基督城杂合性与常染色体显性阿尔茨海默病。

Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

机构信息

From Massachusetts General Hospital (Y.T.Q., J.S.S., S.L., C.V.-C., L.R.G., E.K., K.J., R.A.S.), the Departments of Neurology (Y.T.Q., J.S.S., L.R.G., K.J., R.A.S.), Psychiatry (Y.T.Q., S.L., C.V.-C., E.K.), and Ophthalmology (P.P.-C., J.F.A.-V.), Harvard Medical School, Brigham and Women's Hospital (K.J., R.A.S.), and Schepens Eye Research Institute, Mass Eye and Ear (P.P.-C., J.F.A.-V.) - all in Boston; Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia (Y.T.Q., D.A., D.C.A-A., D.V., Y.Z., A.Y.B., L.M., L.H., R.P.-D., G.G., S.R.V., J.A.O., P.V.-C., F.L.); the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.L.L., N.D.V.-M., S.K., M.G., D.S-F.); the Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, Santa Barbara (K.S.K.); and the Banner Alzheimer's Institute, Phoenix, the University of Arizona, Tucson, and Arizona State University, Tempe - all in Arizona (E.M.R.).

出版信息

N Engl J Med. 2024 Jun 20;390(23):2156-2164. doi: 10.1056/NEJMoa2308583.

DOI:10.1056/NEJMoa2308583

PMID:38899694

Abstract

BACKGROUND

Variants in and (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the variant who also had two copies of the apolipoprotein E3 Christchurch variant ( ). Heterozygosity for the variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the variant is prevalent.

METHODS

We analyzed data from 27 participants with one copy of the variant among 1077 carriers of the variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the variant. Two participants underwent brain imaging, and autopsy was performed in four participants.

RESULTS

Among carriers of who were heterozygous for the variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of carriers without the variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the and variants who underwent brain imaging, F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent F-flortaucipir PET imaging, tau findings were limited as compared with persons with in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the and variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the variant but not the variant.

CONCLUSIONS

Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

摘要

背景

和（分别编码载脂蛋白 E 和早老素 1）的变异会改变阿尔茨海默病的风险。我们之前报道过，一名常染色体显性遗传阿尔茨海默病患者因携带而延迟了认知障碍的发生，该患者还携带了两份载脂蛋白 E3 基督城变异体（）。变异体的杂合性可能会影响认知障碍发生的年龄。我们在一个变异体流行的人群中评估了这一假说。

方法

我们分析了来自哥伦比亚安蒂奥基亚一个家族的 1077 名变异体携带者中的 27 名携带一个变异体的参与者的数据，以估计该组中认知障碍和痴呆的发病年龄与无变异体的个体相比。两名参与者接受了脑部成像，四名参与者接受了尸检。

结果

在携带变异体的杂合子中，认知障碍发病的中位年龄为 52 岁（95%置信区间 [CI]，51 至 58），而在无变异体的匹配组中，发病中位年龄为 47 岁（95%CI，47 至 49）。在两名携带和变异体并接受脑部成像的参与者中，F-氟脱氧葡萄糖正电子发射断层扫描（PET）成像显示，在通常涉及阿尔茨海默病的区域中，代谢活性相对保留。在其中一名参与者中，与在该家族中典型年龄发生认知障碍的个体相比，tau 发现受到限制。对来自携带和变异体的个体的尸检材料进行的四项研究显示，与携带但不携带变异体的个体相比，血管淀粉样病理特征较少。