载脂蛋白E（APOE）和CD33对认知衰退的影响。
Effect of APOE and CD33 on Cognitive Decline.
作者信息
Hayden Kathleen M, Lutz Michael W, Kuchibhatla Maragatha, Germain Cassandra, Plassman Brenda L
机构信息
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America; Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina, United States of America.
Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Neurology, Duke University Medical Center, Durham, North Carolina, United States of America.
出版信息
PLoS One. 2015 Jun 23;10(6):e0130419. doi: 10.1371/journal.pone.0130419. eCollection 2015.
OBJECTIVE
An Alzheimer's disease (AD) diagnosis is preceded by a long period of cognitive decline. We previously demonstrated increased risk of decline among individuals possessing one or more APOE ε4 alleles together with a family history of AD. The objective of this study is to investigate the possibility that such an increased risk might be due to AD risk genes with small effects in combination with APOE.
METHODS
Participants in the Health and Retirement Study (HRS) over the age of 65, who contributed DNA, and had two or more evaluations with an abbreviated version of the modified Telephone Interview for Cognitive Status (TICS-m) were eligible for the study (n = 7451). A genetic risk score (g-score) was derived using AD risk genes' meta-analyses data, assigning risk according to the number of risk alleles and summed over all the risk genes. Trajectories of cognitive function were modeled in four groups of Caucasian participants with and without one or more APOE ε4 alleles and either a high or low g-score: APOE ε4-/low g-score; APOE ε4-/high g-score; APOE ε4+/low g-score; and APOE ε4+/high g-score. Post hoc analyses evaluated interactions between individual genes and APOE.
RESULTS
Individuals in the APOE ε4+/high g-score group exhibited the greatest cognitive decline over time (p<.0001). This risk appeared to be greater than the sum of the effects of either high g-score or APOE ε4 alone. When gene interactions were individually tested with APOE, a statistically significant interaction with CD33 was discovered (p = 0.04) although the interaction was no longer significant when adjusted for multiple comparisons.
CONCLUSIONS
Individuals with multiple AD risk genes in addition to having one or more APOE ε4 alleles are at greater risk of cognitive decline than individuals with either APOE ε4 or a high genetic risk score. Among those with one or more APOE ε4 alleles, having one or more copies of the CD33 C (risk) allele may further increase the risk of cognitive decline.
目的
阿尔茨海默病（AD）的诊断之前有一段很长的认知衰退期。我们之前证明，携带一个或多个APOEε4等位基因且有AD家族史的个体，其认知衰退风险增加。本研究的目的是调查这种风险增加是否可能是由于与APOE共同作用的小效应AD风险基因所致。
方法
年龄在65岁以上、提供了DNA且接受过两次或更多次使用简易版改良认知状态电话访谈（TICS-m）评估的健康与退休研究（HRS）参与者符合本研究条件（n = 7451）。利用AD风险基因的荟萃分析数据得出遗传风险评分（g评分），根据风险等位基因的数量分配风险，并对所有风险基因进行求和。在四组有或没有一个或多个APOEε4等位基因且g评分高或低的白种人参与者中对认知功能轨迹进行建模：APOEε4−/低g评分；APOEε4−/高g评分；APOEε4+/低g评分；以及APOEε4+/高g评分。事后分析评估了单个基因与APOE之间的相互作用。
结果
APOEε4+/高g评分组的个体随时间推移表现出最大程度的认知衰退（p<0.0001）。这种风险似乎大于单独的高g评分或APOEε4效应之和。当单独测试基因与APOE的相互作用时，发现与CD33存在统计学显著的相互作用（p = 0.04），尽管在进行多重比较校正后该相互作用不再显著。
结论
除了有一个或多个APOEε4等位基因外，还携带多个AD风险基因的个体比仅有APOEε4或高遗传风险评分的个体有更高的认知衰退风险。在有一个或多个APOEε4等位基因的个体中，拥有一个或多个拷贝的CD33 C（风险）等位基因可能会进一步增加认知衰退风险。
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