Mezlini Aziz M, Magdamo Colin, Merrill Emily, Chibnik Lori B, Blacker Deborah L, Hyman Bradley T, Das Sudeshna
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
Department of Neurology, Harvard Medical School, Boston, MA, USA.
J Alzheimers Dis. 2020;78(1):467-477. doi: 10.3233/JAD-200228.
The APOEɛ4 allele is the largest genetic risk factor for late-onset Alzheimer's disease (AD). Recent literature suggested that the contribution of APOEɛ4 to AD risk could be population-specific, with ɛ4 conferring a lower risk to Blacks or African Americans.
To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA).
We selected data from 1) the National Alzheimer's Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer's Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU.
In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOEɛ4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification.
Our study finds similar effects of the ɛ4-linked haplotypes defined by rs769449 on AD as compared to ɛ3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations.
APOEɛ4等位基因是晚发型阿尔茨海默病（AD）最大的遗传风险因素。近期文献表明，APOEɛ4对AD风险的影响可能因人群而异，ɛ4对黑人或非裔美国人的风险较低。
研究APOE单倍型对欧洲血统个体（EU）以及黑人或非裔美国人（AA）患AD风险的影响。
我们选取了以下数据：1）国家阿尔茨海默病协调中心：共有3486例AD病例和4511例对照（N = 7997，60%为女性），其基因型来自阿尔茨海默病遗传学联盟（ADGC）；2）拉什大学宗教团体研究与记忆与衰老项目（ROSMAP）队列，有578例AD患者和670例对照（N = 1248，60%为女性）。以ɛ3纯合子为参照，我们比较了AA和EU中各种APOE单倍型与痴呆临床及神经病理学相关因素的关联。
在两个队列中，我们发现AA或EU中由rs769449定义的与ɛ4相关的单倍型在AD的发病几率或发病年龄上均无差异。此外，虽然APOEɛ4与更快的衰退速度相关，但在与ɛ4相关的单倍型之间，衰退速度、临床或神经病理学特征并无差异。对APOE基因座附近其他变异的进一步分析未能发现任何效应修饰。
我们的研究发现，在AA和EU中，由rs769449定义的与ɛ4相关的单倍型对AD的影响与ɛ3相似。未来需要开展研究以了解APOE在不同基因型和人群中赋予AD风险的异质性。
