Estimating the X chromosome-mediated risk for developing Alzheimer’s disease

Parental lineage has been shown to increase the risk of Alzheimer’s disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci have been linked to the risk of developing AD, none has been found on the X chromosome. We propose a new method to estimate the risk for developing AD mediated by the X chromosome in a subgroup of late-onset AD (LOAD) patients with amnestic mild cognitive impairment (aMCI) or early AD and unilateral ancestral history of AD or dementia, and pilot-test it on our clinic data. Records of patients aged 55–80 years presenting to our Memory Disorders Clinic with aMCI or early AD between May 2015 and September 2020, were reviewed, counting patients with a family history of AD or dementia and unilateral ancestral lineage. 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 borne by the X chromosome is equal to (OR-1)/OR. 40 women aged 66.1 ± 5.1 years (mean ± standard deviation) and 31 men aged 68.1 ± 6.5 were identified. The OR was (18:22)/(6:25) = 3.4 (95% confidence interval 1.1–10.1; p = 0.027). The estimated proportion of genetic risk borne by the X chromosome in this population is 70% (95% CI 12–90%). This paper presents the first application of a new method. The numbers are small, the confidence intervals wide. The findings need to be replicated. The method may be generalizable to other diseases.