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Alzheimer's Association International Conference 2026

July 12-15, 2026 | London, United Kingdom, and Online

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1801

Regional Vulnerability Of The Frontal Cortex In Vascular Cognitive Impairment And Dementia

Poster Presenter

Jessica Chalk

Part of Topic

INTRODUCTION

Vascular contributions to cognitive impairment and dementia (VCID) is a leading cause of age-related cognitive decline and is characterized by chronic cerebral hypoperfusion, neurovascular unit (NVU) dysfunction, and neuroinflammation. Although cognitive symptoms are largely driven by cortical dysfunction, the molecular mechanisms underlying regional vulnerability and resilience across the brain remain poorly understood. This study aimed to characterize transcriptomic differences between the frontal cortex and cerebellum in VCID to identify region-specific pathological responses.

MATERIALS & METHODS

Post-mortem frontal cortex (FCX) and cerebellum (CER) tissue from 12 VCID cases underwent gene expression profiling using NanoString’s Human Neuroinflammatory Panel (784 genes). Differential gene expression analysis was performed using Limma, followed by Gene Ontology (GO) enrichment to identify altered biological pathways. In silico cell-type deconvolution based on established marker genes was used to estimate disease-associated shifts in cellular composition across brain regions.

CONCLUSIONS

Regional identity drives transcriptional variation in VCID

•Frontal cortex is enriched for neuronal identity genes: Upregulated genes include cortical transcription factors (MEF2C, TBR1, DLX1), synaptic markers (NRGN), and glutamatergic transporter SLC17A6. Pathway analysis confirms enrichment of axon ensheathment and myelination, processes vulnerable to vascular injury.
•Cerebellum shows a distinct epigenetic and metabolic signature: Upregulated genes include cell cycle regulators (POLE, LMNB1), lipid droplet genes (CIDEA, CIDEB), and chromatin remodelers (KDM4C). Pathway analysis reveals enrichment of heterochromatin organization, epigenetic regulation, and DNA replication.

Implications

•VCID does not produce a uniform transcriptional response across brain regions.
•FCX and CER exhibit distinct disease mechanisms, suggesting region-specific therapeutic targets should be considered in VCID research.

FUTURE DIRECTIONS

•MSD multi-array profiling will be used to validate inflammatory and neurovascular markers at the protein level.
•Spatial proteomics will be used to localize markers within the neurovascular niche.

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