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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Neurology · Behavioral Variant Frontotemporal Dementia

The Biology and Genetics of bvFTD

At a Glance

Behavioral variant frontotemporal dementia (bvFTD) is driven by the abnormal buildup of proteins like TDP-43 or Tau in the brain. About 10% to 20% of cases are caused by inherited genetic mutations (C9orf72, MAPT, or GRN), which carry a 50% chance of being passed to children.

While behavioral variant frontotemporal dementia (bvFTD) is diagnosed based on behavior, the underlying cause is a biological breakdown in the brain. Scientists categorize this breakdown as Frontotemporal Lobar Degeneration (FTLD) [1]. Essentially, proteins that normally help brain cells function begin to misfold, clump together, and become toxic, eventually causing those cells to wither and die [2][3].

The “Bad” Proteins

There are three main proteins associated with FTLD. Knowing which protein is at work can sometimes help doctors predict how the disease will progress, although this is usually confirmed definitively only after a person passes away [2].

  • TDP-43: Found in about half of all cases. When TDP-43 clumps, it can also lead to motor neuron issues, such as ALS (Amyotrophic Lateral Sclerosis) [2][4].
  • Tau: This protein is responsible for about 40% of cases [5]. In healthy brains, Tau acts like railroad ties that keep brain cell structures stable. In bvFTD, it collapses into tangles that choke the cells from the inside [6].
  • FUS: A rarer protein (found in about 5-10% of cases), often associated with very early onset of the disease, sometimes in a person’s 20s or 30s [7][8].

The “Big Three” Genetic Mutations

About 30% to 50% of FTD cases have a family history, and about 10% to 20% are caused by a single, identifiable genetic mutation passed down from a parent [9][10]. The specific genetic mutation directly dictates which protein misfolds.

Gene Mutation Protein Affected Associated Conditions & Symptoms
C9orf72 Leads to TDP-43 clumping. The most common mutation. Often causes “psychotic” symptoms like delusions. Strongly linked to ALS [11][12].
MAPT Leads to Tau tangles. Typically presents with “classic” bvFTD symptoms like loss of empathy. May also cause movement issues similar to Parkinson’s [13][14].
GRN Leads to TDP-43 clumping. Symptoms can vary widely, even within the same family. It often affects language and personality, and is linked to movement disorders [9].

What This Means for Your Family

If a mutation like C9orf72, MAPT, or GRN is found, the disease follows an autosomal dominant inheritance pattern [1]. This means that each child or sibling of the person with the mutation has a 50% chance of inheriting the gene [15].

The Role of Genetic Counseling

Before proceeding with genetic testing, it is vital to meet with a genetic counselor [16]. This is a specialized healthcare professional who helps families navigate the medical, emotional, and practical consequences of a genetic result [17].

  • For the Patient: Testing can provide a definitive cause for the disease and may help qualify the patient for specific clinical trials [9].
  • For at-risk Relatives: Testing someone who does not have symptoms (predictive testing) is a deeply personal decision. A positive result indicates high risk, though it does not dictate exactly when symptoms might start [10].
  • Insurance and Legal Factors: In the U.S., while the GINA act protects against health insurance discrimination based on genetics, it does not protect against discrimination in life insurance, long-term care insurance, or disability insurance [16].

Seeking counseling allows your family to weigh these risks and benefits in a safe, informed environment [18].

Return to Home Page

Common questions in this guide

Is behavioral variant frontotemporal dementia hereditary?
About 30% to 50% of bvFTD cases involve a family history of the disease, and 10% to 20% are caused by a specific, identifiable genetic mutation passed down from a parent. If a parent has one of these mutations, each of their children has a 50% chance of inheriting the gene.
What are the most common genetic mutations that cause bvFTD?
The three most common genetic mutations linked to bvFTD are C9orf72, MAPT, and GRN. These genetic errors dictate which specific proteins in the brain will misfold, clump together, and ultimately damage brain cells.
How is bvFTD related to ALS?
Both bvFTD and ALS (Lou Gehrig's disease) can be caused by the abnormal clumping of a protein called TDP-43. The C9orf72 genetic mutation, which is the most common mutation in bvFTD, is strongly linked to the development of ALS in families.
Should my family get predictive genetic testing for bvFTD?
Predictive genetic testing can help families understand their medical risks and aid in future planning, but it also carries emotional weight and potential implications for life or long-term care insurance. It is highly recommended to meet with a genetic counselor before deciding to test.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Given the specific symptoms, which genetic mutation (C9orf72, MAPT, or GRN) is statistically most likely?
  2. 2.Does our family history of other conditions, like ALS or Parkinsonism, change the genetic testing recommendations?
  3. 3.If a mutation is present, what is the exact risk (percentage) for children and siblings?
  4. 4.What are the pros and cons of predictive testing for at-risk family members who don't have symptoms yet?
  5. 5.Can you refer us to a genetic counselor who specializes specifically in neurodegenerative diseases?

Questions For You

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References

References (18)
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    Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations.

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    Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease.

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    Frontiers in molecular neuroscience 2022; (15()):1000183 doi:10.3389/fnmol.2022.1000183.

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    Research trends and hotspots for frontotemporal dementia from 2000 to 2022: a bibliometric analysis.

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This information regarding the biology and genetics of bvFTD is for educational purposes only. Always consult with a neurologist or a specialized genetic counselor to discuss testing options and family risks.

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