Search for Female-Specific Genetic Factors Contributing to Risk for Alzheimer’s Disease

This multidimensional investigation will seek to elucidate sex-linked factors that determine Alzheimer’s disease risk, age of onset and rate of progression, powerful information that would contribute to the pursuit of a cure for both sexes. Women make up more than two-thirds of the Alzheimer’s patient population, yet very little is known or understood about why this is the case or what it means about the disease’s mechanisms of action, risk factors and progression. Epidemiological evidence suggests that a woman at age 65 faces almost twice the risk of developing Alzheimer’s disease in her lifetime and nearly three times at age 75 than does a man of the same age, differences that are not explained by age of expected mortality alone. We propose to carry out a comprehensive, family-based association meta-analysis of all three AD family sample Whole Genome Sequencing (WGS) datasets separately for each sex, an important and novel investigation since virtually no AD genome-wide association study carried out to date has considered sex-based differences. More specifically, we also will calculate the overall genetic component explained by each of the >47 million single nucleotide variants (SNV) identified in the National Institute of Mental Health WGS project and proceed to estimate the genetic correlation/overlap between males and females. More specific appreciation of the factors that increase or decrease risk of disease, age of onset and rate of progression would benefit both sexes, yet the collection, analysis and publication of scientific data have not yet caught up to this recognized need. Common gender-specific lifestyles, X-linked genetic variants, female hormonal profiles over the lifecycle and other differences offer compelling subjects for investigation as contributing factors.