Li Y; Wang D; Zhou R; Yan S; Wang D; Wei Y; Yao H; Zhou B; Lu J; Wang P; Liao Z; Han Y; Zhang X; Zhang Y; Liu Y; Zhao K; Alzheimer's Disease Neuroimaging Initiative · 2026 · Alzheimer's & dementia : the journal of the Alzheimer's Association
Paper
INTRODUCTION: Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), shows pronounced clinical heterogeneity poorly explained by pathology burden, representing a gap complicating prognosis. As the brain operates as a complex network for information integration, we hypothesized that connectome architecture mediates the link between AD pathology and clinical expression. METHODS: We developed a framework integrating structural and functional connectomes from multi-center cohorts, performing connectome-based subtyping in MCI, with analyses of upstream pathology, downstream phenotypes, and transcriptomic associations. RESULTS: This approach identified an "MCI-compromised" (MCI-C) subgroup characterized by extensive structural-functional connectomic disruption and an "MCI-preserved" (MCI-P) subgroup with relatively preserved connectome integrity. Despite comparable pathology, MCI-C demonstrated more severe neurodegeneration, accelerated cognitive decline, and elevated progression risk. Multiscale analyses linked these patterns to transcriptomic profiles of mitochondrial, synaptic, and neuroimmune processes. DISCUSSION: These findings demonstrate that the connectome acts as a critical mediator, rather than a passive endophenotype, shaping AD clinical expression.
Analysis
This study investigates how the brain's network architecture (connectome) influences the clinical presentation of mild cognitive impairment (MCI) in Alzheimer's disease (AD), suggesting the connectome acts as a mediator between pathology and symptoms.
Discovery
Yang Z; Chang X; Chen J; Pei H; Liao J; Luo X; He H; Duan M; Rodriguez-Labrada R; Jiang S; Yao D; Luo C
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Przywara D; Petniak A; Gil-Kulik P
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