FTD disorders are often misdiagnosed because their symptoms overlap considerably with those of other neurodegenerative and psychiatric disorders. While clinical presentations vary, FTD disorders generally fall into one of three categories, listed below with their most common symptoms:

While people with FTD usually first show symptoms of one specific disorder, over time symptoms of other FTD disorders may appear. Someone with bvFTD may, for example, develop symptoms more closely associated with movement disorders such as PSP or CBS. A person who carries a genetic variant that causes both ALS and FTD, meanwhile, may first only show symptoms of ALS, but as their condition progresses, they may also display bvFTD or PPA symptoms.

Managing these diverse symptoms, especially when they overlap, can be challenging even for seasoned healthcare professionals. It is essential to collect a person’s accurate medical history to understand the development of potential FTD symptoms relative to their baseline. Because anosognosia, which refers to a lack of awareness about one’s condition, is a common symptom of FTD (and is often one of the early symptoms to develop), a close family member or friend might be able to best describe to a doctor any uncharacteristic or distressing changes.

Currently, there are no accepted biomarkers for FTD. It therefore cannot be diagnosed with complete accuracy by simply evaluating a sample of blood or cerebrospinal fluid, for example. Instead, diagnosing FTD relies on a comprehensive assessment that includes a complete review of clinical symptoms, whether observed in the office or report by the person experiencing symptoms or a close family member or friend. A tool that can help to diagnose certain FTD disorders is AFTD’s Diagnostic Checklists (below). Physicians can share these checklists with patients and their families to guide the screening process and help families better prepare for their appointment by documenting what symptoms they have noticed. They also provide physicians with a quick summary of the current diagnostic criteria.

The heterogeneity of FTD symptoms can be attributed to which part of the brain is affected at disease onset. FTD typically begins with the degeneration of the frontal or temporal lobes, or in the motor cortex (a portion of the brain’s outermost layer). The initial site of atrophy determines which FTD symptoms appear first. As the underlying pathology progresses, the disease spreads to other brain regions, creating conditions for symptoms of other FTD disorders to develop.¹

The pathological foundation of the FTD disorders – the physical deterioration of the brain’s frontal and temporal lobes – is rooted in various proteinopathies (disease-causing structural abnormalities in proteins). Dysfunction of crucial proteins leads to the formation of aggregates that initially form in certain regions of the brain. Two key proteins have been identified as causing most FTD cases, with a protein linked to a significant fraction of remaining diagnoses. The three main proteins associated with FTD, in descending order of prevalence, are:

Due to the lack of biomarkers, the only way currently to pathologically diagnose FTLD is through brain autopsy.⁴

Approximately 40% of people diagnosed with FTD have familial FTD, meaning that a blood relative has been diagnosed with an FTD disorder, another neurodegenerative disorder, or another similar neuropsychiatric condition. Of those with familial FTD, a specific genetic cause can be identified in approximately 15-20% of diagnoses. Researchers are working to understand the relationship between the specific genetic causes, the underlying proteinopathies, and the clinical presentations of FTD.

To date, variants in over a dozen genes cause FTD, contributing to the heterogeneity of FTD disorders. Most people diagnosed with genetic FTD have pathogenic variants in one of the following three genes:

Genetic testing can help determine whether a person has inherited an FTD-causing gene variant. Before testing, AFTD strongly recommends genetic counseling to ensure families understand the benefits, risks, and limitations of genetic testing, including what is and is not protected by the Genetic Information Non-discrimination Act (GINA). Counseling is particularly important when there is a family history of neurodegenerative disorders. Counseling helps families make a well-informed decision about whether genetic testing is the right choice for them.

Researchers are working to identify fluid biomarkers that can be reliably used to identify specific FTD pathologies and their related genetic underpinnings. Several promising biomarkers are being evaluated for FTD⁵, both for diagnostic purposes and to track target engagement in clinical trials, but they require further study. More research is needed to fully understand variability in protein levels, though tracking changes in progranulin levels is already being used in FTD clinical trials to analyze the efficacy of interventions. A confirmed FTD biomarker can play a crucial role in diagnosis and in clinical trials for potential FTD treatments. Clinicians should therefore encourage families to investigate research opportunities to consider if participation is right for them.