Abstract：
BACKGROUND: Alzheimer\'s disease (AD) is associated with the accumulation of neuropathological beta-amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab-40 and Ab-38 due to their high solubility, may be indicative of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. The apolipoprotein E (APOE) e4 allele, which is the strongest genetic risk factor for AD, has been linked to impaired Ab clearance and disruption of the amyloid precursor protein (APP) pathway that is responsible for Ab production. However, the association between early Ab dysregulation and other genetic risk variants remains understudied. Thus, we aimed to explore whether genetic risk for AD is related to early markers of Ab overproduction by examining associations between polygenic risk scores (PRS) and CSF Ab-40 and Ab-38 in an AD-vulnerable population.
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.
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.
摘要：
背景：阿尔茨海默病（AD）与神经病理性β-淀粉样蛋白（Ab）斑块的积累有关，这被认为是由Ab过度产生和功能失调的Ab清除之间的不平衡引起的。动物和人体研究都表明，脑脊液（CSF）中Ab肽的水平增加，特别是Ab-40和Ab-38，由于它们的高溶解度，可能表明临床前AD的总体Ab失调，在病理性Ab斑块开始聚集之前几年。载脂蛋白E(APOE)e4等位基因，是AD最强的遗传风险因素，已与Ab清除受损和负责Ab产生的淀粉样蛋白前体蛋白（APP）途径的破坏有关。然而,早期Ab失调与其他遗传风险变异之间的关联仍未得到充分研究.因此，我们旨在通过在AD易感人群中检测多基因风险评分(PRS)与CSFAb-40和Ab-38之间的关联,探讨AD的遗传风险是否与Ab过量产生的早期标志物相关.
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。
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。
