What are the causes of Frontotemporal Dementia (FTD)?

From the Guidelines

Frontotemporal dementia (FTD) is primarily caused by genetic mutations, particularly in genes that produce tau protein (MAPT), progranulin (GRN), and C9ORF72, which lead to abnormal protein accumulation in the brain's frontal and temporal lobes, resulting in progressive nerve cell damage. The most common genetic causes of FTD include mutations in the C9ORF72, MAPT, and GRN genes, with C9ORF72 being the most common genetic cause of FTD 1. These mutations can lead to the abnormal buildup of tau protein or TDP-43 protein in brain cells, resulting in brain cell death.

Some key points to consider when evaluating the causes of FTD include:

• Genetic mutations are found in 1-10% of sporadic bvFTD cases, with C9ORF72, MAPT, and GRN being the most common mutations 1
• C9ORF72 repeat expansions have almost complete penetrance, but some carriers may not show symptoms until 40-80 years of age 1
• GRN mutations can also lead to FTD, with visual hallucinations and delusions occurring in up to 25% of patients during the course of the disease 1
• MAPT mutations can also cause FTD, with paranoid delusions and hallucinations occurring in some cases 1

It is essential to note that while genetic mutations are a significant cause of FTD, environmental factors may also contribute to the development of the disease, although their exact role remains unclear 1. Understanding the causes of FTD is crucial for guiding symptom management and supporting ongoing research for potential treatments targeting the underlying protein abnormalities.

In terms of diagnosis, distinguishing patients with bvFTD from patients with primary psychiatric disorders (PPD) is crucial due to the drastically different prognosis and treatment approaches 1. A systematic approach to diagnosis, including clinical assessment, neuropsychiatric consultation, and imaging studies, can help improve diagnostic accuracy 1. However, the diagnosis of bvFTD remains challenging due to the absence of molecular biomarkers and the symptomatic overlap with PPD.

Overall, the identification of genetic mutations, particularly in C9ORF72, MAPT, and GRN, is critical for understanding the causes of FTD and guiding diagnosis and treatment. Further research is needed to elucidate the role of environmental factors and to develop effective treatments for FTD.

From the Research

Causes of Frontotemporal Dementia

The causes of frontotemporal dementia (FTD) are complex and multifaceted. Some of the key factors include:

• Genetic mutations: Mutations in certain genes, such as MAPT, GRN, and C9orf72, have been identified as major causes of FTD 2, 3, 4, 5
• Protein abnormalities: Abnormalities in proteins such as transactive response DNA-binding protein 43 (TDP-43), microtubule-associated protein tau (MAPT), and FUS have been linked to FTD pathology 6
• Brain network disruption: FTD has been characterized as a "molecular nexopathy," where pathogenic proteins selectively target and destroy brain networks, leading to abnormal neural network physiology and complex clinical symptoms 2

Genetic Factors

Genetic factors play a significant role in the development of FTD. Some key points include:

• Heritability: FTD is highly heritable, with around 30% of patients having a strong family history 3
• Specific genes: Mutations in MAPT, GRN, and C9orf72 genes account for a substantial proportion of FTD cases, with C9orf72 mutations being the most common 3, 4
• Genetic modifiers: Certain genetic modifiers, such as TMEM106B and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10, can influence the age of symptom onset and disease progression 3

Protein Abnormalities

Protein abnormalities are a key feature of FTD pathology. Some key points include:

• TDP-43: TDP-43 is a major component of the pathological inclusions found in FTD, accounting for approximately 50% of cases 6
• MAPT: MAPT is another key protein involved in FTD pathology, with mutations in the MAPT gene leading to abnormal tau protein production 6, 5
• FUS: FUS is a protein that is also involved in FTD pathology, although to a lesser extent than TDP-43 and MAPT 6