DNA mutations that increase the length of a certain part of Ataxin-1 gene (ATXN1) is known to cause spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that primarily impairs coordinated movement and deteriorates cognitive function in patients. In a recent genetic study of Alzheimer’s families, our research group found ATXN1 also is associated with Alzheimer’s disease. In this project, utilizing mouse models, we found Ataxin-1 plays a key role in regulating BACE1 expression in the brain. BACE1 is an enzyme to cleave the amyloid precursor protein (APP) and initiates the first step to generate amyloid beta, the main culprit of senile plaques in AD brains. We found Ataxin-1 regulates the transcription of BACE1 in AD-vulnerable brain regions, and the lack of Ataxin-1 can increase amyloid beta plaque deposition in the brain. We also discovered the loss of Ataxin-1 can lead to, potentially through BACE1 regulation, severe deficits in newborn neuron generation and neuronal wiring. These two impairments in the brain, as well as the accumulation of amyloid beta, would establish a predisposition to AD.