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

2.2. Statistical analysis The OR calculated using the method described in

The data in this study were analyzed in accordance with the Table 1’s legend may be used to estimate the RR conferred
previously described methods. In the original report, all by the X chromosome, under several assumptions. First,
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the affected individuals had symptomatic disease: aMCI or this analysis method can be used if AD has a relatively low
early AD. In contrast, the subjects included in this analysis occurrence rate. In fact, the frequency of LOAD patients
are individuals documented in the UPDB who were with a unilateral family history of disease was quite low, both
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AD-verified per their death certificates. in our clinic population and in the UPDS population.
We consider that the OR calculation method described can
We used the affected individual’s sex chromosomes (XX control for several confounders, which may be expressed
or XY) and the parent’s sex chromosomes (XX or XY) to equally to influence disease occurrence in each of the four
infer which chromosomes may be involved in transmitting cells or each of the four cell pairs of the 2×2 table. These
the risk of AD: 22A+X (from mothers to all offspring and include non-nuclear-mediated modes of maternal effect on
from fathers to daughters) or 22A+Y (from fathers to risk, such as mitochondrial transmission and gestational
sons). For this calculation, we assumed the risk borne by environment; any effect of the Y chromosome unrelated
the Y chromosome to be negligible and removed it from to the risk of developing AD or of the phenomenology or
the calculation (it is not reflected in the table). The X indirect effect of being a woman or a man; and most of
chromosome-attributable RR was estimated by calculating the effects of imprinting mechanisms, as male and female
the OR using the formula in the following:
probands are positioned equally to inherit a culpable
OR = (a/b)/(c/d) (I) autosomal chromosome from either father or mother and
Where a = Number of women with paternal lineage; b to have it expressed differently depending on whether it was
= Number of women with maternal lineage; c = Number of inherited from father or mother. A recent review concludes
men with paternal lineage; and d = Number of men with that X chromosome inactivation (XCI) occurs randomly
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maternal lineage. in humans, regardless of parental origin. Hence, the
effects of XCI would impact women with LOAD equally,
This calculation reframes the question of the mode
of transmission. Rather than asking “who is the parent” regardless of their family history. The Y chromosome-
attributable risk for AD remains a moving target, and our
or “what is the parental lineage” (as in “maternal” vs. assumption that we can ignore its role in the transmission
“paternal” transmission), it asks “which chromosomes
might mediate the transmission of risk.” It seeks to isolate of risk of developing AD in the present calculation may
the risk imparted by the X chromosome. This method and not withstand the test of time. A recent report indicates
its rationale, in terms of elucidating the genetic pathways that mosaic loss of chromosome Y (mLOY), a common
of inheritance, are shown in Table 1. aging-related somatic event, confers an increased risk of
developing AD. However, the genes used to calculate
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Table 1. Method of analysis based on ancestral family the polygenic risk score for mLOY are found to reside on
history, sex of the affected patients, and sex of the affected autosomal chromosomes and could be transmitted equally
relatives. from the father or mother. Completion of the sequencing
of the Y chromosome, may broaden the opportunity to
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Probands Affected ancestral side elucidate its role in normal brain development and the
Paternal Maternal occurrence of neurodegeneration, including AD.
Women a b
22A+X 22A+X The estimated proportion of the total genetic risk
Men c d carried by the X chromosome (expressed as a percentage)
22A 22A+X may be derived using the following formula:
Notes: a: Number of female AD probands with father or/and paternal Estimated proportion of genetic risk borne by the X
relatives affected by AD. Risk can be conferred by the 22 autosomal chromosome = (OR-1)/OR × 100% (II)
chromosomes and/or the X chromosome; b: Number of female AD
probands with mother or/and maternal relatives affected by AD. Risk can be The interpretation of the formula is as follows: an OR
conferred by the 22 autosomal chromosomes and/or the X chromosome; c: of 1.0 means that no risk resides on the X chromosome;
Number of male AD probands with father or/and paternal relatives affected an OR of 1.2 means that 17% of the risk resides on the X
by AD. Risk can be conferred only by the 22 autosomal chromosomes. This
feature is unique only to this group; d: Number of male AD probands with chromosome; an OR of 1.33 means that 25% of the risk
mother or/and maternal relatives affected by AD. Risk can be conferred by resides on the X chromosome.
the 22 autosomal chromosomes and/or the X chromosome. The odds ratio
(OR) is determined by finding the ratio of (a: b) to (c: d) and estimates the ORs, CIs, and P-values were calculated using an online
relative risk (RR) conferred by the X chromosome. calculator (https://www.medcalc.org/calc/odds_ratio.php).

Volume 3 Issue 2 (2024) 4 doi: 10.36922/an.3122