Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Nov;2(8):673-679. doi: 10.1016/j.bpsc.2017.08.004. Epub 2017 Aug 26.
We explored the cumulative effect of several late-onset Alzheimer's disease (LOAD) risk loci using a polygenic risk profile score (RPS) approach on measures of hippocampal function, cognition, and brain morphometry.
In a sample of 231 healthy control subjects (19-55 years of age), we used an RPS to study the effect of several LOAD risk loci reported in a recent meta-analysis on hippocampal function (determined by its engagement with blood oxygen level-dependent functional magnetic resonance imaging during episodic memory) and several cognitive metrics. We also studied effects on brain morphometry in an overlapping sample of 280 subjects.
There was almost no significant association of LOAD-RPS with cognitive or morphometric measures. However, there was a significant negative relationship between LOAD-RPS and hippocampal function (familywise error [small volume correction-hippocampal region of interest] p < .05). There were also similar associations for risk score based on APOE haplotype, and for a combined LOAD-RPS + APOE haplotype risk profile score (p < .05 familywise error [small volume correction-hippocampal region of interest]). Of the 29 individual single nucleotide polymorphisms used in calculating LOAD-RPS, variants in CLU, PICALM, BCL3, PVRL2, and RELB showed strong effects (p < .05 familywise error [small volume correction-hippocampal region of interest]) on hippocampal function, though none survived further correction for the number of single nucleotide polymorphisms tested.
There is a cumulative deleterious effect of LOAD risk genes on hippocampal function even in healthy volunteers. The effect of LOAD-RPS on hippocampal function in the relative absence of any effect on cognitive and morphometric measures is consistent with the reported temporal characteristics of LOAD biomarkers with the earlier manifestation of synaptic dysfunction before morphometric and cognitive changes.
我们使用多基因风险评分（RPS）方法，研究了几个迟发性阿尔茨海默病（LOAD）风险基因座的累积效应，以评估海马功能、认知和大脑形态计量学。
在 231 名健康对照受试者（年龄 19-55 岁）中，我们使用 RPS 研究了最近荟萃分析中报告的几个 LOAD 风险基因座对海马功能（通过其在情景记忆期间与血氧水平依赖功能磁共振成像的相互作用来确定）和几种认知指标的影响。我们还在重叠的 280 名受试者样本中研究了对大脑形态计量学的影响。
LOAD-RPS 与认知或形态计量学指标几乎没有显著关联。然而，LOAD-RPS 与海马功能呈显著负相关（全基因组错误校正[海马感兴趣区]p<.05）。基于 APOE 单倍型的风险评分和 LOAD-RPS+APOE 单倍型风险评分也存在类似的关联（全基因组错误校正[海马感兴趣区]p<.05）。在计算 LOAD-RPS 时使用的 29 个单核苷酸多态性中，CLU、PICALM、BCL3、PVRL2 和 RELB 中的变体显示出强烈的效应（全基因组错误校正[海马感兴趣区]p<.05）对海马功能的影响，但在进一步校正所测试的单核苷酸多态性数量后，没有一个幸存下来。
即使在健康志愿者中，LOAD 风险基因也会对海马功能产生累积的有害影响。LOAD-RPS 对海马功能的影响而对认知和形态计量学指标没有影响，这与报道的 LOAD 生物标志物的时间特征一致，即突触功能障碍先于形态和认知变化出现。
