An interactive journey through the human genome to understand why behaviour and language change — and what role genes such as C9orf72, MAPT (tau) and GRN (progranulin) play.
The whole journey of this page, summarised in steps.
Before getting into the genetics, it helps to understand the disease that these genes help to explain.
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia (before age 65). The frontal and temporal lobes of the brain degenerate selectively — the regions that govern personality, behaviour and language. Unlike Alzheimer's disease, episodic memory is relatively preserved early on. The pathology shows aggregates of the tau protein or the TDP-43 protein.
In 1892, the neurologist and psychiatrist Arnold Pick described, in Prague, cases of focal atrophy of the frontal and temporal lobes with aphasia and behavioural changes: the entity that for decades was known as "Pick's disease". For more than a century it was a clinical and anatomical entity; the genetic era began in 1998 with mutations in MAPT (tau).
Symptoms depend on which region is affected first, and they define the major clinical variants:
The most common form: personality changes, disinhibition, apathy and loss of empathy. Atrophy of the frontal lobe predominates.
Language deteriorates progressively: the semantic variant (losing the meaning of words) or the non-fluent/agrammatic variant (struggling to produce speech).
Early on, episodic memory remains relatively intact. What fails first is behaviour or language, not the recollection of recent events.
A subset of patients also develops amyotrophic lateral sclerosis (FTD-ALS): they share the C9orf72 gene and TDP-43 pathology.
The behavioural variant affects personality first; the language variants (semantic or non-fluent primary progressive aphasia) affect speech first.
Some forms are associated with motor neuron disease: they are the two ends of a single continuum, linked by C9orf72 and TDP-43.
Each gene has its signature: C9orf72 (often with ALS), MAPT (tau pathology) and GRN (TDP-43 pathology).
FTD usually begins subtly (a change in character or language) and spreads to more functions as it progresses.
Changes in character, impulsive decisions or language difficulties that are often attributed to another cause.
The variant becomes recognisable: behavioural (disinhibition, apathy) or language (primary progressive aphasia).
More cognitive functions become affected; dependence increases. In some cases motor or ALS signs appear.
Widespread loss of autonomy and, frequently, mutism. Supportive care is the mainstay of management.
There is no drug that halts or modifies the disease. The approach aims to control symptoms and support the person and their family.
Non-pharmacological strategies and, when needed, medication for disinhibition, apathy or agitation. There is no treatment that halts the disease.
Speech and language therapy for the language variants, communication aids and strong support for carers, who bear much of the burden.
Alzheimer's drugs (cholinesterase inhibitors) are not indicated and can worsen behaviour. The hope lies in gene therapies under trial.
Science-based educational content (Pick, 1892; MAPT/tau, Hutton et al. 1998; GRN/progranulin, Baker et al. 2006; C9orf72, DeJesus-Hernandez/Renton 2011). It does not replace assessment by a healthcare professional.
DNA (deoxyribonucleic acid) is the molecule that stores the genetic instructions of every living thing, spread across some 3 billion base pairs.
Four bases — A, T, C and G — form the double helix. In FTD, the variants affect proteins such as tau (which stabilises the cytoskeleton), progranulin, or proteins that handle RNA: when they fail, toxic aggregates form in the neurons of the frontal and temporal lobes.
FTD genes are spread across several chromosomes. The most prominent are 9 (C9orf72) and 17 (MAPT and GRN). Click a chromosome to see its regions, the evidence and the genes involved.
Causal and risk genes for FTD. Each one leaves a tau or TDP-43 fingerprint. Search and filter by mechanism; click a card to see its function and the studies.
FTD genes converge on a few processes within the neuron. Hover over a node to identify the gene; click to see the detail.
Two keys to FTD: the two major pathologies (tau ↔ TDP-43) and frontotemporal atrophy. Explore them.
Almost all FTD is explained by the build-up of one of two proteins: tau or TDP-43. Each is associated with different genes and clinical variants. Click to compare.
The GGGGCC expansion in C9orf72 can cause frontotemporal dementia, amyotrophic lateral sclerosis or both: two ends of a single continuum. It is a repeat, but it is worth remembering that FTD has several genes and mechanisms, not only the repeat.
FTD selectively degenerates the frontal lobe and the temporal lobe. Click each region of the diagram.
From Pick's disease to the C9orf72 gene and the biomarkers and antisense therapies in development.
How FTD genes damage the neurons of the frontal and temporal lobes.
FTD has a strong genetic component: around 30–40 % of cases are familial, and inheritance is almost always autosomal dominant (a single altered copy is enough).
C9orf72, MAPT and GRN account for most familial forms and are inherited in a dominant manner: each child of a carrier has a 50 % chance of inheriting the variant. C9orf72 is, in addition, the link with amyotrophic lateral sclerosis (FTD-ALS spectrum).
The essentials about the genetics of frontotemporal dementia:
The most important point: identifying the gene guides prognosis and opens the door to targeted therapies. Researchers are investigating ASOs against C9orf72 and strategies that raise progranulin in GRN carriers. For now there is no drug that halts the disease.
FTD is a neurodegenerative disease. It is worth dispelling some mistaken ideas:
FTD is often mistaken for depression or a psychiatric disorder because of its behavioural changes; and although C9orf72 is a repeat expansion, FTD has several genes and mechanisms (tau, progranulin, proteostasis), not only the repeat.
Genetics is starting to turn FTD into a disease with concrete therapeutic targets.
In GRN-related FTD, the disease is due to a shortage of progranulin. Several strategies (gene therapy, drugs) aim to restore its levels; it is one of the clearest targets.
Because C9orf72 causes both FTD and ALS, the ASOs that reduce the toxic RNA from the GGGGCC expansion are being investigated for both; several are in clinical trials.
Blood neurofilaments and progranulin, together with brain imaging, allow damage and treatment response to be estimated, accelerating trials.
Sequencing each person to choose the strategy according to their gene: FTD is moving towards a personalised treatment by mutation (tau, progranulin or C9orf72).
Immunotherapies and anti-tau ASOs, and strategies targeting TDP-43 and its cryptic exons, could halt the two major pathologies of FTD.
Detecting the disease — even before symptoms in known carriers — to intervene while there are still neurons to protect.
Research is moving fast and some of these results are preliminary: the specific dates and figures may change as trials mature.
The questions that come up most when learning about FTD.
Milestones and scientific sources on which this page is based.
An educational synthesis page; not a primary clinical source. For medical decisions, consult professionals and the official resources of frontotemporal dementia associations.
Six questions to check what you take away. It marks itself: tap an answer and you'll instantly see whether you got it right, with the explanation.