Abstract
The key pathological hallmarks-extracellular plaques and intracellular neurofibrillary tangles (NFT)-described by Alois Alzheimer in his seminal 1907 article are still central to the postmortem diagnosis of Alzheimer's disease (AD), but major advances in our understanding of the underlying pathophysiology as well as significant progress in clinical diagnosis and therapy have changed the perspective and importance of neuropathologic evaluation of the brain. The notion that the pathological processes underlying AD already start decades before symptoms are apparent in patients has brought a major change reflected in the current neuropathological classification of AD neuropathological changes (ADNC). The predictable progression of beta-amyloid (Aβ) plaque pathology from neocortex, over limbic structures, diencephalon, and basal ganglia, to brainstem and cerebellum is captured in phases described by Thal and colleagues. The progression of NFT pathology from the transentorhinal region to the limbic system and ultimately the neocortex is described in stages proposed by Braak and colleagues. The density of neuritic plaque pathology is determined by criteria defined by the Consortium to establish a registry for Alzheimer's diseases (CERAD). While these changes neuropathologically define AD, it becomes more and more apparent that the majority of patients present with a multitude of additional pathological changes which are possible contributing factors to the clinical presentation and disease progression. The impact of co-existing Lewy body pathology has been well studied, but the importance of more recently described pathologies including limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy (ARTAG) still needs to be evaluated in large cohort studies. In addition, it is apparent that vascular pathology plays an important role in the AD patient population, but a lack of standardized reporting criteria has hampered progress in elucidating the importance of these changes for clinical presentation and disease progression. More recently a key role was ascribed to the immune response to pathological protein aggregates, and it will be important to analyze these changes systematically to better understand the temporal and spatial distribution of the immune response in AD and elucidate their importance for the disease process. Advances in digital pathology and technologies such as single cell sequencing and digital spatial profiling have opened novel avenues for improvement of neuropathological diagnosis and advancing our understanding of underlying molecular processes. Finally, major strides in biomarker-based diagnosis of AD and recent advances in targeted therapeutic approaches may have shifted the perspective but also highlight the continuous importance of postmortem analysis of the brain in neurodegenerative diseases.