biostudies-literaturePerez SEBrighFocusNIA NIH HHSArizona Alzheimer's ConsortiumNINDS NIH HHSBarrow Neurological FoundationNIH HHSe70004https://www.ebi.ac.uk/biostudies/studies/S-EPMC12352929biostudies-literatureUnknown35(5)Default mode network (DMN) is comprised in part of the frontal (FC), precuneus (PreC), and posterior cingulate (PCC) cortex and displays amyloid and tau pathology in Alzheimer's disease (AD). The PreC hub appears the most resilient to AD pathology, suggesting differential vulnerability within the DMN. However, the mechanisms that underlie this differential pathobiology remain obscure. Here, we investigated changes in RNA polymerase II (RNA pol II) and splicing proteins U1-70K, U1A, SRSF2, and hnRNPA2B1, phosphorylated AT8 tau, 3R and 4Rtau isoforms containing neurons and amyloid plaques in layers III and V-VI in FC, PreC, and PCC obtained from individuals with a preclinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild/moderate mAD. We found a signifBrain pathology (Zurich, Switzerland)Spliceosome protein alterations differentiate hubs of the default mode connectome during the progression of Alzheimer's disease.PMC12352929K08 NS087121RF1AG081286P30 AG072975P30 AG066511P30AG066511P01 AG014449RF1 AG081286P30 AG010161P01AG014449NS087121P30AG10161CA2018010Nadeem MMiguel JCPerez SEMoreno DGMoreno-Rodriguez MMalek-Ahmadi MMufson EJHales CMHe BfalseSpliceosome protein alterations differentiate hubs of the default mode connectome during the progression of Alzheimer's disease.Default mode network (DMN) is comprised in part of the frontal (FC), precuneus (PreC), and posterior cingulate (PCC) cortex and displays amyloid and tau pathology in Alzheimer's disease (AD). The PreC hub appears the most resilient to AD pathology, suggesting differential vulnerability within the DMN. However, the mechanisms that underlie this differential pathobiology remain obscure. Here, we investigated changes in RNA polymerase II (RNA pol II) and splicing proteins U1-70K, U1A, SRSF2, and hnRNPA2B1, phosphorylated AT8 tau, 3R and 4Rtau isoforms containing neurons and amyloid plaques in layers III and V-VI in FC, PreC, and PCC obtained from individuals with a preclinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild/moderate mAD. We found a signif2025-01-01T00:00:00Z2025 Sep2026-05-29T15:07:24.832Z2026-04-08T05:10:22.917ZS-EPMC123529294012267910.1111/bpa.70004