{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T06:56:14Z","timestamp":1764399374276,"version":"3.46.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":287,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u2018prion-like\u2019 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\u2019s 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.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf404","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:21:32Z","timestamp":1760448092000},"source":"Crossref","is-referenced-by-count":0,"title":["Apolipoprotein E gene allele 4 and amyloid-beta mediate tau-related network breakdown"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4633-3340","authenticated-orcid":false,"given":"Fardin","family":"Nabizadeh","sequence":"first","affiliation":[{"name":"School of Medicine, Iran University of Medical Sciences , Tehran 14535 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