Porter Tenielle, Burnham Samantha C, Savage Greg, Lim Yen Ying, Maruff Paul, Milicic Lidija, Peretti Madeline, Ames David, Masters Colin L, Martins Ralph N, Rainey-Smith Stephanie, Rowe Christopher C, Salvado Olivier, Taddei Kevin, Groth David, Verdile Giuseppe, Villemagne Victor L, Laws Simon M
Collaborative Genomics Group, Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
Cooperative Research Centre (CRC) for Mental Health, Carlton, VIC, Australia.
Front Aging Neurosci. 2018 Dec 19;10:423. doi: 10.3389/fnagi.2018.00423. eCollection 2018.
Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (PRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample ( = 151). These were then summed to generate a PRS either including (PRS) or excluding (PRS ). Resultant PRS were then evaluated, in a test sample ( = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of PRSs were observed with baseline cognition, the PRS was associated with longitudinal global cognition (-0.237, = 0.0002), verbal episodic memory (-0.259, = 0.00003) and the AIBL-PACC (-0.381, = 0.02). The PRS was also associated with global cognition (-0.169, = 0.021) and verbal episodic memory (-0.208, = 0.004). Stratification by ε4 revealed that the association between the PRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The PRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel PRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.
关于阿尔茨海默病风险加权多基因风险评分（PRSs）与认知表现的研究报告了不一致的关联。当独立于基因型评估PRSs时，这种不一致尤为明显。因此，有必要开发和评估针对临床前阿尔茨海默病认知衰退的特定表型权重，以得出PRSs。为此，我们推导了一个情景记忆加权的PRS，并在来自澳大利亚成像、生物标志物和生活方式（AIBL）研究的226名脑Aβ-淀粉样蛋白负担高的健康认知正常老年人中，根据认知表现的下降情况对其进行评估。在一个参考样本（n = 151）中，分别确定了27个基因变异对言语情景记忆下降的效应大小。然后将这些效应大小相加，生成一个包含（PRS+）或不包含（PRS-）ε4的PRS。然后在一个测试样本（n = 75）中，评估所得的PRS在7.5年期间与整体认知、言语情景记忆和阿尔茨海默病前认知综合指标（AIBL-PACC）下降的相关性。226名参与者的平均（标准差）年龄为72.2（6.6）岁，116名（51.3%）为女性。参考样本和测试样本在人口统计学上没有显著差异。虽然未观察到PRSs与基线认知之间的关联，但PRS+与纵向整体认知（-0.237，p = 0.0002）、言语情景记忆（-0.259，p = 0.00003）和AIBL-PACC（-0.381，p = 0.02）相关。PRS-也与整体认知（-0.169，p = 0.021）和言语情景记忆（-0.208，p = 0.004）相关。按ε4分层显示，PRS+与言语情景记忆之间的关联仅限于不携带ε4或携带一个ε4等位基因的情况。整体认知也观察到了这种情况。在携带一个ε4等位基因的人群中，PRS+与AIBL-PACC的下降率相关。总体而言，所描述的新型PRS可用于预测临床前阿尔茨海默病的认知衰退。本研究为支持在PRS开发中进一步使用和评估表型权重提供了证据。
