FTD in our lifetime. None of these factors will cause FTD on their own, but their complex interactions somehow result in the abnormal accumulation of tau, TDP-43, or FUS protein in the brain cells. Exactly how or why this happens continues to be studied.

Up to 40% of people with FTD will report a family history of FTD or other neurological conditions such as amyotrophic lateral sclerosis (ALS) or Parkinson’s disease. These cases of FTD are described as familial.

In some families, these clusters of FTD or other neurological disorders are suspected to have a multifactorial etiology, and they are seen in multiple relatives because of significant sharing of underlying genetic susceptibility and/or lifestyle factors. In these families, FTD isn’t directly passed on from one generation to the next, but the close relatives of affected individuals may have an increased chance of developing FTD, as compared to the general population.

In other families, having multiple cases of FTD or other neurological disorders represents a purely genetic, or inherited, form of familial FTD. In these families, persons with FTD have abnormal TDP-43, tau, or FUS protein accumulation in their brain cells because of a variant in a single causative gene that can be directly passed on from one generation to the next. All known purely genetic forms of familial FTD are autosomal dominant, meaning that if an individual has an FTD-causing gene variant, each of their children will have a 50% chance of inheriting it.

Although most individuals with purely genetic forms of FTD will have a family history of FTD and/or other neurological disorder, family history doesn’t always tell the whole story. The gene variants that cause purely genetic forms of FTD have variable expression; the same variant can cause a wide range of symptoms and ages of onset, even in the same family. Furthermore, some of these FTD gene variants have reduced penetrance, meaning that an individual can carry the variant but live their entire life without developing FTD or a related condition. Researchers have found a small percentage of familial FTD gene variants in people with apparently sporadic FTD (i.e. no family history of FTD or other neurological disease).

More than a dozen causative familial FTD genes have been identified. Variants in three of these genes (C9orf72, GRN, and MAPT) explain the majority of purely genetic FTD cases. Variants in the other genes (including VCP, CHMP2B, TARDBP, FUS, SQSTM1, CHCHD10, TBK1, OPTN, CCNF, and TIA1) are rarer, with some being identified in only a handful of families around the world. Researchers anticipate that additional causative familial FTD genes will be identified in the future.

Common familial FTD genes include:

  • C9orf72 – FTD-causing C9orf72 variants consist of a section of the genetic code that gets repeated over and over, creating an expanded version of the C9orf72 gene. This expansion disrupts the gene’s normal function, leading to a cascade of events that result in abnormal accumulation of TDP-43 protein in the brain cells, along with another protein called GA dipeptide. Current research suggests that the combination of TDP-43 and GA dipeptide protein is only found in individuals with C9orf72 expansions. C9orf72 expansions are known to cause both FTD and ALS. Some C9orf72 expansion carriers can also present with psychiatric illness such as schizophrenia or bipolar disorder.
  • GRN (Progranulin) – The GRN gene provides instructions for making progranulin, a protein that is involved in cell survival and the regulation of inflammation. FTD-causing variants in GRN lead to reduced progranulin levels. For reasons that remain unclear, decreased levels of progranulin result in the abnormal accumulation of TDP-43 protein in brain cells. Individuals with GRN variants most often develop FTD symptoms, but some individuals present with parkinsonism.
  • MAPT (Microtubule-associated protein tau) – The MAPT gene provides instructions for making the tau protein, which plays a role in the assembly and stabilization of neurons. Variants in MAPT result in an abnormal form of tau, which can accumulate in the brain cells. Individuals with MAPT variants most often develop FTD symptoms, but some individuals present with parkinsonism.

Genetic Testing for FTD
Genetic testing for familial FTD is available at several clinical genetics laboratories in the U.S. and Europe. The testing must be ordered by a physician and involves analysis of the known causative familial FTD genes using a DNA sample from blood, saliva, or cheek cells.

Genetic testing ideally begins with a family member who has an FTD diagnosis. A positive result – meaning that a gene variant is identified – would confirm that they have a purely genetic form of FTD, and that each of their children and siblings have a 50% chance of carrying the same variant. Those first-degree relatives would then be able to undergo predictive genetic testing.

A negative result can provide some reassurance that an individual’s FTD is multifactorial. However, it would not rule out the possibility that they have a purely genetic form of familial FTD caused by a variant in a gene that has yet to be discovered. In this scenario, predictive genetic testing is not available to family members.

Deciding to have genetic testing can be difficult. Each family making this decision will have unique motivations, perspectives, and values. Testing should only be completed upon careful consideration of all test limitations and implications, including medical, social, psychological, and insurance consequences. Pre-test genetic counseling is recommended to ensure that individuals and families considering genetic testing are informed and supported during the decision-making process and beyond.

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