The complex multifactorial nature of AD pathogenesis has been highlighted by evidence implicating additional neurodegenerative mechanisms, beyond that of amyloid-β (Aβ) and tau. To provide insight into cause and effect, we here investigated the temporal profile and associations of pathological changes in synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers. Quantifications were established via immunoblot and immunohistochemistry protocols in post-mortem lateral temporal cortex (n = 46). All measures were assessed according to diagnosis (non-AD vs. AD), neuropathological severity (low (Braak ≤ 2) vs. moderate (3–4) vs. severe (≥ 5)) and individual Braak stage, and were correlated with Aβ and tau pathology and cognitive scores. Postsynaptic PSD-95, but not presynaptic synaptophysin, was decreased in AD cases and demonstrated a progressive decline across disease severity and Braak stage, yet not with cognitive scores. Of all investigated ER stress markers, only phospho-protein kinase RNA-like ER kinase (p-PERK) correlated with Braak stage and was increased in diagnosed AD cases. A similar relationship was observed for the astrocytic glial fibrillary acidic protein (GFAP); however, the associated aquaporin 4 and microglial Iba1 remained unchanged. Pathological alterations in these markers preferentially correlated with measures of tau over those related to Aβ. Notably, GFAP also correlated strongly with Aβ markers and with all assessments of cognition. Lateral temporal cortex-associated synaptic, ER stress and neuro-inflammatory pathologies are here determined as late occurrences in AD progression, largely associated with tau pathology. Moreover, GFAP emerged as the most robust indicator of disease progression, tau/Aβ pathology, and cognitive impairment.

AD 发病机制的复杂多因素性质已通过涉及淀粉样蛋白-β (Aβ) 和 tau 之外的其他神经退行性机制的证据突出显示。为了深入了解因果关系，我们在此研究了突触、内质网 (ER) 应激和神经炎症标志物病理变化的时间分布和关联。通过死后外侧颞叶皮层（n = 46)。根据诊断（非 AD 与 AD）、神经病理学严重程度（低 (Braak ≤ 2) 与中度 (3-4) 与严重 (≥ 5)）和个体 Braak 阶段评估所有测量值，并与Aβ 和 tau 病理学和认知评分。在 AD 病例中，突触后 PSD-95 而不是突触前突触素减少，并且在疾病严重程度和 Braak 阶段表现出进行性下降，但与认知评分无关。在所有研究的 ER 应激标记中，只有磷酸蛋白激酶 RNA 样 ER 激酶 (p-PERK) 与 Braak 阶段相关，并且在诊断的 AD 病例中增加。星形胶质细胞胶质纤维酸性蛋白 (GFAP) 也观察到类似的关系。然而，相关的水通道蛋白 4 和小胶质细胞 Iba1 保持不变。这些标志物的病理改变优先与 tau 的测量相关，而不是与 Aβ 相关的测量。值得注意的是，GFAP 还与 Aβ 标志物和所有认知评估密切相关。外侧颞叶皮层相关突触、ER 应激和神经炎症病理在此被确定为 AD 进展的晚期发生，主要与 tau 病理相关。此外，GFAP 成为疾病进展、tau/Aβ 病理学和认知障碍的最有力指标。