Dementia encompasses a spectrum of neurodegenerative disorders that can emerge in both childhood and adulthood, often driven by overlapping molecular pathways. While adult-onset dementias are typically polygenic, childhood-onset dementias are usually caused by rare, high-impact mutations. Despite their distinct clinical timelines, increasing evidence suggests that these disorders converge on shared cellular mechanisms, particularly lysosomal and metabolic pathways.
To identify points of genetic convergence between adult- and childhood-onset dementia, we leveraged genome-wide association data from adult-onset dementias alongside curated rare disease gene sets for childhood dementia. Using network colocalisation analyses, we integrated these datasets to pinpoint loci and pathways jointly implicated across disease categories. This approach revealed a shared network across adult and childhood-onset dementia consisting of genes involved in lysosomal function, lipid metabolism and metal homeostasis. We also identified a strong colocalisation signal between genes causing lysosomal storage disorders and risk loci for dementia with Lewy bodies.
These findings support a unifying model in which rare, high-impact variants in childhood dementias and common risk alleles in adult dementias perturb shared cellular systems. This genetic overlap offers new opportunities to uncover fundamental disease mechanisms, prioritise therapeutic targets, and accelerate translational research across the lifespan.