From the Seattle University (M.-K.S.), Washington; George Washington University (Y.C., A.A., N.M.D., E.Z.), Washington, DC; DC VA Medical Center (A.A.), Washington, DC; University of Alabama at Birmingham (J.M.R.); Irvine Clinical Research (E.Z.), California.
Neurology. 2024 Nov 26;103(10):e210009. doi: 10.1212/WNL.0000000000210009. Epub 2024 Oct 31.
Cerebral amyloid angiopathy (CAA) is common in older adults and is associated with dementia. Less is known whether this association is mediated by Alzheimer disease (AD) neuropathologic changes, the examination of which was the objective of this study.
This was a retrospective cross-sectional examination of the Kaiser Permanente Washington database of the Adult Changes in Thought (ACT) autopsy cohort with information on CAA, dementia, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (amyloid neuritic plaques), and Braak (tau neurofibrillary tangles). CAA was diagnosed by immunohistochemistry and dementia by ACT Consensus Diagnostic Conference. AD neuropathology was categorized by CERAD scores and Braak stages. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CIs of the associations of CAA with dementia, adjusting for age at death and sex, and with additional adjustments separately for CERAD scores (moderate-severe vs mild-absent), Braak stages (V-VI vs 0-IV), ε4, and stroke. Formal mediation analyses were conducted to estimate age-sex-adjusted OR (95% CI) for natural indirect effects (NIEs) of CERAD scores and Braak stages.
The 848 participants had a mean age of 86.7 ± 4.6 years at death, and 57.6% were female. CAA was present in 322 participants (38.0%), of whom 152, 145, and 25 had mild, moderate, and severe CAA, respectively. Dementia was present in 384 participants (45.3%), of whom 317 had AD. Dementia was more common in those with CAA than without (53.7% vs 40.1%; age-sex-adjusted OR 1.57, 95% CI 1.18-2.10). This association remained significant after separate adjustment for other covariates but lost significance when adjusted for CERAD scores (OR 1.27, 95% CI 0.93-1.71) and Braak stages (OR 0.96, 95% CI 0.69-1.33). Findings from our formal mediation analyses show that ORs (95% CIs) for NIE of CERAD scores and Braak stages were 1.25 (1.13-1.37) and 1.63 (1.38-1.88), respectively, and CERAD scores and Braak stages mediated 53% and 111% of the total association, respectively.
We observed a significant association between CAA and dementia that disappeared when adjusted for CERAD or Braak stages. Findings from our mediation analyses suggest that the CAA-dementia association may be potentially mediated by AD neuropathologic changes. This hypothesis needs to be tested in future mechanistic studies in AD accounting for unmeasured confounders.
脑淀粉样血管病（CAA）在老年人中很常见，与痴呆有关。然而，我们对于这种关联是否通过阿尔茨海默病（AD）神经病理变化来介导知之甚少，本研究的目的就是探讨这一问题。
本研究回顾性分析了 Kaiser Permanente Washington 数据库中成人思维变化（ACT）尸检队列的信息，包括 CAA、痴呆、阿尔茨海默病合作研究（CERAD）（淀粉样神经纤维缠结）和 Braak（tau 神经原纤维缠结）。CAA 通过免疫组织化学进行诊断，痴呆通过 ACT 共识诊断会议进行诊断。AD 神经病理学通过 CERAD 评分和 Braak 分期进行分类。多变量逻辑回归模型用于估计 CAA 与痴呆之间的关联的优势比（OR）和 95%置信区间（CI），调整了死亡时的年龄和性别，并分别针对 CERAD 评分（中重度 vs 轻度-无）、Braak 分期（V-VI vs 0-IV）、ε4 和中风进行了额外的调整。进行了正式的中介分析，以估计 CERAD 评分和 Braak 分期的自然间接效应（NIE）的年龄性别调整 OR（95%CI）。
848 名参与者的平均死亡年龄为 86.7±4.6 岁，57.6%为女性。322 名参与者（38.0%）存在 CAA，其中 152、145 和 25 名参与者的 CAA 分别为轻度、中度和重度。384 名参与者（45.3%）存在痴呆，其中 317 名参与者患有 AD。与无 CAA 相比，有 CAA 的参与者中痴呆更为常见（53.7% vs 40.1%；年龄性别调整 OR 1.57，95%CI 1.18-2.10）。这种关联在分别针对其他协变量进行调整后仍然显著，但在针对 CERAD 评分（OR 1.27，95%CI 0.93-1.71）和 Braak 分期（OR 0.96，95%CI 0.69-1.33）进行调整后则失去了显著性。我们的正式中介分析结果表明，CERAD 评分和 Braak 分期的 NIE 的 OR（95%CI）分别为 1.25（1.13-1.37）和 1.63（1.38-1.88），CERAD 评分和 Braak 分期分别介导了总关联的 53%和 111%。
我们观察到 CAA 与痴呆之间存在显著关联，而当调整 CERAD 或 Braak 分期时，这种关联就消失了。我们的中介分析结果表明，CAA 与痴呆之间的关联可能是通过 AD 神经病理变化来介导的。在未来的 AD 机制研究中，需要针对未测量的混杂因素进行进一步的测试。
