METHODS: We selected 88 non-demented Veterans (Age: M = 68.22, SD = 3.75 years) from the Alzheimer\'s Disease Neuroimaging Initiative-Department of Defense (ADNI-DOD) database with available genetic markers and CSF measures for Ab-40 and Ab-38. Genetic propensity for AD was assessed using genome-wide PRS, both with and without the APOE region, employing a p-value threshold < 0.01. CSF Ab concentrations were measured using a 2D-UPLC-tandem mass spectrometry method outlined by ADNI-DOD. Partial spearman\'s correlations related PRS to CSF Ab-38 and Ab-40 levels adjusting for age.
RESULTS: CSF Ab-40 levels were positively associated with PRS for AD (rhopartial = 0.22, p = 0.037). When variants in the APOE region were excluded from the score, the relationship between CSF Ab-40 and PRS remained significant (rhopartial = 0.23, p = 0.035). The relationship between PRS for AD and CSF Ab-38 levels was not significant, regardless of whether APOE regions were included in the score (all p\'s > 0.1).
CONCLUSIONS: Genetic risk for AD may lead to early Ab overproduction, as evidenced by elevated CSF Ab levels, particularly Ab-40. Other genetic variants, in addition to APOE, may play an integral role in disrupting the APP pathway and dysregulating Ab production.
方法:我们从阿尔茨海默病神经影像学计划-国防部(ADNI-DOD)数据库中选择了88名非痴呆退伍军人(年龄:M=68.22,SD=3.75岁),并提供了Ab-40和Ab-38的遗传标记和CSF测量值。使用全基因组PRS评估AD的遗传倾向,有和没有APOE区域,采用P值阈值<0.01。CSFAb浓度使用由ADNI-DOD概述的2D-UPLC串联质谱方法测量。部分Spearman相关性将PRS与CSFAb-38和Ab-40水平相关,以调整年龄。
结果:CSFAb-40水平与AD的PRS呈正相关(r=0.22,p=0.037)。当APOE区域的变体从评分中排除时,CSFAb-40与PRS之间的关系仍然显着(r=0.23,p=0.035)。AD的PRS与CSFAb-38水平之间的关系不显著,无论APOE区域是否包含在评分中(所有p/s>0.1).
结论:AD的遗传风险可能导致早期Ab过量产生,CSFAb水平升高证明了这一点,特别是Ab-40。其他遗传变异,除了APOE,可能在破坏APP途径和调节Ab产生中起着不可或缺的作用。