In about 30% of FTLD cases, multiple members of a family are affected. These cases of familial FTLD (f-FTLD) are usually caused by changes in the genetic code called mutations, which are associated with a very high risk (more than 90%) of developing FTLD during a person’s lifetime. Mutations in genes that cause f-FTLD follow an autosomal dominant inheritance pattern; each child of someone with a mutation faces a 50% risk of inheriting the mutation. Occasionally, a mutation will be found in a person whose family history does not reveal other people with FTLD. In such cases, it is possible that the mutation first occurred in that individual. It’s more likely that the family history is not well known or the family is small and other family members carrying the mutation died from another cause before they showed symptoms of FTLD. (Source: ALLFTD)

The MAPT gene encodes “microtubule-associated protein tau” which is expressed within the neurons in the brain. Mutations in the MAPT gene can exert several different effects on how this process functions. These differences in function can be unique to each specific mutation, but all result in the formation of aggregated tau inclusions, also known as tangles, which are theorized to drive neuronal loss and brain atrophy.

The MAPT genetic mutation is inherited in an autosomal dominant manner, meaning any child of a parent with the mutation has a 50/50 (or 1 in 2) chance of inheriting the mutation. Across all other genetic FTD groups, MAPT onset and duration of disease closely follows the parental and mean family ages, meaning history will repeat itself. If your parent started symptoms around ~55 years old, it is highly likely that as a carrier, you will start symptoms within a similar age as your parent.‍

The prevalence of MAPT-FTD is unclear. A recent epidemiologic study in the UK suggests that prevalence of all FTD is 11:100,000 [Coyle-Gilchrist et al 2016]. In the authors' experience, genetic FTD accounts for ~30% of all FTD; thus the prevalence of genetic FTD is estimated to be 3.3:100,000. However, few patients are diagnosed accurately or tested for the FTD mutations to confirm diagnosis, likely resulting in an undercount of statistical prevalence. Based on the recent large retrospective study of genetic FTD [Moore et al 2020], MAPT-FTD accounts for about 25% of genetic FTD, resulting in an estimated prevalence of MAPT-FTD of 0.8:100,000. Per these numbers, with the global population of 8 billion, it can be assumed that there would be 64,000 individuals globally impacted by MAPT FTD. Currently only 584 MAPT individuals have been identified by the global longitudinal FTD research studies through the FTD Prevention Initiative (FPI) – likely a severe underrepresentation of the MAPT FTD population, due to limited global access & participation in this research.

MAPT mutations cause disease in an age-dependent manner, meaning that disease occurs more often when age increases; cases are diagnosed in adulthood, most often diagnosed in early middle age or even old age in some. A large study of MAPT FTD cases arrived at an average age of diagnosis for a carrier of 49.5 years old. It shows a bell curve pattern of diagnosis: about half of cases are diagnosed approximately between the ages 40 and 55 with a fewer number of cases diagnosed earlier (rarely as young as in the 20’s) and later (carriers over 70 have been diagnosed). Specific variations may have more discrete age of onset predictions. It is important to note that the average age of diagnosis is made up of those who are diagnosed with the disease. It does not capture the people who are not diagnosed in their lifetime. As disease manifests in an age-dependent manner, there are many more asymptomatic carriers at any one time than there are carriers with an active diagnosis.‍

A biomarker is a term referring to biological measurements that provide information on a disease course. In some cases, biomarkers may be able to signal disease activity before there are serious symptoms.In Alzheimer’s disease, tau protein forms neurofibrillary tangles, contributing to cognitive decline. In Frontotemporal Dementia (FTD), the tau pathology can involve 3R or 4R tau isoforms, leading to distinct subtypes. The specific tau isoforms and their distribution in the brain contribute to the clinical differences between Alzheimer’s and FTD. Some promising biomarkers in MAPT are: 
- Brain MRI (magnetic resonance imaging of the brain): Studies have repeatedly shown that MAPT  carriers have less estimated brain volume on MRI than their unaffected siblings as early as adulthood and up to 15 years before diagnosis with an accelerated rate of change 2 years prior to diagnosis. MRI machines are available in most major medical centers, but when used for clinical care, they tend to have high costs for patients to access them and these data have only been evaluated in a research setting.   
- Tau Pet: Studies have shown that binding agents they have to perform a Tau sensitive PET scan, have not been proven to be helpful in FTD, as opposed to their success in Alzheimer's disease, but this is a promising area of research. 
- Blood: currently, there has not been a 4R tau isoform blood based biomarker established to detect neurodegeneration or tau tangles occurring in FTD or other 4R tauopathies. In Alzheimer’s disease, they are afflicted by a 3R isoform that causes phosphorylated tau. Therefore, the p-tau biomarkers used in AD, would not detect the 4R tau tangles in FTD. This is a large interest area of study to develop this further to allow for efficient and precise diagnosis of disease.
- CSF: Similarly to blood, there has not been a 4R tau isoform biomarker established within the CSF. Total tau (T-tau) protein levels in CSF can be measured, and are typically reduced in patients with FTD.

Currently there are no interventional, drug or gene therapy trials that are available for MAPT patients, regardless of symptom status. Any type of intervention that patients receive is for symptom management. However, because the main protein causing the tangles in the neurons is Tau, the good news is there are drugs currently in trial for the Tau tangles that occur with Alzheimer’s Disease. These are potentially promising for the MAPT families, pending their success with Alzheimer's Disease. IONIS- MAPT Rx is the current interventional trial that could show some promise. It's critical that MAPT families participate in any promising trial, while we organize to create our own through fundraising and advocacy efforts. Below are some worth watching and/or participating in.

Brain MRI (magnetic resonance imaging of the brain): Studies have repeatedly shown that MAPT carriers have less estimated brain volume on MRI than their unaffected siblings as early as adulthood and up to 15 years before diagnosis with an accelerated rate of change 2 years prior to diagnosis. MRI machines are available in most major medical centers, but when used for clinical care, they tend to have high costs for patients to access them and these data have only been evaluated in a research setting.‍

Tau Pet: Studies have shown that binding agents they have to perform a Tau sensitive PET scan, have not been proven to be helpful in FTD, as opposed to their success in Alzheimer's disease, but this is a promising area of research. ‍

Visit ALLFTD for a Glossary of Key Medical Terms related to frontotemporal dementia (FTD). ‍