Frontotemporal Dementia and Related Neurodegenerative Disorders

Frontotemporal dementia (FTD) encompasses a spectrum of early-onset neurodegenerative syndromes characterised by progressive atrophy of frontal and temporal lobes. Clinically, patients present with behavioural variant FTD—marked by disinhibition, apathy and executive dysfunction—or primary progressive aphasia, affecting language production or comprehension. Pathological hallmarks include abnormal aggregation of proteins such as TDP-43, tau or FUS, often overlapping with amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. Approximately 30–40 per cent of cases are familial, linked principally to mutations in progranulin (GRN), microtubule-associated protein tau (MAPT) and hexanucleotide expansions in C9orf72. Emerging evidence implicates lysosomal dysfunction, lipid dysregulation and neuroinflammation in disease progression. Diagnosis integrates clinical assessment with neuroimaging markers—particularly fronto-insula-anterior cingulate atrophy—and fluid biomarkers such as neurofilament light chain. While symptomatic management addresses behavioural and cognitive disturbances, recent advances in gene therapy, immunomodulation and biomarker-driven trials offer promise for disease-modifying interventions.

Research from Nature Portfolio

Recent studies have evaluated restorative strategies targeting progranulin insufficiency in genetic FTD. A first-in-human trial of adeno-associated virus-mediated GRN gene delivery demonstrated safety and sustained increases in cerebrospinal fluid progranulin, alongside manageable adverse events. Parallel preclinical work has revealed that progranulin reduction exacerbates tau and α-synuclein aggregation via impaired glucocerebrosidase activity, linking TDP-43 proteinopathy with comorbid tauopathies. These findings establish a lysosomal PGRN–GCase pathway as a convergent therapeutic target and support translational efforts towards gene and small-molecule therapies aimed at restoring lysosomal homeostasis.

Frontotemporal Dementia and Related Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in frontotemporal dementia and related neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Frontotemporal dementia (FTD): A group of early-onset neurodegenerative disorders characterised by atrophy of frontal and temporal lobes and progressive behavioural or language impairment.

Progranulin: A lysosomal protein encoded by GRN whose deficiency leads to neuroinflammation and TDP-43 pathology in FTD.

TDP-43: A nuclear protein that aggregates in cytoplasmic inclusions, defining a common pathological subtype of FTD and amyotrophic lateral sclerosis.

Tauopathy: A class of neurodegenerative diseases marked by abnormal aggregation of tau protein, including certain FTD variants and Alzheimer’s disease.

Glucocerebrosidase (GCase): A lysosomal enzyme that degrades glucosylceramide, whose dysfunction links lipid accumulation to protein aggregation in neurodegeneration.

SuStaIn model: A computational approach that infers data-driven subtypes and stages of disease progression by modelling regional brain atrophy patterns.

Hippocampal lipidome: The full complement of lipids in the hippocampus, alterations in which may reflect glial dysfunction contributing to FTD pathogenesis.

References

1. Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results. Nature Medicine (2024).
2. The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus. Molecular Neurodegeneration (2023).
3. Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase. Nature Communications (2024).
4. Novel data-driven subtypes and stages of brain atrophy in the ALS–FTD spectrum. Translational Neurodegeneration (2023).