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

of amyloid-β (Aβ) peptides generated by the cleavage of relative (as determined by death certificate data linked
amyloid pre-cursor protein, strings of hyperphosphorylated to genealogy) is concordant with the observed increased
tau proteins accumulating inside neurons known as incidence in men of amnestic mild cognitive impairment
neurofibrillary tangles, and neuronal loss. However, the (aMCI) – an early manifestation of AD. 10,11 In women, the
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underlying molecular mechanisms leading to the disease greater life-time risk and prevalence of AD observed is
are poorly understood, and a study of brain samples from accounted for by their longer lifespan.
AD patients reveals differential changes in gene expression Despite the evidence that the sex of patients and their
in neuronal and glial populations, with astrocytes and positive family history affect the estimated risk of developing
microglia displaying the greatest transcriptomic impacts. sporadic and familial LOAD, no risk loci had been
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Three genes (APP, PRES1, and PRES2) have been found found consistently on the X chromosome until recently.
to account for the autosomal dominant inheritance of an Epigenetic mechanisms offer an explanation of how the
early-onset form of the disease. The pathogenesis of late- X chromosome might be involved in the pathogenesis of
onset AD (LOAD) also has a genetic basis. Prominent AD. A recent publication has identified an X-linked
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among the risk factors for LOAD are having one or more ubiquitin-specific peptidase 11 that increases tauopathy
copies of the e4 allele of the APOE gene and a family vulnerability in women. An additional locus that provides
history for the disease. By comparison, the risk conferred sex-specific resilience to AD is located on chromosome
by more than 40 other genes/loci linked to AD is minor. 10. Differential effects of X chromosome gene expression
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Variants in exon 2 of TREM2, which encodes the triggering on cognition and AD pathology have also been described.
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receptor expressed on myeloid cells 2 protein, are more In particular, “X chromosome gene expression assessed by
frequent in patients with AD than in controls. Of these, the RNA sequencing was associated with cognitive change
most commonly associated variant, rs75932628 (encoding in women but not men in a manner independent of AD
R47H), shows a highly significant association with AD. 5 pathology. In contrast with cognition, X chromosome
A study based on the Utah Population Database gene expression was associated with neuropathologic tau
(UPDB), which contains death certificate data, has burden in men but not women” (p.1250). A second X
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contributed additional information concerning disease chromosome has been shown to confer resilience against
status in second-degree relatives (SDR) and third-degree disease emergence in mouse models of AD, possibly
relatives (TDRs), which is helpful for assessing the relative mediated by the candidate gene Kdm6a located on the X
risk (RR) of AD occurrence in probands, beyond what chromosome. The role of the X chromosome in mediating
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could be determined by considering first-degree relatives the risk of AD remains enigmatic and may be mediated by
(FDRs) alone. The study showed divergent directions for loci on the chromosome itself or other chromosomes, or
the effect of parental lineage on the risk of AD in probands may depend on the degree of gene expression.
when considering the degree of affected relatives. The A new method has been proposed to address the
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estimated RR for an individual with an affected father impact of the X chromosome on developing AD which is
exceeded the 95% confidence interval (CI) for the estimated independent of the precise pathway by which the risk might
RR for individuals with an affected mother. Individuals be conferred. It focused specifically on the sub-population
with an affected maternal SDR (mother’s brother or sister) with LOAD and unilateral parental lineage history for the
had a significantly elevated RR, which was not observed in disease. The novelty of the method is that it uses the sex
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individuals with an affected paternal SDR (father’s brother of the affected proband and the parental lineage of the
or sister). RR for probands with TDRs (first cousins) affected relatives to identify the chromosomes that might
affected was comparably elevated for maternal or paternal be involved in transmitting the risk for developing AD to
family history. the proband, then isolates the risk that may be mediated
When analyzing the RR based on the sex of the by the X chromosome. Specifically, an affected female
probands, given an equivalent family history, men proband can inherit the genetic contribution to her risk of
were at higher risk for AD than women. Some of these developing AD via the 22 autosomal chromosomes and/
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observations appear discordant from other published or the X chromosome, regardless of whether the affected
studies. Maternal inheritance has long been identified in relatives are on the father’s or the mother’s side because she
LOAD, with the risk manifesting not only in symptomatic inherits 22 autosomal chromosomes and an X chromosome
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individuals but also in cognitively normal offspring, who from each parent. In contrast, an affected male proband can
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were evaluated through imaging or screening for AD inherit the genetic contribution to the risk of developing
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biomarkers. In contrast, based on general (mostly sporadic) AD via the 22 autosomal chromosomes and/or the X
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population-based, age-specific data, the observation of chromosome if the risk arises from the mother’s side, but
greater risk for AD in men when there is an affected the genetic contribution to the risk can be transmitted
Volume 3 Issue 2 (2024) 2 doi: 10.36922/an.3122