Clinical Neuroanatomy/Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany.
Institute for Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
J Alzheimers Dis. 2024;101(4):1333-1353. doi: 10.3233/JAD-240483.
Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-β (Aβ) deposition in Alzheimer's disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aβ deposition as a 'primary age-related tauopathy' (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon's horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART.
To test the 'definite PART' hypothesis.
We used AT8-immunohistochemistry in 100μm sections to examine the EC, transentorhinal cortex (TRE), and Ammon's horn in 325 brains with tau inclusions lacking Aβ deposits (average age at death 66.7 years for females, 66.4 years for males).
100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD.
Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD.
尸检系列的神经病理学研究表明，tau 包含物（预缠结、神经原纤维缠结）在阿尔茨海默病（AD）中淀粉样蛋白-β（Aβ）沉积之前超过十年即可检测到，并且以形成 AD 分期基础的特征方式发展。另一种观点认为，没有 Aβ沉积的病理性 tau 是一种“原发性年龄相关性 tau 病”（PART），而不是前驱 AD。最近，有人提出，在齿状回（EC）中出现 tau 包含物之前，Ammon's 角第二区（CA2）中 tau 包含物的早期焦点以及 CA1 的相对保留，作为 PART 的另一个特征。
验证“明确 PART”假说。
我们使用 AT8-免疫组织化学方法在 325 例缺乏 Aβ 沉积的 tau 包含物的大脑中（女性死亡时平均年龄为 66.7 岁，男性为 66.4 岁），检查了 EC、transentorhinal 皮质（TRE）和 Ammon's 角。
100%的病例在 TRE 中均显示 tau 包含物。在 89%的病例中，CA1 的 tau 评分大于或等于 CA2。在 25%的病例中，CA2 没有 tau 包含物。只有 4%的病例 CA2 的 tau 评分高于 TRE、EC 和 CA1。穿通纤维也显示出早期 tau 变化。APOE 基因分型可用于 199/325 个人。其中，44%的人携带有增加发生后期 NFT 阶段风险的ɛ4 等位基因，因此，可能会发展为临床 AD。
我们的新发现对 PART 假说提出了质疑，并且与我们的病例代表前驱 AD 的观点一致。
