Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Section Genomics of Neurdegenerative Diseases and Aging, Department of Human Genetics Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
J Alzheimers Dis. 2021;83(1):269-279. doi: 10.3233/JAD-210365.
Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.
We tested if genetic variants in part explain the heterogeneity in DLB.
We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.
We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.
These finding increase our understanding of the pathological and clinical heterogeneity in DLB.
路易体痴呆（DLB）是一种复杂的、进行性的神经退行性疾病，具有相当大的表型、病理和遗传异质性。
我们测试遗传变异是否部分解释了 DLB 的异质性。
我们测试了先前与 DLB 相关的变异（APOE 附近、GBA 和 SNCA）以及阿尔茨海默病（AD-PRS）和帕金森病（PD-PRS）多基因风险评分的影响。我们研究了来自阿尔茨海默病痴呆队列的 190 名可能的 DLB 患者，并将其与 2552 名对照进行比较。脑脊液中的 tau/Aβ1-42 比值被用作分离 DLB 病例为伴有 AD 病理的 DLB（DLB-AD）或无 AD 的 DLB（DLB-纯）的体内替代物。我们研究了临床指标年龄、简易精神状态检查（MMSE）以及诊断时和疾病持续时间的核心症状的存在。
我们发现所有研究的遗传因素都与 DLB 风险显著相关（所有-DLB）。其次，我们根据 AD 病理的存在对 DLB 患者进行分层，发现 APOE ɛ4 和 AD-PRS 与 DLB-AD 特异性相关，但与 DLB-纯的相关性较小。此外，GBA p.E365K 变体与 DLB-纯相关，与 DLB-AD 相关较少。最后，我们研究了临床指标，发现 APOE ɛ4 与 MMSE 降低、波动的可能性更高和疾病持续时间更短相关。此外，GBA p.E365K 变体使发病年龄降低了 5.7 岁，但其他变体和 PRS 与临床特征无关。
这些发现增加了我们对 DLB 中病理和临床异质性的理解。
