X chromosome-wide association study of quantitative biomarkers from the Alzheimer’s Disease Neuroimaging Initiative study

Wang, Kai-Wen; Yuan, Yu-Xin; Zhu, Bin; Zhang, Yi; Wei, Yi-Fang; Meng, Fan-Shuo; Zhang, Shun; Wang, Jing-Xuan; Zhou, Ji-Yuan; ,

doi:10.3389/fnagi.2023.1277731

Cited by 5 publications

(2 citation statements)

References 130 publications

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“…Some patients suffering from this disease can exhibit cognitive impairment, and a shift towards amyloidogenesis in memory-specific brain regions was found in mice mutated in the DMD gene (mdx mouse) compared to wild-type mice 34 . Additionally, the DMD rs5927116 variant was reportedly associated with the volume of entorhinal cortex in a small sample (N = 792); however, this signal is 1.4 Mb away from our AD signal and the variants are independent (LD measured by r 2 < 0.2) 35 .…”

Section: Discussioncontrasting

confidence: 67%

X-Chromosome-wide association study for Alzheimer’s disease

Le Borgne,

Gomez,

Heikkinen

et al. 2024

Preprint

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Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To finally address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified four X-chromosome-wide significant loci (P ≤ 1.7 × 10−6). Two signals locate in theFRMPD4andDMDgenes, while the two others are more than 300 kb away from the closest protein coding genesNLGN4XandGRIA3. Overall, this XWAS found no common genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

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Section: Discussioncontrasting

confidence: 67%

X-Chromosome-wide association study for Alzheimer’s disease

Le Borgne,

Gomez,

Heikkinen

et al. 2024

Preprint

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“…Historically understudied, sex chromosomes are becoming a new focus for the investigation of sex-specific differences in AD. X chromosome instability has been associated with AD, and X chromosome-related studies have identified loci that are associated with AD risk . X-linked risk could be associated with epigenetic changes (ie, genomic imprinting) such that parent-specific epigenetic modifications are passed to offspring .…”

Section: Discussionmentioning

confidence: 99%

Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

Seto,

Hohman,

Mormino

et al. 2024

JAMA Neurol

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ImportanceStudies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes.ObjectiveTo characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults.Design, Setting, and ParticipantsThis cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded.Main Outcomes and MeasuresDemographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite.ResultsOf 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10−5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10−5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10−5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10−5). Paternal history of early-onset memory impairment (age &lt;65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10−6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition.Conclusions and RelevanceIn this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

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β-Amyloid in Cognitively Unimpaired Individuals—Blame Mom?

Dubal,

Elser

2024

JAMA Neurol

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Family history is one of the biggest risk factors-behind advanced age-for developing late-onset Alzheimer disease (AD). This is especially true if the family history involves a firstdegree relative, such as a parent, increasing AD risk by at least 2-to 4-fold. 1 Several questions arise. Do parents transmit AD risk? If so, who is to blame? Why does it matter?A history of parents with AD increases risk in offspring for reasons that may be biological, sociocultural, or both. In late-onset AD, mounting studies support a preferential risk of developing AD with a maternal, but not paternal, history of the disease. Maternal transmission of AD may be rooted in biological origins (Figure) related to passing on the maternal X chromosome, mitochondria, and specific genomic imprinting (or silencing of genes) to offspring. More maternal history of AD in a family could also result from gender disparities and secular trends. For example, in studies to date, the generations of women with AD had less access to and systematically experienced less formal education compared with men, potentially decreasing brain reserve. Thus, it may seem justified, although not fair, to blame your mom for part of your AD risk.In this issue of JAMA Neurology, Seto et al 2 investigated whether history of a mother or father with memory impairment was associated with the brain β-amyloid burden in cognitively unimpaired individuals. In this well-powered study, the authors analyzed cross-sectional data from more than 4400 participants screened with positron emission tomography (PET) to assess their cortical β-amyloid (Aβ) burden as part of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study. Patients were aged 65 to 85 years and cognitively unimpaired. Adjusting for participant age, sex, and apolipoprotein E genotype, they found that early-onset of either maternal or paternal memory impairment was associated with increased burden of Aβ, measured by PET, in offspring. This suggests a strong genetic predisposition in those with earlyonset impairments. Importantly, a maternal history of memory impairment-either early or late onset-preferentially associated with increased Aβ in offspring. The maternally based risk in offspring persisted in late-onset AD, regardless of offspring sex or maternal age.These new data build on previous reports demonstrating an increased risk of AD-typical biomarker changes associated with a maternal family history of dementia, [3][4][5][6] with several strengths that bolster the current findings. Because of their much larger sample size of more than 4400 individuals (prior studies range from N = 42 to N = 403), Seto et al 2 provide sub-

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X chromosome-wide association study of quantitative biomarkers from the Alzheimer’s Disease Neuroimaging Initiative study

Cited by 5 publications

References 130 publications

X-Chromosome-wide association study for Alzheimer’s disease

X-Chromosome-wide association study for Alzheimer’s disease

Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

β-Amyloid in Cognitively Unimpaired Individuals—Blame Mom?

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