Alzheimer disease (AD), the most common form of dementia globally, classically defined a clinicopathological entity, is a heterogenous disorder with various pathobiological subtypes, currently referred to as Alzheimer continuum. Its morphological hallmarks are extracellular parenchymal β-amyloid (amyloid plaques) and intraneuronal (tau aggregates forming neurofibrillary tangles) lesions accompanied by synaptic loss and vascular amyloid deposits, that are essential for the pathological diagnosis of AD. In addition to “classical” AD, several subtypes with characteristic regional patterns of tau pathology have been described that show distinct clinical features, differences in age, sex distribution, biomarker levels, and patterns of key network destructions responsible for cognitive decline. AD is a mixed proteinopathy (amyloid and tau), frequently associated with other age-related co-pathologies, such as cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease. These and other co-pathologies essentially influence the clinical picture of AD and may accelerate disease progression. The purpose of this review is to provide a critical overview of AD pathology, its defining pathological substrates, and the heterogeneity among the Alzheimer spectrum entities that may provide a broader diagnostic coverage of this devastating disorder as a basis for implementing precision medicine approaches and for ultimate development of successful disease-modifying drugs for AD.

阿尔茨海默病 (AD) 是全球最常见的痴呆形式，经典定义为临床病理实体，是一种具有各种病理生物学亚型的异质性疾病，目前称为阿尔茨海默病连续体。其形态学特征是细胞外实质 β-淀粉样蛋白（淀粉样蛋白斑块）和神经元内（形成神经原纤维缠结的 tau 聚集体）病变，伴有突触丢失和血管淀粉样蛋白沉积，这对于 AD 的病理诊断至关重要。除了“经典” AD 之外，还描述了具有 tau 病理学特征区域模式的几种亚型，这些亚型显示出不同的临床特征、年龄差异、性别分布、生物标志物水平以及导致认知能力下降的关键网络破坏模式。AD 是一种混合蛋白病（淀粉样蛋白和 tau），通常与其他与年龄相关的共病相关，例如脑血管病变、Lewy 和 TDP-43 病理、海马硬化或嗜银性谷物病。这些和其他共病本质上影响 AD 的临床表现，并可能加速疾病进展。本综述的目的是对 AD 病理学、其定义的病理学基础以及阿尔茨海默病谱实体之间的异质性进行重要概述，这些实体可能为这种破坏性疾病提供更广泛的诊断覆盖范围，作为实施精准医学方法和最终治疗的基础。开发成功的 AD 疾病缓解药物。这些和其他共病本质上影响 AD 的临床表现，并可能加速疾病进展。本综述的目的是对 AD 病理学、其定义的病理学基础以及阿尔茨海默病谱实体之间的异质性进行重要概述，这些实体可能为这种破坏性疾病提供更广泛的诊断覆盖范围，作为实施精准医学方法和最终治疗的基础。开发成功的 AD 疾病缓解药物。这些和其他共病本质上影响 AD 的临床表现，并可能加速疾病进展。本综述的目的是对 AD 病理学、其定义的病理学基础以及阿尔茨海默病谱实体之间的异质性进行重要概述，这些实体可能为这种破坏性疾病提供更广泛的诊断覆盖范围，作为实施精准医学方法和最终治疗的基础。开发成功的 AD 疾病缓解药物。