AD-FTLD Spectrum: New Understanding of the Neurodegenerative Process from the Study of Risk Genes

Abstract

Typical cases of primary neurodegenerative diseases causing dementia, such as Alzheimer’s disease (AD), diffuse Lewy body disease, frontotemporal lobar degeneration (FTLD), and corticobasal degeneration, show characteristic clinical signs and symptoms, but there are some cases in which the differential diagnosis among neurodegenerative dementias is difficult because of their atypical clinical presentation. Considering recent findings in molecular genetics of ­familial cases of AD and FTLD, the relationship between causative genes and clinical signs is becoming more complicated, and the concept of an AD-FTLD spectrum is proposed. Protein fragments derived from amyloid precursor proteins, tau and TDP-43, are deposited in the cerebral tissue of patients with AD and FLTD in different degrees. In familial cases, these deposited protein fragments are caused by mutations in the precursor protein genes. The majority of cases of AD and FTLD are sporadic, wherein loss of function of presenilin and progranulin increases the risk of these neurodegenerative disorders. Under the concept of AD-FTLD, it is more helpful to elucidate the common neurodegenerative pathway in which aggregated protein fragments are deposited after partial proteolysis, phosphorylation, and ubiquitination, leading to the formation of amyloid angiopathy, senile plaque, ­neurofibrillary tangles, and the inclusion body of FTLD.