# Apolipoprotein E gene allele 4 and amyloid-beta mediate tau-related network breakdown

## TL;DR

This study explores how the APOE4 gene and amyloid-beta influence tau-related brain connectivity breakdown in Alzheimer's disease.

## Contribution

The study identifies APOE4 and amyloid-beta as mediators of tau-induced functional disconnection in Alzheimer's.

## Key findings

- APOE4 carriers and amyloid-beta-positive individuals show increased tau-related functional disconnection.
- Tau aggregates spread through brain networks, disrupting connectivity between affected and non-affected regions.
- Functional connectivity to tau epicenters is mediated by APOE4 and amyloid-beta status.

## Abstract

There have been reports of altered functional connectivity in Alzheimer's disease, which is associated with the buildup of pathogenic proteins in the brain, including neurofibrillary tau tangles and amyloid-beta plaques. It is believed that the tau aggregates are the main driver of functional disconnection and resulted in cognitive decline in Alzheimer's disease. Tau propagates through connected neurons, a phenomenon often described as the ‘prion-like’ properties of tau, which can locally result in functional connectivity disruption. Apolipoprotein E gene allele 4 status and amyloid-beta are accelerating factors for tau-related pathological changes in Alzheimer's disease. However, the potential role of apolipoprotein E gene allele 4 and amyloid-beta in mediating the tau-related functional disconnection is not clear. I aimed to investigate the mediating effect of apolipoprotein E gene allele 4 and amyloid-beta on the local association of tau spreading on functional connections. I analysed follow-up resting-state functional MRI (fMRI) (non-baseline visit) and longitudinal tau-PET data from 211 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 138 healthy elderly individuals from the Harvard Aging Brain Study (HABS). The follow-up resting-state fMRI (non-baseline visit) was studied in order to study the time needed effect of tau pathology. The top 10 regions with the highest probability-weighted SUVR values using Gaussian mixture models were selected as individual-level tau-PET epicentres. I looked at how the relationship between functional connectivity to epicentres and individualized connectivity-related tau spreading was mediated by amyloid-beta status and the apolipoprotein E gene allele 4 genotype. Higher rates of tau aggregation accumulation were seen in areas with stronger connectedness (shorter distance-based connectivity) to the baseline-defined tau epicentres. Moreover, the association between functional connectivity to epicentres and tau spreading through functional connections was mediated by apolipoprotein E gene allele 4 and amyloid-beta status in both dataset’s participants. Tau aggregates spread through functional connections and locally disrupt connectivity between tau epicentre and non-epicentre regions, which is mediated in apolipoprotein E gene allele 4 carriers and amyloid-beta-positive participants. These findings have implications for trial designs, proposing that apolipoprotein E gene allele 4 carriers and amyloid-beta-positive participants might need earlier intervention to attenuate tau spreading and tau relative functional disconnection.

Nabizadeh investigated the potential role of apolipoprotein E4 and amyloid-beta in mediating the tau-related functional disconnection using functional MRI data. It was found that tau aggregates spread through functional connections and locally disrupt connectivity between tau epicentre and non-epicentre regions, which is mediated in apolipoprotein E4 carriers and amyloid-beta positive participants.

Graphical Abstract