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Human brain connectome profiles mediate the relationship between pathology burden and clinical phenotypes in

Yating Li1,2, Dong Wang1,2, Rongshen Zhou1,2

  • 1School of Artificial Intelligence, Beijing University of Posts and Telecommunications, Beijing, China.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|July 1, 2026
PubMed
Abstract

Insights

Brain network integrity, not just Alzheimer's disease pathology, determines mild cognitive impairment progression. Connectome architecture significantly influences clinical outcomes in individuals with MCI.

Area of Science:

  • Neuroscience
  • Alzheimer's Disease Research
  • Computational Psychiatry

Background:

  • Mild cognitive impairment (MCI) presents significant clinical variability, challenging accurate prognosis.
  • The role of brain network architecture in mediating Alzheimer's disease (AD) pathology and clinical presentation remains unclear.

Purpose of the Study:

  • To investigate how connectome architecture influences the clinical heterogeneity observed in MCI.
  • To determine if brain network integrity mediates the relationship between AD pathology and cognitive decline.

Main Methods:

  • Developed a framework integrating structural and functional connectomes from multi-center cohorts.
  • Performed connectome-based subtyping in MCI cohorts.
  • Analyzed associations between connectomic patterns, pathology, clinical phenotypes, and transcriptomics.

Main Results:

  • Identified two MCI subgroups: MCI-compromised (MCI-C) with disrupted connectomes and MCI-preserved (MCI-P) with intact connectomes.
  • MCI-C exhibited more severe neurodegeneration, faster cognitive decline, and higher progression risk despite similar pathology burden.
  • Connectomic disruptions in MCI-C were linked to transcriptomic profiles involving mitochondrial, synaptic, and neuroimmune pathways.

Conclusions:

  • Connectome architecture is a critical mediator, not merely a passive marker, of clinical expression in MCI.
  • Brain network integrity plays a key role in shaping individual trajectories within the Alzheimer's disease continuum.
Keywords:
Alzheimer's diseasebrain resilienceclinical heterogeneitymediatormultimodal brain network

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