杂合性可减轻临床前 AD 中与淀粉样蛋白相关的负担。
heterozygosity attenuates -related amyloid burden in preclinical AD.
机构信息
From the Geriatric Research Education and Clinical Center (C.L.G., C.M.C., S.A., S.C.J., O.C.O.), William S. Middleton Memorial VA Hospital; Wisconsin Alzheimer's Disease Research Center (C.M.E., J.M.O., Y.M., C.M.C., B.B.B., S.A., B.P.H., M.A.S., C.D.E., B.T.C., S.C.J., O.C.O.); Departments of Population Health Sciences (B.F.D., C.D.E.), Neurology (C.L.G., B.P.H.), Radiology (M.A.S.), Medical Physics (T.B., B.T.C.), and Biostatistics & Medical Informatics (D.N.), University of Wisconsin School of Medicine and Public Health, Madison; Division of Biology and Biomedical Sciences (S.A.S.), Washington University in St. Louis, MO; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institute of Neurology (C.L.G., H.Z.), University College London, Queen Square; UK Dementia Research Institute (H.Z.), London; Wisconsin Alzheimer's Institute (C.M.C., B.B.B., S.A., B.P.H., M.A.S., C.D.E., S.C.J., O.C.O.), Madison; and Department of Neurology and Weill Institute for Neurosciences (D.B.D.), University of California, San Francisco.
出版信息
Neurology. 2019 Apr 16;92(16):e1878-e1889. doi: 10.1212/WNL.0000000000007323. Epub 2019 Mar 13.
OBJECTIVE
To examine whether the gene variant KL-VS attenuates associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors.
METHODS
Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and status and underwent CSF sampling (n = 238) and/or C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of on Aβ was different among KL-VS heterozygotes compared to noncarriers.
RESULTS
carriers exhibited greater Aβ burden than -negative participants. This effect was stronger in CSF ( = -5.12, < 0.001) compared with PiB-PET ( = 3.93, < 0.001). In the stratified analyses, this effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: = -5.09, < 0.001; PiB-PET: = 3.77, < 0 .001). In contrast, among KL-VS heterozygotes, -positive individuals did not exhibit higher Aβ burden than -negative individuals (CSF: = -1.03, = 0.308; PiB-PET: t = 0.92, = 0.363). These differential effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex.
CONCLUSION
In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against linked pathways to disease onset in AD.
目的
研究基因变异 KL-VS 是否能减轻富含阿尔茨海默病（AD）风险因素的中老年队列中β-淀粉样蛋白（Aβ）的积累。
方法
威斯康星州阿尔茨海默病预防注册中心和威斯康星州阿尔茨海默病研究中心的 309 名中老年成年人接受基因分型以确定 KL-VS 和 状态，并进行 CSF 采样（n=238）和/或 C-Pittsburgh 化合物 B（PiB）-PET 成像（n=183）。采用协变量调整回归分析来研究 KL-VS 基因型（非携带者与杂合子；无纯合子）是否对 Aβ负担产生预期的影响。根据 KL-VS 基因型进行的随访回归分析（即非携带者与杂合子；无纯合子），评估 KL-VS 杂合子与非携带者之间 KL-VS 对 Aβ 的影响是否不同。
结果
与 阴性参与者相比，携带者表现出更大的 Aβ 负担。这种影响在 CSF 中更强（ = -5.12， < 0.001），而在 PiB-PET 中较弱（ = 3.93， < 0.001）。在分层分析中，KL-VS 非携带者中重现了这种 KL-VS 对 Aβ 负荷的影响（CSF： = -5.09， < 0.001；PiB-PET： = 3.77， < 0.001）。相比之下，在 KL-VS 杂合子中， 阳性个体的 Aβ 负担并未高于 阴性个体（CSF： = -1.03， = 0.308；PiB-PET：t = 0.92， = 0.363）。在 KL-VS 杂合子和非携带者按年龄和性别匹配后，这些差异仍存在。
结论
在具有风险的中老年人群中，KL-VS 杂合性与相关 Aβ 聚集的减弱有关，表明 KL-VS 杂合性赋予了对 AD 发病相关途径的保护作用。
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