Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
Alzheimers Dement. 2015 Nov;11(11):1277-85. doi: 10.1016/j.jalz.2014.12.008. Epub 2015 Apr 24.
Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored.
In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia.
In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]).
Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s).
神经退行性疾病是认知障碍的主要原因，并最终导致痴呆。全基因组关联研究发现了许多赋予神经退行性疾病风险的遗传变异，但它们在认知障碍中的作用仍未得到探索。
在前瞻性、基于人群的鹿特丹研究中，对 3605 名年龄≥55 岁的非痴呆个体进行基因分型，在 2002 年至 2005 年期间筛查轻度认知障碍（MCI），并在 2012 年前对痴呆症进行连续随访。构建并研究了阿尔茨海默病（AD）、帕金森病（PD）和额颞叶变性/肌萎缩侧索硬化症谱（FTLD/ALS）遗传变异的多基因风险评分与 MCI 及随后向痴呆症的转化之间的关系。
共有 360 人（10.0%）患有 MCI，其中 147 人（4.1%）为遗忘型，213 人（5.9%）为非遗忘型。AD 风险评分与两种 MCI 亚型均相关（所有 MCI 的比值比为 1.15[95%置信区间，1.03-1.28]），而 PD 和 FTLD/ALS 风险评分仅与非遗忘型 MCI 相关（比值比分别为 1.15[1.00-1.32]和 1.19[1.03-1.37]）。AD 风险评分与痴呆风险增加相关（风险比 1.55[1.37-1.77]），而 PD 和 FTLD/ALS 风险评分则没有。
遗传证据支持这样一种观点，即多种神经退行性途径导致 MCI，而随后向痴呆症的转化，主要是 AD 亚型，主要归因于 AD 途径（多个）。
