From the Department of Neuroscience (D.W.D., M.E.M., A.I.S., R.W., N.E.-T., G.B., O.A.R.), Division of Biomedical Statistics and Informatics (M.G.H., N.N.D.), and Departments of Neurology (J.A.v.G., R.J.U., Z.K.W., N.E.-T., N.R.G.-R.) and Psychiatry and Psychology (T.J.F.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (D.S.K., R.C.P., B.F.B.), Mayo Clinic, Rochester, MN.
Neurology. 2018 Sep 18;91(12):e1182-e1195. doi: 10.1212/WNL.0000000000006212. Epub 2018 Aug 24.
To evaluate whether ε4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology.
Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for . In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between ε4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with ε4 according to severity of AD pathology.
As expected, ε4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all ≤ 0.004). Of note, ε4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, = 0.001). In the low AD pathology LBD subgroup, ε4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all ≤ 0.002).
Our results indicate that ε4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of ε4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that ε4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.
评估 ε4 是否与路易体（LB）病理学的严重程度相关，而与阿尔茨海默病（AD）病理学无关。
对 652 例尸检证实的 LB 疾病（LBD）病例和 660 例临床对照进行了 ε4 基因分型。在病例对照分析中，根据 LB 病理学（脑干、过渡、弥漫）和 AD 病理学（低、中、高）的严重程度，将 LBD 病例分为 9 个不同组，以评估 ε4 与不同神经病理学定义的 LBD 亚组的风险之间的关联与对照组相比。仅在 LBD 病例中，我们还测量了 5 个皮质区域的 LB 计数，并根据 AD 病理学的严重程度评估了与 ε4 的关联。
正如预期的那样，ε4 与 AD 病理学中度或高度的过渡性和弥漫性 LBD 风险增加相关（所有比值比≥3.42，所有 P≤0.004）。值得注意的是，ε4 还与 AD 病理学低的弥漫性 LBD 风险增加相关（比值比=3.46， P=0.001）。在 AD 病理学低的 LBD 亚组中，ε4 与 5 个皮质区域的 LB 计数显著增加相关，与 Braak 分期和 Thal 期无关（所有 P≤0.002）。
我们的结果表明，ε4 与 LB 病理学的严重程度独立相关。这些发现增加了我们对报道的 ε4 与路易体痴呆和帕金森病伴痴呆风险之间关联背后机制的理解，并表明 ε4 可能作为促进 LB 传播的过程的修饰因子，而不是直接作用于 LB 病理学的起始。
