Genetic frontotemporal degeneration across the lifespan? A critical appraisal of the neurodevelopmental hypothesis.

Potential neurodevelopmental effects of genetic frontotemporal degeneration (FTD)-related variants have been postulated by observational studies over the past 25 years. Recent data from large FTD cohort studies have delineated biological and phenotypic characteristics of presymptomatic stages of disease, with some genetic variants showing effects even in young adults. However, human data on whether differences exist in youth are not yet available. This review critically appraises evidence from preclinical and human studies regarding the potential roles of FTD-associated genetic variants in neurodevelopment. We focus on the three major contributing pathogenic variant groups: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT). No causal evidence has been reported that supports the neurodevelopmental hypothesis in genetic FTD despite converging correlational findings. Theories are raised behind potential connections between neurodevelopmental and neurodegenerative processes in FTD. Understanding potential cellular and network responses to the presence of FTD genetic variants in early life may inform novel approaches to therapeutic development.