Neuropathological assessment of the Alzheimer spectrum

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.