Pang Ran, Wang Jianli, Kanekar Samika, Karunanayaka Prasanna, Beselia Gela, Kanekar Sangam, Meadowcroft Mark, Connor James R, Yang Qing X
Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Department of Radiology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
J Alzheimers Dis. 2025 Oct;107(3):1114-1128. doi: 10.1177/13872877251363211. Epub 2025 Aug 3.
BackgroundWhile mutation impacts normal myelination through disruptions of iron and lipid homeostasis, the (homeostatic iron regulatory gene) polymorphism directly participates in white matter (WM) myelination and neuroinflammations processes via modulating iron homeostasis.ObjectiveThis study investigated effects of polymorphism in gene carriers in the context of WM degeneration and neuroinflammation in Alzheimer's disease (AD).MethodsWM degeneration in AD subjects of carriers with and without polymorphism was evaluated and compared with age- and sex-matched cognitive normal (CN) groups using diffusion tensor imaging (DTI) data from the Alzheimer's Disease Neuroimaging Initiative database.ResultsDTI radial and mean diffusivity demonstrated an extensive and precipitous age-related WM degeneration in all the AD groups compared to the CN cohorts. This AD-related WM degeneration, however, was significantly attenuated with polymorphism than that of wildtype along with reduced cognitive decline in the AD group. To link the observed protective effect of polymorphism to WM degeneration and cognitive decline in AD, a mediation model was developed and verified using structure equation modeling. This protective effect of polymorphism on WM is also associated with higher cerebrospinal fluid sTREM2 level.ConclusionsThis is the first genetic-to-imaging study linking polymorphism to WM degeneration and consequentially to cognitive declines in AD. Our data provide original information on the role of iron homeostasis specifically in WM degeneration, which suggests that manipulating iron homeostasis could be incorporated into the overall AD prevention and intervention strategies.
背景
虽然突变通过破坏铁和脂质稳态影响正常髓鞘形成，但（稳态铁调节基因）多态性通过调节铁稳态直接参与白质（WM）髓鞘形成和神经炎症过程。
目的
本研究在阿尔茨海默病（AD）的WM变性和神经炎症背景下，研究基因携带者中多态性的影响。
方法
使用来自阿尔茨海默病神经影像倡议数据库的扩散张量成像（DTI）数据，评估并比较有和没有多态性的携带者的AD受试者的WM变性，并与年龄和性别匹配的认知正常（CN）组进行比较。
结果
与CN队列相比，所有AD组的DTI径向扩散率和平均扩散率均显示出广泛且急剧的与年龄相关的WM变性。然而，与野生型相比，多态性使这种与AD相关的WM变性显著减轻，同时AD组的认知下降也有所减少。为了将观察到的多态性的保护作用与AD中的WM变性和认知下降联系起来，使用结构方程模型开发并验证了一个中介模型。多态性对WM的这种保护作用还与脑脊液中更高的sTREM2水平相关。
结论
这是第一项将多态性与WM变性以及AD中的认知下降联系起来的基因到成像的研究。我们的数据提供了关于铁稳态在WM变性中具体作用的原始信息，这表明操纵铁稳态可以纳入整体AD预防和干预策略中。
