Glycolysis-enhancing α1-adrenergic antagonists have therapeutic potential in Alzheimer's disease.

BACKGROUND

Terazosin (TZ) is widely prescribed for hypertension and benign prostatic hyperplasia. Recent studies suggest that TZ enhances glycolysis and may protect against neurodegenerative diseases.

METHODS

We tested the hypothesis that TZ is neuroprotective in Alzheimer's disease (AD) in a yeast model, a mouse model, and two human datasets.

RESULTS

We report four main results. First, TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired metabolism, and reduced Amyloid-beta42 (Aβ42) aggregation. Second, in 5xFAD mice, TZ attenuated amyloid pathology and rescued cognitive impairments in spatial memory and interval timing. Third, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, AD patients taking glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and metabolic neuroimaging biomarkers (18 F-fluorodeoxyglucose positron emission tomography (FDG-PET)). Finally, in the Merative Marketscan dataset, patients taking glycolysis-enhancing drugs had lower risks of developing AD.

CONCLUSION

These data provide preliminary evidence that glycolysis-enhancing drugs have therapeutic potential in AD.