The impact of Alzheimers Disease neuropathology on immune cell senescence in older African Americans

摘要 本行政补充提案是为了响应NOSI NOT-AG-20-034而提交的， 老年痴呆症相关研究与PI的父母提案“衰老中免疫细胞衰老的原因” 人类。”父母补助金的目的是测试这一假设，即老化导致各种子集的 人类循环免疫细胞越来越多地经历端粒功能障碍诱导的细胞 随着年龄的增长而衰老，从而导致与年龄相关的免疫细胞调节异常 功能原始提案中的初步数据显示， 随着年龄的增长，衰老的CD 8 + T细胞的百分比，从人的24%左右， 到60多岁的时候，他们的衰老细胞减少到65%左右，但在整个年龄段， 不同的捐赠者主动拨款不包括任何与阿尔茨海默氏症有关的研究问题 疾病（AD）。因此，在不改变家长补助金的目的的情况下，我们寻求补充资金， 其他方法和参与者招募，以解决健康老年人中 在招募的参与者中，有些人可能具有较高的AD遗传风险，并且可能处于早期阶段 临床前AD，尽管没有明显的认知缺陷。这是一个重大 这是因为人们越来越认识到AD涉及免疫系统的破坏。到 为了解决这种可能性，我们已经与两个备受尊敬的团队进行了新的合作， 资金充足的广告研究人员与罗格斯大学纽瓦克分校的Mark Gluck一起，老化与大脑健康 联盟，我们建议招募32名年龄在60岁及以上的非洲裔美国人参与者， 非裔美国人健康老龄化的途径。格鲁克现有的大规模群体 允许我们预先选择具有最高和最低APOE风险的个体;这些参与者中有一半 将预先选择AD的高遗传风险（APOE基因型ε4ε4，ε3ε4），另一半具有 AD遗传风险低（APOE基因型ε2ε2、ε2ε3）。我们还将招募16名非洲人- 20多岁和30多岁的美国人作为年轻的对照。第二组新的合作者，博士。 来自哥德堡大学的Blennow和Zetterberg是血液生物标志物方面的专家， 早期AD;血浆将被送到这些瑞典合作者那里，他们将评估血液AD 生物标志物，包括P-Tau 181。我们将进行外周免疫细胞衰老的测量， 在这些队列中，如父母资助中所述，使用流式细胞术、显微镜和基因组学方法， 分析。我们假设老年参与者（60岁及以上）谁是高载脂蛋白E遗传 AD的风险将显示CD 8 + T细胞的衰老水平提高， 组织化学证据表明，与那些 AD的APOE遗传风险较低，P-Tau 181水平较高。

Abstract This administrative supplement proposal is submitted in response to NOSI NOT-AG-20-034 to add Alzheimer’s-relevant studies to the PIs’ parent proposal “Causes of Immune Cell Senescence in Aging Humans.” The parent grant was designed to test the hypothesis that aging causes various subsets of human circulating immune cells to increasingly undergo telomere dysfunction-induced cellular senescence with advancing age, thereby resulting in an age-associated dysregulation of immune cell function. Preliminary data included in the original proposal revealed a dramatic and significant increase in the percentages of senescent CD8+ T cells with advanced age, ranging from about 24% in people’s 20s to levels of about 65% by the time they reach their 60s, but with a range of senescent cells across different donors. The active grant does not include any research questions relating to Alzheimer’s Disease (AD). As such, without changing the aims of the parent grant, we seek supplemental funding for additional methods and participant recruitment to address the possibility that, among the healthy older participants recruited, some may have higher genetic risk for AD, and possibly be in the earliest stages of preclinical AD, despite presenting with no readily-apparent cognitive deficits. This is a significant concern because there is a growing appreciation that AD involves disruption to the immune system. To address this possibility, we have entered into new collaborations with two teams of well-respected and well-funded AD-researchers. With Mark Gluck at Rutgers University-Newark’s Aging & Brain Health Alliance, we propose to recruit 32 additional African-American participants, ages 60 and above, from their Pathways to Health Aging in African Americans cohort. The large size of Gluck’s existing cohort allows us to pre-select those individuals with the highest and lowest APOE risk; half of these participants will be pre-selected for high genetic risk for AD (APOE genotypes ε4ε4, ε3ε4), with the other half having low genetic risk for AD (APOE genotypes ε2ε2, ε2ε3). We will also recruit an additional 16 African- American individuals in their 20’s and 30’s as younger controls. A second new set of collaborators, Drs. Blennow and Zetterberg, from the University of Gothenburg, are experts in blood-based biomarkers for early AD; plasma will be sent to these Swedish collaborators where they will assess blood-based AD biomarkers, including P-Tau181. We will carry out measurements of peripheral immune cell senescence in these cohorts as described in the parent grant using flow cytometric, microscopic and genomic analyses. We hypothesize that older participants (ages 60 and above) who are at high APOE-genetic risk for AD will show enhanced levels of senescence in CD8+ T cells and will have enhanced histochemical evidence of telomere dysfunction in their CD8+ T cells as compared to participants who have low APOE-genetic risk for AD, and will have higher levels of P-Tau181.