Chasing shadows: Investigating X chromosome mediation in late-onset Alzheimer's disease

Alzheimer's disease (AD) is a major cause of dementia. While maternal inheritance has been recognized for late-onset AD (LOAD), risk factors have not been identified consistently on the X chromosome. We recently developed a new method to identify an apparent risk of 70% mediated by the X chromosome in newly-presenting cognitive disorders clinic patients with amnestic mild cognitive impairment (aMCI) or early LOAD with unilateral parental lineage for AD or dementia. We sought to confirm our preliminary findings in the Utah Population Database (UPDB). We obtained previously published aggregate data on the risk of AD in the UPDB based on family history, stratified the data by the sex of the proband, and analyzed them using the new method. The X chromosome-attributable relative risk was estimated by calculating the following: Odds ratio (OR) = (women with paternal lineage: Women with maternal lineage)/(men with paternal lineage: Men with maternal lineage). The proportion of genetic risk attributable to the X chromosome is equal to (OR-1)/OR. The analysis did not reveal any risk mediated by the X chromosome, and the null result could be attributed to methodological limitations. Factors that impact the initial or early presentation (incidence) of LOAD, which are appropriate for consideration as risk factors, may not be detectable in a (prevalent) population of deceased individuals. Thus, epidemiological evidence for the contribution of the X chromosome to the development of LOAD will need to be sought prospectively in incident patient populations with newly diagnosed, biologically-confirmed aMCI or LOAD.