Bruce Willis' battle spotlights complex dementia
Key Takeaways
Bruce Willis’ diagnosis has put frontotemporal dementia (FTD) in the spotlight as a leading cause of neurodegenerative cognitive decline in individuals under 65.
FTD, often misdiagnosed as Alzheimer's or psychiatric disorders, is a complex neurodegenerative condition that causes profound changes in behavior, personality, and language.
While there is no cure, accurate and timely diagnosis is crucial for effective symptomatic management, patient support, and slowing disease progression.
In March 2022, Bruce Willis' family announced that he had been diagnosed with aphasia—a language disorder impairing his cognitive abilities—prompting his retirement from acting.[] Aphasia can stem from either an acute brain injury or a neurodegenerative condition.
Given Willis' age at the time (67) and the absence of acute brain lesions, neurodegeneration was suspected to be the most likely cause.[]
By February 16, 2023, the Willis family released a statement that said, “We now have a more specific diagnosis: frontotemporal dementia (FTD),” aligning with the link between progressive aphasia and FTD.[] Unfortunately, most media reports inaccurately suggested that his aphasia "progressed" into FTD, failing to recognize aphasia as a symptom of the underlying FTD.[]
Pathobiology of FTD
FTD is a group of neurodegenerative conditions primarily affecting the frontal and temporal lobes, leading to cognitive, behavioral, and motor symptoms.[] This condition involves the progressive loss of neurons in these brain regions, often due to the accumulation of misfolded proteins like tau or TDP-43.
A common misconception is that aphasia can "progress" into FTD, overlooking the fact that aphasia is just a symptom of the underlying FTD rather than a separate condition that transforms over time. Primary progressive aphasia (PPA), characterized by a gradual worsening of language abilities, can arise from neuropathological processes, with FTD and atypical presentations of Alzheimer's disease being the most common underlying causes.
FTD vs Alzheimer’s disease
While less common than Alzheimer's, FTD is not as rare as once thought. Per the Association for Frontotemporal Degeneration (AFTD) stats, 50,000 to 200,000 people in the US are living with FTD.[] However, since there are several types of FTD variants, these numbers are most likely an underestimation.[]
Alzheimer’s is characterized by early memory loss, while FTD's early symptoms invariably involve language and behavior dysfunction, with memory often preserved until later stages. This difference can lead to FTD’s being overlooked or misdiagnosed as Alzheimer's, especially in older adults.[]
FTD is also more likely to present in younger individuals, with many cases diagnosed in people in their 50s or 60s, which can further complicate its recognition and treatment. The disease is now recognized as the third most common form of dementia across all ages, following Alzheimer's and Lewy body dementia; it is the leading cause of neurodegenerative cognitive decline in individuals under 65.[]
Characteristics and subtypes of FTD
FTD is more prevalent in men, left-handed individuals, and those with thyroid disease or other autoimmune disorders.[][] The disease has two primary subtypes:
Behavioral variant FTD (bvFTD): Characterized by significant changes in personality, social conduct, and behavior due to frontal lobe degeneration. Patients may display impulsivity, lack of empathy, apathy, or socially inappropriate actions.
Language variant FTD (lvFTD): Presents with PPA that severely affects communication and is further subdivided into agrammatic/nonfluent PPA and semantic PPA. Agrammatic PPA involves difficulty constructing grammatically correct sentences, often due to tau-positive inclusions in the inferior frontal lobe. At the same time, semantic PPA is linked with the loss of word meanings and is associated with TDP-43 pathology in the temporal lobe.
Current therapeutic approaches
Currently, no treatments halt FTD progression.[] Management focuses on symptom control and quality of life improvement.
Antidepressants, antipsychotics, and trazodone are used to manage behavioral symptoms, while dopaminergic agents, anti-epileptics, and oxytocin are employed for motor symptoms.
Emerging treatments and genetic insights
While the FDA has not approved any FTD-specific therapies, many promising treatments are in development. As discussed in a 2023 review from the Journal of Experimental Pharmacology, the most promising therapies target tau pathophysiology, such as MAPT gene modulation, tau aggregation, clearance modulation, microtubule stabilization, and immune neutralization.[]
Genetic mutations, notably in MAPT, GRN, and C9orf72, play a significant role in FTD, with each mutation present in approximately 10% of cases.[] New trials are expanding gene therapy's scope to target these mutations:
Latozinemab (AL001), a monoclonal antibody designed to increase progranulin levels by inhibiting sortilin-mediated degradation, has shown promising results in the INFRONT-2 Phase 2 clinical trial—which led the FDA to grant it the “Breakthrough Therapy Designation." The drug is currently in Phase 3 trials.[]
AVB-101, an investigational gene therapy, aims to restore progranulin levels directly in the brain and is being evaluated in the ASPIRE-FTD clinical trial, currently ongoing in Europe and the United States (NCT06064890).[]
WVE-4, a stereopure antisense oligonucleotide targeting C9orf72 gene variants, showed promising results in a 2022 preclinical study by selectively reducing harmful RNA transcripts in both in vitro and in vivo models, with effects lasting at least 6 months.[]
Other experimental therapies showing favorable results include non-invasive transcranial magnetic stimulation[] and reducing neuroinflammation with endogenous lipid mediators like palmitoylethanolamide.[]
Despite these advancements, there are still no FDA-approved curative therapies. At the moment, according to the authors of a review on FTD, “physical, occupational, and speech therapies, together with proper caregiver education, improvement of the environment, and support provided by the health services and dedicated associations, are the cornerstone in patient management.”[]
In a recent interview, Willis' eldest daughter, Rumer Willis, shared that the family has received overwhelming support from the public, which has been both touching and encouraging.[]
While media coverage has been mixed in accuracy, Bruce Willis’ diagnosis has definitely put FTD on the map. Much like how Lou Gehrig brought ALS into the spotlight, Willis' situation has sparked a wave of curiosity and awareness about FTD.
What this means for you
Recent media coverage has brought much-needed attention to FTD. Yet, the disease stays largely under- and misdiagnosed due to its atypical symptoms, often overlapping with psychiatric disorders or Alzheimer's. Until definitive treatments are available, early diagnosis, symptomatic management, and physical therapies are essential to improve the quality of life for patients with FTD.