Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, Cambridge, UK.
John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
J Alzheimers Dis. 2019;69(1):91-109. doi: 10.3233/JAD-181179.
Genetic factors that influence Alzheimer's disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E, influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology.
To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS.
To assess allele frequency and haplotype associations ApoE, Tau, TREM2, and HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry.
Haplotype analysis showed that individuals with Tau H1/H1 and ApoEɛ4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus.
Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoEɛ4, Tau/H1, and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia.
影响阿尔茨海默病（AD）风险的遗传因素包括 TREM2 突变和载脂蛋白 E 的等位基因变体，影响一般人群和唐氏综合征（DS）中的 AD 病理学。有证据表明，脉络丛功能障碍可能会损害血脑屏障，改变分泌、转运和免疫功能，从而影响 AD 病理学。
研究与脉络丛损伤和血脑屏障渗漏相关的 DS 个体的基因型和表型，以确定有助于早期诊断 DS 中 AD 的标志物。
通过 SNP 分析评估 DS 参与者（n=47）和对照组（n=50）中 ApoE、Tau、TREM2 和 HLA-DR 的等位基因频率和单倍型关联。通过 ELISA 测量相应的血浆蛋白水平。通过免疫组织化学分析 DS、AD 和年龄匹配对照的死后大脑。
单倍型分析显示，与 H1/H2 单倍型（6%）相比，具有 Tau H1/H1 和 ApoEɛ4 基因型的个体在具有早期痴呆诊断的 DS 参与者中更为常见（17%）。DS 中 TREM2 水平随年龄降低，磷酸化 tau 水平升高。在 AD 和 DS 大脑中，发现不溶性 tau 和 ApoE 在脉络丛中积累。
tau 和 ApoE 在脉络丛中的积累可能会增加 Aβ42 的寡聚化速度并损害 tau 转运，从而导致 AD 病理学。我们已经确定了一种高风险单倍型：ApoEɛ4、Tau/H1 和 TREM2/T，其表现出与年龄相关的变化，可能在 AD 痴呆症表现之前多年就为治疗开辟了一个窗口。
