ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-β copathology

Introduction Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid-beta (A beta) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of A beta. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology. Methods We analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without A beta copathology. Results The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of A beta pathology. Discussion We conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD-tau pathology, independent of A beta.