Alzheimer disease and Apolipoprotein E4: meningeal brain lymphatics point to new clues in pathogenesis

ABSTRACT The role of the lymphatic system in brain function and/or dysfunction has long been an enigma. However, recent reports that meningeal lymphatic vessels exist within the mouse and human brain, as well as evidence that mouse meningeal lymphatic vessels play a role in clearing the toxic amyloid-beta peptide connected with Alzheimer’s disease (AD), may herald novel diagnostic and therapeutic avenues. Here, we explore new evidence connecting the lymphatic system of the brain with AD. In particular, we focus on new findings showing that meningeal lymphatic vessels play a role in drainage of cerebrospinal fluid and egress of immune cells from the brain, and that disrupting this vessel system leads to accumulation of amyloid - beta peptide and cognitive dysfunction. We also discuss the hypothesis that apolipoprotein E isoform e4 (APO E4) ─ the leading genetic risk for developing AD ─ is involved in meningeal lymphatic vessel function. By reanalyzing previously published RNA-Seq data, we show that APO E4 knock-in microglia cells express lower levels of genes representing lymphatic markers (a phenomenon we call “attenuated lymphaticness”) and of genes in which functional missense mutations are linked to lymphedema. Accordingly, we propose the hypothesis that APO E4 is involved in the shrinkage of lymphatic vessels. This notion could lead, if verified by additional anatomic and mechanistic data, to the concept that APO E4-related AD (such as in late onset AD or trisomy 21-related AD) is related to lymphosclerosis coupled with lymphedema.