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

only via the 22 autosomal chromosomes if the risk arises UPDB, approximately 1.3 million have genealogy data for
from the father’s side. This approach assumes that the risk at least 12 of their 14 immediate ancestors spanning at least
for AD mediated by the genes on the Y chromosome is three generations. The genealogy data in the UPDB analyzed
negligible. This may be an oversimplification. By counting for this study have been linked to computerized Utah death
the numbers of affected probands with unilateral parental certificates issued from 1904 to 2014. Cause of death was
lineage in a population-based sample, stratified based on coded using the International Classification of Diseases
proband sex and lineage sex, it is possible to calculate an (ICD) revisions 6 – 10, depending on the year of death.
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odds ratio (OR) to isolate the contribution to risk mediated Only individuals with genealogy-linked death certificates
by the X chromosome. This method does not assume coded with ICD-9 or ICD-10 were included because AD
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that all the risk in these patients is genetically-mediated. first appeared as a coded cause of death in ICD-9.
The details, assumptions, and limitations of this approach
are elaborated in the Methods section. When applied to 2.1.2. Case selection
a small, single-center Cognitive Disorders Clinic sample Individuals with an ICD code for AD as a primary or
of convenience, mainly consisting of incident patients, contributing cause of death (ICD-9: 331.0; ICD-10:
the estimated proportion of genetic risk borne by the F00 or G30) were identified as AD cases. This definition
X chromosome was as high as 70%, with a broad CI. was also used previously. All individuals with ancestral
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The limitations of these preliminary findings have been genealogy and a linked Utah death certificate were
recognized, and it is necessary to replicate and validate analyzed to estimate population rates for AD in the UPDB
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these findings. (n = 270,818). Cohort-specific rates for AD were estimated
In this study, we sought an available dataset of patients for cohorts classified by sex, 5-year birth year range, and
with AD who had a family history documented adequately birthplace (Utah or not) by determining the ratio of the
to permit application of the new method and replication number of AD deaths in a cohort to the number of Utah
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of the original analysis. We attempted to access one large deaths in the cohort. 6
database, but the information needed was not available, as 2.1.3. Estimation of RRs
family history was documented only as positive or negative
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without further elaboration regarding parental lineage. We In the original report, RRs were estimated for many
then explored the possibility of utilizing the UPDS. The different family history constellations, based on the number
UPDB is a population-based dataset of uniformly defined of affected FDRs, SDRs, and TDRs, age at death from AD,
patients and family histories and has already analyzed its sex of proband, and maternal vs. paternal inheritance.
data to demonstrate the impact not only of FDRs but also Probands in the UPDB might be either affected (with AD)
of SDRs and TDRs on the risk of AD. Proband sex-specific or unaffected. FDRs include parents, offspring, and
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data were available for Table 1 of the original study. We siblings; SDRs are the FDRs of FDRs; and TDRs are the
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analyzed the sex-specific data using the new method to FDRs of SDRs. For each constellation, all probands with
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replicate, if possible, the original observations. 17 the specific family history constellation in the UPDB were
identified. The estimated RR for each specific family history
2. Methods constellation was calculated as the ratio of the observed
number of AD cases among the probands to the expected
2.1. Overview number of AD cases among the probands; 95% CIs for the
This section has two major components. First, we describe RR were calculated using the method proposed by Agresti.
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the UPDB, and how cases were selected for the present The expected number of AD cases among the probands
analysis. The UPDB, case selection, and RR estimation have was estimated by counting all the probands by cohort,
been described previously in detail and are summarized multiplying the number of probands in each cohort by the
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here, focusing on the data used for the present analysis. cohort-specific rate of AD, and summing over all cohorts. 6
Next, we describe the new method of analysis that we
applied to the UPDB data. 2.1.4. Specific summary data used in the present
report
2.1.1. UPDB data The present analysis employed data presented in Table 5 of
The UPDB encompasses the computerized genealogy the original report, which were made available separately
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of the Utah pioneer founders from the 1800s, and for female and male probands. The same proband may
their descendants to the modern day, linked to many be considered several times, for example, with mother’s
demographic and health-related data registries. Of the brother, father’s brother, mother’s sister, or father’s sister. The
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11 million Utah-connected individuals represented in the present analysis relied on the proband numbers provided.

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