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

Table 6. Comparison of populations and methods between the present study and the previous study 17
Attribute Present study (UPDB) Previous study (Cognitive Disorders Clinic) 17
Population Deceased individuals in a database Patients presenting to the clinic, mostly for initial
diagnosis
Diagnosis Based on death certificates Based on clinical criteria to diagnose early disease
Percentage of probands in 3% (4436/149303) 22% (71/320)
population from which they were
drawn
Proband sex ratio (F: M) 64:36=2:1 40:31=1.3:1
Age-based inclusion criteria No Between 55 and 80 years at presentation
Proband age 85 years (median) at death (range 39 – 103) 66.1±5.1 years for women and 68.1±6.5 years for
men at presentation (mean±standard deviation)
Unilateral parental family history Methods do not permit the exclusion of Methods specifically excluded 25 “bilateral” cases
“bilateral” cases
Observation Only 40 probands (<1%) had a parent with In most probands, it was a parent who had
AD identified (14 fathers, 27 mothers) AD/dementia

had AD as compared to the chances of identifying male (several hundred) would be required to replicate, with
patients whose mothers had AD or female patients whose greater sensitivity, the results of our earlier study. 17
fathers or mothers had AD. However, the low number
of patients in the clinic study was the main reason this 4.3.2. Future genetic studies
population-based database study was conducted, and it is A more ambitious goal of future research would be to seek
instructive to note that insofar as identifying large absolute genetic localization of X chromosome changes. Following
numbers of parents of patients with AD who also had AD, the approach of relying on individuals with a unilateral
we were not more successful with the population-based family history of disease, a much larger number of incident
database. Furthermore, this is not a unique circumstance. cases are needed to compare the X chromosomes of men
We conclude that searching for risk factors for AD, including with a maternal family history of AD (that might carry
genetic risk factors, has severe limitations when performed some risks for the disease) to those of men with a paternal
in prevalent populations or deceased populations. history of the disease (which would not be carrying risk

4.3. Implications for future research factors for the disease). A modified design would be
needed to perform a similar analysis in women with
4.3.1. Future epidemiological studies unilateral parental history of disease because 50% of their
Pinpointing the role of an elusive risk factor, the X X chromosomes might not confer risk for disease. If each
chromosome, will require that special efforts be invested X chromosome could be identified as arising from the
in the methodology of the search. We suggest that a affected or the unaffected parent, it would be appropriate
strategy based on looking for X-linked genetic risk in the to compare the X chromosome from the affected female
subpopulation of LOAD patients with a unilateral family parent to that from the unaffected female parent. While
history of the disease may increase the yield of the search. the specifics of designing genetic studies are beyond the
Epidemiological evidence for the contribution of the X scope of this project, we suggest that looking for genetic
chromosome to the development of AD will need to be risk factors in the subset of patients with a unilateral family
sought prospectively in incident patient populations with history of LOAD may provide new insights into the sex-
newly diagnosed aMCI or LOAD and a positive family specific genetic causes of AD, which have been elusive thus
history for an amnestic disorder. Contemporary studies far. A possible direction may be to focus on genes already
should avail themselves of confirmation of the diagnosis known to be responsible for mental functions, which are
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of AD in the probands using biologic markers. A represented disproportionately on the X chromosome,
standardized protocol will be needed to acquire a family comprising perhaps 15% of the total genes responsible for
history from these patients. While family history may be mental functions, while only 4% of the total number of
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limited in many patients, it may be positive in close to protein-coding genes in the genome are represented on
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30%; of these – perhaps upto three-quarters may report the X chromosome. The X chromosome is represented
unilateral parental lineage, or 22% (absolute). A relatively disproportionately in the Online Mendelian Inheritance in
small number of patients with unilateral parental lineage Man (OMIM) listing of genes linked to mental retardation.

Volume 3 Issue 2 (2024) 7 doi: 10.36922/an.3122