The Clinical Spectrum of Young Onset Dementia Points to Its Stochastic Origins

Abstract

Background: Dementia is a major global health problem and the search for improved therapies is ongoing. The study of young onset dementia (YOD)—with onset prior to 65 years—represents a challenge owing to the variety of clinical presentations, pathology, and gene mutations. The advantage of the investigation of YOD is the lack of comorbidities that complicate the clinical picture in older adults. Here we explore the origins of YOD. Objective: To define the clinical diversity of YOD in terms of its demography, range of presentations, neurological examination findings, comorbidities, medical history, cognitive findings, imaging abnormalities both structural and functional, electroencephagraphic (EEG) data, neuropathology, and genetics. Methods: A prospective 20-year study of 240 community-based patients referred to specialty neurology clinics established to elucidate the nature of YOD. Results: Alzheimer’s disease (AD; n = 139) and behavioral variant frontotemporal (bvFTD; n = 58) were the most common causes with a mean age of onset of 56.5 years for AD (±1 SD 5.45) and 57.1 years for bvFTD (±1 SD 5.66). Neuropathology showed a variety of diagnoses from multiple sclerosis, Lewy body disease, FTD-MND, TDP-43 proteinopathy, adult-onset leukoencephalopathy with axonal steroids and pigmented glia, corticobasal degeneration, unexplained small vessel disease, and autoimmune T-cell encephalitis. Non-amnestic forms of AD and alternative forms of FTD were discovered. Mutations were only found in 11 subjects (11/240 = 4.6%). APOE genotyping was not divergent between the two populations. Conclusion: There are multiple kinds of YOD, and most are sporadic. These observations point to their stochastic origins.