A group of researchers from the University Research Institute of Child & Maternal Health and Precision Medicine of the National & Kapodistrian University of Athens, from the Hellenic Pasteur Institute, and from the Faculty of Medicine of the University of Thessaly, in Greece, have recently proposed a new conceptual framework to explain how Alzheimer disease (AD) develops and, consequently, how it could potentially be treated, bringing new perspectives for patients suffering from this common neurological disease that manifests as dementia.

Lymphatic vessels are a special type of thin vessels that carry the lymph, the excess tissue fluid that may contain bacteria and malignant cells and carry them to lymph nodes for destruction. Although it has long been believed that there are no lymphatic vessels in the brain, we now know that meningeal lymphatic vessels could be linked to, and possibly drain, the efferent paravascular glial lymphatic system (glymphatic system), carrying cerebrospinal fluid after solute and immune cell exchange with brain interstitial fluid.

Although still not much is known about this newly discovered system in the brain, there is evidence that it may be important for removing the toxic and waste products of the brain cells, as well as inflammatory mediators, and, as such, contributes to maintaining normal brain microenvironment and prevents several neurological diseases. Indeed, recent studies suggested that amyloid-beta, a peptide which accumulates in the brain of patients with AD, may be evacuated from the cerebrospinal fluid to meningeal lymphatics. If that is correct, any reduction or impairment of the meningeal lymphatic system would cause accumulation of amyloid-beta in the brain, thereby favoring the development of AD.

Mentis and colleagues have here hypothesized that the function of meningeal lymphatic vessels is influenced by apolipoprotein E4 (APOE4), a molecule known as the leading genetic risk factor for AD development.

“Our main goal is to propose a new conceptual framework on the role of reduced meningeal lymphatic function in APOE4-related Alzheimer disease”, say the authors. Specifically, they aimed to identify genes that were differentially expressed in the APOE4 (pathological state) compared with the APOE3 (control) knock-in induced pluripotent stem cells (iPSCs). They studied the expression of selected gene markers in parental cells in the starting iPSCs and in iPSCs-derived neurons, astrocytes, and microglia.

Their re-analysis of previously published and publicly open RNA-Sequencing data showed that iPSCs carrying the APOE4 allele (either as APOE4 knock-in or stemming from APOE4 patients) did not reveal significant differences in the expression of genes of interest in iPSCs, neurons, and astrocytes.

However, in the microglial cells (which share some aspects of embryological origin with lymphatic vessels), there were statistically significant differences in the expression of several genes related to features of lymphatic vessels between the APOE4 and APOE3 knock-in cells. Specifically, iPSCs carrying the APOE4 allele expressed lower levels of genes associated with lymphatic markers and genes for which well-characterized missense mutations have been linked to peripheral lymphedema.

In this context, APOE4 was identified as an important player in the premature shrinkage of meningeal lymphatic vessels (a term the authors called ‘meningeal lymphosclerosis’), which could potentially lead to abnormal meningeal lymphatic functions (‘meningeal lymphedema’), and, in turn, reduction in the clearance of amyloid-beta, other macromolecules and inflammatory mediators, as well as immune cells, from the brain.

“This conceptual framework supported by reanalyzed data is rather unique as it associates recent findings on meningeal lymphatic vessels with the most solid risk factor for Alzheimer disease”, says the head of the team – George Chrousos. Indeed, “deciphering the role of APOE4, the strongest known genetic link to AD, in the meningeal lymphatic system, could reveal a missing link in our understanding of the etiology and pathology of AD”, state the authors. The authors also suggested potential associations between APOE4 and molecules of the vascular endothelial growth factor (VEGF) pathway.

So what does this mean for the patients’ outcomes? The authors propose that their conceptual framework, if further verified by additional, mechanistic studies, may set the basis for the development of new drugs to be delivered via cerebrospinal fluid to cure AD. Specifically, intrathecal administration of certain factors could restore normal meningeal lymphatic function anatomy and function of meningeal lymphatic vessels in AD, thereby allowing passage of glymphatic and lymphatic fluid into the lymphatic system of the rest of the body. This would allow improved removal of amyloid-beta, but also other toxic products from the brain, likely alleviating the symptoms of AD.

The authors also highlight the power of reanalyzing open data to produce new perspectives in the precision medicine era, and emphasize recent, dramatic advances in this research field. “While I was a medical student some years ago, neither the observation on brain lymphatics nor CRISPR/Cas9 in vitro models existed”, says Alexios-Fotios Mentis, a physician and currently PhD student and the first author of the paper, “so, merging such approaches was something a pretty novel experience for me”. “In every case, further studies are needed to validate these findings in patients and evaluate potential therapeutic options to help patients with AD”, highlights Prof. Dardiotis from the co-authors of this study.

The article “Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework” was published in Molecular Psychiatry at DOI: 10.1038/s41380-020-0731-7.