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

The plan of analysis was developed (by C.A. and S.W.) for AD is mediated by the X chromosome. We considered
before accessing the sex-specific UPDB data. We decided that the null result might be caused by an inherent error
a priori that our primary analysis would be based on the in our formula. The inherent assumptions in applying
175 AD probands with SDRs affected by AD (father’s this formula are stated in the methods section. However,
brother or sister vs. mother’s brother or sister) and that these assumptions do not account for the gap between the
our secondary analysis would be based on the 1850 AD current findings and those of our previous study. 17
probands with TDRs affected by AD (father’s first
cousins vs. mother’s first cousins). We did not calculate Table 2. Comparison of estimated RRs between paternal and
a combined OR or percent risk estimate because of maternal relationships, regardless of all other relationships,
the imbalance between the groups — the sample size for female probands identified from UPDB
used in the secondary analysis was more than 10 times
larger than that in the primary analysis. We also did not Family history N Obs Exp RR P 95% CI
perform an analysis based on the mother’s or father’s ≥1 maternal first cousin 18,884 582 523.37 1.11 0.01 1.02, 1.21
involvement because the total number of parents affected ≥1 paternal first cousin 19,122 629 553.3 1.14 0.001 1.05, 1.23
(40) was small (Table 3 of Cannon-Albright et al. ), ≥1 mother’s brother 745 25 17.04 1.44 0.07 0.93, 2.12
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largely due to the small window of view to AD deaths in ≥1 father’s brother 606 11 11.97 0.92 0.89 0.46, 1.64
the UPDB, from which only ICD-9 and ICD-10 coding ≥1 mother’s sister 1339 42 31.9 1.32 0.077 0.95, 1.78
was available.
≥1 father’s sister 1163 26 25.0 1.04 0.84 0.68, 1.53
2.3. Standard protocol approvals, registrations, and Note: Data from second-degree relatives are presented in boldface.
patient consent Data from third-degree relatives are in regular font.
Abbreviations: N: Number of individuals; Obs: Observed;
The study was approved by the University of Utah Exp: Expected; RR: Relative risk; P: P value; 95% CI: 95% confidence
Institutional Review Board and the Utah Resource for interval (lower limit, upper limit).
Genetic Epidemiological Research, which collectively
oversees the use of UPDB data. Individual consent was Table 3. Comparison of estimated RRs between paternal and
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not required to access the data. maternal relationships, regardless of all other relationships,
for male probands identified from UPDB
3. Results Family history N Obs Exp RR P 95% CI
The data from Table 5 of the original publication are ≥1 maternal first cousin 19,535 296 288.2 1.03 0.66 0.91, 1.15
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shown separately for female and male probands (with and ≥1 paternal first cousin 19,922 343 305.2 1.12 0.03 1.01, 1.25
without AD) (Tables 2 and 3). ≥1 mother’s brother 951 21 11.7 1.79 0.0098 1.11, 2.74

3.1. Primary analysis ≥1 father’s brother 782 8 8.1 0.99 1 0.43, 1.95
≥1 mother’s sister 1650 25 20.1 1.24 0.31 0.80, 1.84
As shown in Tables 2 and 3, there were 175 AD probands
(=25+11+42+26+21+8+25+17) with parental lineage of ≥1 father’s sister 1450 17 15.5 1.09 0.80 0.64, 1.75
AD determined by SDRs; this proband group consisted Note: Data from second-degree relatives are presented in boldface.
of 104 women and 71 men. Their distribution by parental Data from third-degree relatives are in regular font.
Abbreviations: N: Number of individuals; Obs: Observed;
lineage is presented in Table 4. Exp: Expected; RR: Relative risk; P: P value; 95% CI: 95% confidence
interval (lower limit, upper limit).
3.2. Secondary analysis
As shown in Tables 2 and 3, there were 1850 AD probands Table 4. Analysis based on ancestral family history, based on
(=582+629+296+343) with parental lineage of AD the sex of the affected probands, and the sex of the affected
determined by third-degree relatives; this proband group parental side
consisted of 1211 women and 639 men. Their distribution Proband (n=175) Lineage
by parental lineage is presented in Table 5. Paternal (father’s Maternal (mother’s
brother or sister) brother or sister)
3.3. Summary of results
Female (104) 37 (11+26) 67 (25+42)
These results do not support the role of genetic information Male (71) 25 (8+17) 46 (21+25)
carried on the X chromosome in conferring a risk for AD.
The null result – the absence of support for a role for genetic Notes: (1) The parental lineage of AD was determined by
second-degree relatives (data taken from Tables 2 and 3).
information carried on the X chromosome in conferring a (2) The calculated OR is 1.01 (37:67/25:46), with a
risk for AD – may have occurred because indeed no risk 95% CI of 0.54 – 1.91 (P=0.96).

Volume 3 Issue 2 (2024) 5 doi: 10.36922/an.3122