Multivariate investigation of aging in mouse models expressing the Alzheimer's protective APOE2 allele: integrating cognitive metrics, brain imaging, and blood transcriptomics.
APOE2
Aging
Brain
Multivariate modeling
Neurodegeneration
Journal
Brain structure & function
ISSN: 1863-2661
Titre abrégé: Brain Struct Funct
Pays: Germany
ID NLM: 101282001
Informations de publication
Date de publication:
13 Dec 2023
13 Dec 2023
Historique:
received:
08
08
2023
accepted:
03
11
2023
medline:
13
12
2023
pubmed:
13
12
2023
entrez:
13
12
2023
Statut:
aheadofprint
Résumé
APOE allelic variation is critical in brain aging and Alzheimer's disease (AD). The APOE2 allele associated with cognitive resilience and neuroprotection against AD remains understudied. We employed a multipronged approach to characterize the transition from middle to old age in mice with APOE2 allele, using behavioral assessments, image-derived morphometry and diffusion metrics, structural connectomics, and blood transcriptomics. We used sparse multiple canonical correlation analyses (SMCCA) for integrative modeling, and graph neural network predictions. Our results revealed brain sub-networks associated with biological traits, cognitive markers, and gene expression. The cingulate cortex emerged as a critical region, demonstrating age-associated atrophy and diffusion changes, with higher fractional anisotropy in males and middle-aged subjects. Somatosensory and olfactory regions were consistently highlighted, indicating age-related atrophy and sex differences. The hippocampus exhibited significant volumetric changes with age, with differences between males and females in CA3 and CA1 regions. SMCCA underscored changes in the cingulate cortex, somatosensory cortex, olfactory regions, and hippocampus in relation to cognition and blood-based gene expression. Our integrative modeling in aging APOE2 carriers revealed a central role for changes in gene pathways involved in localization and the negative regulation of cellular processes. Our results support an important role of the immune system and response to stress. This integrative approach offers novel insights into the complex interplay among brain connectivity, aging, and sex. Our study provides a foundation for understanding the impact of APOE2 allele on brain aging, the potential for detecting associated changes in blood markers, and revealing novel therapeutic intervention targets.
Identifiants
pubmed: 38091051
doi: 10.1007/s00429-023-02731-x
pii: 10.1007/s00429-023-02731-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : RF1 AG057895
Pays : United States
Organisme : NIH HHS
ID : R01 AG066184
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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