Genetics and molecular mechanisms of frontotemporal lobar degeneration: an update and future avenues

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common form of dementia after Alzheimer s disease. The study and the dissection of FTLD is complex due to its clinical, pathological, and genetic heterogeneity. In this review, we survey the state-of-the-art genetics of familial FTLD and recapitulate our current understanding of the genetic architecture of sporadic FTLD by summarizing results of genome-wide association studies performed in FTLD to date. We then discuss the challenges of translating these heterogeneous genetic features into the understanding of the molecular underpinnings of FTLD pathogenesis. We particularly highlight a number of susceptibility processes that appear to be conserved across familial and sporadic cases (e.g., and the cellular waste disposal pathways, and immune system signaling) and finally describe cutting-edge approaches, based on mathematical prediction tools, highlighting novel intriguing risk pathways such as DNA damage response as an emerging theme in FTLD.