Estrogen activates Alzheimer's disease genes

Area of Science:

• Neuroscience
• Genetics
• Endocrinology

Background:

• Women exhibit a higher risk for Alzheimer's disease (AD), with the underlying causes remaining unclear.
• A leading hypothesis suggests that diminished estrogen levels during menopause may heighten AD vulnerability, though this remains unproven.

Purpose of the Study:

• To investigate the potential link between estrogen loss during menopause and increased Alzheimer's disease risk in women.
• To explore the genomic and molecular mechanisms underlying sex-based differences in AD susceptibility.

Main Methods:

• Compared estrogen-responsive neuronal genes in macaques to gene sets from the human brain.
• Utilized rare variant burden testing on exome sequencing data from female AD patients and controls.

Main Results:

• Identified significant overlap between estrogen-upregulated genes in macaques and downregulated genes in the human AD brain.
• Estrogen was found to upregulate the APOE gene, while progesterone showed genome-wide antagonistic effects.
• Female AD patients displayed an excess of rare mutations in the early menopause gene MCM8.

Conclusions:

• Genomic data suggest that the loss of estrogen during menopause could be a contributing factor to the elevated risk of Alzheimer's disease in women.