Dr. Dylan Terstege
Work done at University of Calgary
Article citation
Terstege, D. J., Ren, Y., Ahn, B. Y., Seo, H., Adigun, K., Alzheimer’s Disease Neuroimaging Initiative, Galea, L. A. M., Sargin, D., Epp, J. R. (2025). Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease. Science Advances, 11(18), eadt8976.
Reduced activity in a brain region called the retrosplenial cortex is linked to sex-dependent vulnerability in Alzheimer’s disease
Alzheimer’s disease (AD) occurs more often and progresses faster in women than men. Understanding the causes of these sex differences will help us to better understand the pathobiology of the disease. Here, Dylan Terstege, working in the laboratory of Jonathan Epp at the University of Calgary, identified a novel, sex-dependent vulnerability in a brain region called the retrosplenial cortex (RSC) that links dysfunction of a specific brain cell-type, parvalbumin interneurons (PV-interneurons), to early cognitive decline in Alzheimer’s disease. Using a mouse model of Alzheimer’s disease (called 5xFAD mice), the researchers noted that female but not male 5xFAD mice exhibited early reduced metabolic activity and higher excitability in the RSC brain region.
To study gene expression in the RSC, the researchers used a technique called Spatial Transcriptomics. This tool allowed the researchers to determine that fewer PV-interneurons survived in the RSC brain region in female 5xFAD mice but also that the remaining PV-interneurons were less active. Conversely, stimulation of these same cells in female 5xFAD mice rescued memory deficits, highlighting its therapeutic potential.
To show the relevance of these discoveries for humans, the researchers observed a parallel, sex-dependent dysregulation of RSC functional connectivity in human fMRI data across progressive stages of Alzheimer’s disease pathogenesis. This signature connectivity impairment was supported by impaired expression of PV-interneurons across the RSC in human Alzheimer’s disease postmortem tissue.
This work establishes the RSC as a key brain area for early dysfunction in Alzheimer’s disease, especially in females. The sex-specificity of this effect is particularly important, as the incidence of Alzheimer’s disease is greater and the rate of progression from mild cognitive impairment to Alzheimer’s disease is more rapid in women than in men. Collectively, these data demonstrate the potential for RSC PV-interneurons as a target for early therapeutic intervention and the use of RSC neuroimaging as a clinical tool for tracking progression of Alzheimer’s disease.
Early results in this manuscript inspired further investigation of early RSC hypometabolism. From an Alzheimer’s disease research database called ADNI (Alzheimer’s Disease Neuroimaging Initiative), subjects initially presenting with mild cognitive impairment were identified. Many, but not all, of these subjects later progressed to Alzheimer’s disease. Statistical analysis of mapping scans collected during trial intake identified RSC hypometabolic activity in individuals who later develop Alzheimer’s disease. These results identify reduced RSC metabolism as a biomarker of Alzheimer’s disease progression risk. Furthermore, while females are affected earlier, this study demonstrated the predictive impact of RSC dysfunction in later Alzheimer’s disease progression remains important in males as well.
In addition to direct implications in Alzheimer’s disease research, this study highlights several technical advancements. Immediate early gene-based functional connectivity analyses are becoming increasingly popular, as they provide a snapshot of brain-wide functional connectivity underlying rodent behavioural tasks without the need for expensive equipment. However, prior to the current study, the ability for this approach to identify human-relevant changes in functional connectivity had not been assessed.
About Dr. Dylan Terstege
Dr. Dylan Terstege conducted this work as part of Dr. Jonathan Epp’s research group which focuses on mechanisms supporting learning, memory, and forgetting at the University of Calgary. This study was the centerpiece of Dylan’s doctoral dissertation, focusing on early pathological changes at the RSC in Alzheimer’s disease and how these disruptions impair and degrade inhibitory circuits.
Dr. Dylan Terstege is currently a postdoctoral fellow in Dr. Rosa Cossart’s lab at the Mediterranean Institute of Neurobiology (INMED) in Marseille, France. As a postdoctoral fellow, he is using in vivo calcium imaging in mouse pups to study how inhibitory circuits supporting learning and memory function are established under physiological and pathological conditions during early development.
Sources of funding
This work was supported by an Alzheimer’s Society Research Program (ASRP) new investigator grant, a Canadian Foundation for Innovation (CFI) grant, and a Women’s Brain Health Initiative Grant in partnership with Brain Canada to J.R.E., as well as an Alzheimer’s Association Grant in partnership with Brain Canada to D.S. D.J.T. received a doctoral fellowship from NSERC and Y.R. received doctoral awards from the Hotchkiss Brain Institute and the ASRP.