Xicota Laura, Dang Lam-Ha T, Lee Alice, Krinsky-McHale Sharon, Pang Deborah, Melilli Lisa, O'Bryant Sid, Henson Rachel L, Laymon Charles, Lai Florence, Rosas H Diana, Ances Beau, Lott Ira, Hom Christy, Christian Bradley, Hartley Sigan, Zaman Shahid, Head Elizabeth, Mapstone Mark, Jin Zhezhen, Silverman Wayne, Schupf Nicole, Handen Benjamin, Lee Joseph H
Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
EBioMedicine. 2024 Dec;110:105433. doi: 10.1016/j.ebiom.2024.105433. Epub 2024 Nov 4.
Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.
We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ, Aβ, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ, Aβ, tau, ptau181, and NfL) and amyloid and tau PET data.
For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ and Aβ concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia.
Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted.
National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).
唐氏综合征（DS）患者患早发性阿尔茨海默病（AD）的风险很高；然而，约20%的患者直到65岁以后或一生中都没有出现任何痴呆症状。嵌合体可能导致这种表型变异，其中一些二体细胞可能导致21号染色体基因产物水平降低。
我们检查了两项关于DS的大型研究的纵向神经心理学和生物标志物数据：阿尔茨海默病生物标志物联盟唐氏综合征研究（ABC-DS）（n = 357）；以及一项遗留研究（n = 468）。我们使用核型分析或全基因组关联研究（GWAS）数据评估嵌合体。参与者有血浆AD生物标志物（Aβ、Aβ、tau和NfL）数据以及纵向认知测量数据。一部分人有脑脊液生物标志物（Aβ、Aβ、tau、ptau181和NfL）以及淀粉样蛋白和tau正电子发射断层扫描（PET）数据。
对于两个队列，嵌合体的患病率均<10%（ABC-DS：7.3%；遗留研究：9.6%），且嵌合体患者的血浆Aβ和Aβ浓度较低。对于年龄较大的遗留队列，与完全三体患者相比，嵌合体患者的总神经认知得分和年化神经认知得分下降明显更小，痴呆的发病率和患病率更低。
DS中的嵌合体与血浆Aβ肽浓度较低有关，这可能导致AD风险降低。然而，在较年轻的ABC-DC队列中，其临床影响尚不清楚，有必要进行后续研究。
美国国立卫生研究院（R01AG014673、P01HD035897、R56AG061837）、美国国立衰老研究所（U01AG051412、U19AG068054）、美国国立儿童健康与人类发展研究所、ADRC项目、尤尼斯·肯尼迪·施莱佛智力和发育障碍研究中心项目以及美国国立转化医学推进中心（UL1TR001873）。
