# A Neural-Glial Model of the ApoE-SORT1-FABP7 Axis Tied to Sleep Disruption and Alzheimer’s Disease Pathophysiology

## TL;DR

This paper explores how a genetic pathway involving ApoE, SORT1, and FABP7 may link sleep disruption and lipid imbalances to Alzheimer’s disease progression.

## Contribution

The study introduces a novel neural-glial model connecting the ApoE-SORT1-FABP7 axis to Alzheimer’s disease and sleep disruption.

## Key findings

- The SORT1 gene variant rs141749679 increases Alzheimer’s risk by affecting lipid and amyloid β regulation.
- ApoE-SORT1 signaling is neuroprotective but disrupted in the presence of the ApoE4 allele.
- FABP7 mediates neuron-glia communication and regulates sleep through PUFA and endocannabinoid binding.

## Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder where age, genetic factors and sleep disturbance significantly influence disease risk. Recent genome-wide association studies identified a C/T missense variant (rs141749679) in the sortilin (SORT1) gene linked to heightened AD risk, revealing SORT1’s role as a key player in the disease’s pathophysiology. This type I membrane glycoprotein is implicated in amyloid β (Aβ) accumulation and associated lipid dysregulation, particularly through its interaction with apolipoprotein E (ApoE). SORT1 facilitates the uptake of ApoE-bound polyunsaturated fatty acids (PUFAs), conversion to endocannabinoids (eCBs), and the regulation of anti-inflammatory pathways via peroxisome proliferator-activated receptors (PPARs). Notably, this neuroprotective signaling is contingent on the APOE allele, exhibiting functionality in presence of ApoE3 but disrupted with ApoE4. Additionally, the brain-type fatty acid binding protein, FABP7, mediates this signaling cascade, emphasizing its role in neuron-glia communication. FABP7 is known to regulate sleep across species and binds PUFAs and eCBs. Therefore, dysfunction of the ApoE-SORT1-FABP7 axis may underlie the neuroprotective loss observed in AD, linking sleep disruption and lipid homeostasis to disease progression. This perspective aims to elucidate the intricate neural-glial mechanisms governing the ApoE-SORT1-FABP7 interaction and their implications for targeting therapeutic interventions in Alzheimer’s disease.