Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.

中文翻译：

---

认知健康的中年成年人患痴呆症的遗传风险以及脑小血管疾病和炎症标志物的进展：预防痴呆症研究

脑小血管疾病（SVD）和炎症越来越被认为是阿尔茨海默病（AD）的关键因素，尽管它们在疾病过程早期的时间、轨迹和关系尚不清楚。因此，为了调查非常早期的变化，我们比较了 158 名有或没有遗传性 AD 易感性的健康中年成年人（APOE4 携带（38% 阳性）、父母痴呆家族史 (FH)（54% 阳性））的 SVD 标记。两年来的横断面和纵向数据显示白质高信号 (WMH)、脑微出血）和炎症（C 反应蛋白 (CRP)、纤维蛋白原）。虽然基线时各组之间的 WMH 严重程度相当，但高危组（APOE4+ 和 FH+）的 WMH 纵向进展更大。从拓扑结构上看，调整 FH 后，APOE4 只与深部 WMH 进展相关，但与脑室周围 WMH 进展无关。相反，APOE4 携带者的 CRP 水平低于非携带者，但纤维蛋白原则不然。此外，相互作用分析表明，FH 可以调节 SVD 和炎症对反应时间（SVD 的早期特征）的影响，但不能调节情景记忆或执行功能。研究结果表明，血管和炎症变化可能在痴呆症发病前几十年就发生，并且可能与预测早期临床进展相关。