The profile of autoantibodies is dysregulated in patients with Alzheimer’s disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET⁻ CN, 169 Aβ-PET⁺ cognitively normal subjects (preclinical AD), and 31 Aβ-PET⁺ cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.

阿尔茨海默病 （AD） 患者的自身抗体谱失调。人体血液中存在针对 β 位点淀粉样蛋白前体蛋白 （APP） 裂解酶 1 （BACE1） 的自身抗体。本研究旨在探讨 BACE1 自身抗体在 AD 中的临床相关性和病理生理作用。临床研究在两个独立的队列中进行，重庆队列和澳大利亚成像、生物标志物和生活方式 （AIBL） 队列。重庆队列包括 55 例 AD 患者、28 例非 AD 痴呆患者和 70 例认知正常的受试者 （CN）。AIBL 队列包括 162 名 Aβ-PET⁻ CN、169 名 Aβ-PET⁺ 认知正常受试者（临床前 AD）和 31 名 Aβ-PET⁺ 认知障碍受试者（临床 AD）。BACE1 的血浆自身抗体通过单位点 Elisa 测定。研究了 BACE1 血浆自身抗体与脑 Aβ 负荷和认知轨迹的相关性。在 APP/PS1 小鼠和 SH/APPswe/PS1wt 细胞系中研究 BACE1 自身抗体对 AD 型病理的影响和潜在机制。在重庆队列中，与 CN 和非 AD 痴呆患者相比，AD 患者的 BACE1 血浆自身抗体更高。在 AIBL 队列中，临床 AD 患者 BACE1 血浆自身抗体最高，其次是临床前 AD 和 CN 受试者。BACE1 自身抗体水平较高与随访期间脑淀粉样蛋白阳性转化的发生率增加相关。BACE1 的自身抗体加剧了 APP/PS1 小鼠的脑淀粉样蛋白沉积和随后的 AD 型病理，包括 Tau 过度磷酸化、神经炎症和神经变性。 BACE1 自身抗体通过抑制 PPARγ 信号传导促进 BACE1 表达，从而增加 Aβ 的产生。这些发现表明，针对 BACE1 的自身抗体在 AD 中具有致病性，这些自身抗体的上调可能会促进疾病的发展。本研究从自身免疫的角度为 AD 的机制提供了新的见解。