Testing a therapeutic strategy for hippocampal sclerosis of aging, a key AD mimic

Diseases that mimic Alzheimer’s disease (AD) are understudied causes of cognitive impairment in the elderly. Poor understanding of these diseases has hampered AD clinical trials while leaving important illnesses largely unaddressed from a research perspective. A common and high-morbidity “AD mimic” is hippocampal sclerosis of aging (HS-Aging). HS-Aging is characterized by cell loss and astrocytosis in the hippocampus and amygdala, with phosphorylated TDP-43 (P-TDP-43) pathology, not correlated with AD-type plaques and tangles, nor with APOE genotype. HS-Aging afflicts a rapidly expanding demographic group: persons of advanced old age. The PI of the current proposal has studied HS-Aging extensively, including the largest autopsy series published to date and the first HS-Aging genome-wide association study (GWAS). A genetic polymorphism in the ABCC9 gene -- rs704178 -- is linked to HS-Aging pathology with genomewide statistical significance. ABCC9 protein regulates ATP-sensitive potassium channels, termed “KATP” channels. This enables us to address a central promise of genomics studies: clinical relevance. Remarkably, the GWAS-identified HS-Aging risk gene ABCC9 is a “druggable target”—both agonist and antagonist drugs are used widely in humans. In a prior published study, we found that exposure to sulfonylureas (popular oral anti-diabetic drugs that antagonize ABCC9 protein function) is associated with increased risk for HS-Aging pathology in humans, controlling for other factors. We need to assess the potential to target ABCC9 in a preclinical model for more rigorous control of experimental parameters. That will enable us to test the impact of an ABCC9 agonist drug, with the opposite effects of sulfonylureas, as a potential therapy for clinical HS-Aging.