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Advanced Neurology X chromosome-mediated risk in Alzheimer’s disease

It is estimated, using 2014 – 2016 data, that 22.3% of the outstripped by those on the 22 autosomal chromosomes.
total number of genes contributing to mental retardation This is particularly puzzling because the X chromosome
reside on the X chromosome. 29,30 The search to explain carries a disproportionate share of genetic material coding
the role of the X chromosome in the development of AD for neural network development, and is implicated in mental
may be advanced by focusing on genes residing on the X function and dysfunction. 29,30 We, therefore, proposed a new
chromosome that already have been implicated in carrying method, developed based on an epidemiological approach
a risk for neurological disease (listed in OMIM) by looking and a unique approach to data analysis, to estimate the
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for minor changes in these genes in X chromosomes risk conferred by the X chromosome in a subpopulation of
enriched for the likelihood of carrying risk by the unilateral patients with LOAD who had a unilateral parental family
parental family history of their bearers. history of dementia. When first applied to a population of
4.4. Clinical implications newly diagnosed, incident patients, the analysis indicated
that 70% of the risk was mediated by the X chromosome
Identifying the risk for AD carried by the X chromosome in this population. We then set out to replicate the findings
will permit refinement of the prognostic information in an existing database but were not successful. This led
regarding the lifetime risk of developing AD that can be us to examine the differences between the populations
given to the offspring of parents with AD, based on the sex of the original study and the present study. We saw that
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of the affected parent and that of the offspring. Identifying the inherent characteristics of this pre-existing dataset
the proportion of risk mediated by the X chromosome may were greatly different from those of the incident dataset
serve as an impetus to develop the methodology to help of the original study, in a way that biased the study toward
identify the genetic loci mediating the risk. producing a null result. Thus, it is necessary to focus future
If genetic risk factors can be identified as specific efforts on searching risk factors for LOAD on datasets of
polymorphisms on the X chromosome, further refinement newly diagnosed incident cases, if there is to be a chance
of prognostic information may be possible. In turn, once not only to replicate the findings of our original study
a complete map of genetic risk factors including those but also to have a substrate for genetic analysis that truly
residing on the X chromosome is developed, it may be carries in excess the risk factors for which we are looking.
possible to stratify individuals based on their lifetime The implications are that the dataset would need to be
risk of developing AD and to use preventative and early assembled prospectively. A further implication of our
therapeutic interventions in high-risk individuals, which approach is that the search for genetic risk factors on the
are tailored to their genetic makeup. Besides, it may be X chromosome might become more fruitful if performed
possible to apply established genome editing techniques 31-33 by comparing X chromosomes derived from a sample of
to modify polymorphisms to mitigate disease risk. A good individuals that is enriched for the likelihood for carrying
understanding of the risk factors can also considerably pathogenic polymorphisms on chromosome X (men who
benefit individuals carrying an increased genetic risk for had an affected maternal line) to X chromosomes from
AD. They may manipulate the modifiable individual and individuals with little risk of having the disease mediated
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environmental risk factors for the disease so as to mitigate by the X chromosome (men who had an affected paternal
the risk for AD development.
line). The corollary of these considerations, in our opinion,
5. Conclusion is that if these or similar approaches are not implemented,
and we continue to look for genetic markers for LOAD on
At present, the precise mechanisms by which the risk the X chromosome in the same way we have looked for
of LOAD is transmitted genetically are incompletely them so far, we will continue to have limited success in
clarified. Except for the ApoE4 allele, other polymorphisms finding them.
convey very minimal risk. There are some indications that
maternally-transmitted risk may be greater than paternally- The introduction of new treatments for LOAD 36,37
transmitted risk, but the observation is not consistent, and presents an exciting opportunity to enroll newly-diagnosed,
the mechanism is unclear. There are additional indications biologically-confirmed incident cases into epidemiological
that the transmission of risk to men may be different than studies of the disease’s inheritance patterns. Only a few
the mode of transmission to women, although such findings hundred individuals with unilateral parental lineage would
are inconsistent from one study to another. If there is indeed be needed to generate a robust estimate of the risk mediated
a clear-cut difference in the mode of risk transmission, we by the X chromosome. A larger number of individuals with
can assume that the transmission is mediated by the X unilateral parental lineage for the disease would be able to
chromosome. At present, studies focusing on discovering contribute an enriched substrate necessary for identifying
risk-conferring polymorphisms on the X chromosome are new pathogenic loci on the X chromosome.

Volume 3 Issue 2 (2024) 8 doi: 10.36922/an.3122