What is ‘Alzheimer's disease’? The neuropathological heterogeneity of clinically defined Alzheimer's dementia

Beta-amyloid with paired helical filaments (PHF)-tau neurofibrillary tangles define hallmark Alzheimer's disease neuropathologic changes (AD-NC). Yet persons with Alzheimer's dementia, defined broadly as an amnestic multidomain progressive dementia, often exhibit postmortem evidence of other neuropathologies including other neurodegenerative (Lewy body disease and transactive response DNA-binding protein disease) and vascular-related brain lesions. Clinicopathologic and epidemiologic analyses demonstrate the significance of these substrates, as coinciding neuropathologies mitigate the threshold for diagnosis of Alzheimer's dementia. In addition, other biologic processes may also independently underlie a progressive amnestic dementia. Advances in research on the relationship between age-related cognitive decline and the underlying neuropathologic substrates indicate that consensus neuropathologic criteria or disease nomenclature may need new considerations or refinement. This review appraises seminal literature as well as mixed pathologies and biological factors that may be determinants of clinical and pathologic disease.Cognition in aging (spanning from normal cognition to dementia) represents a clinical continuum. Traditional neuropathologic substrates of dementia however do not explain the variability of cognitive decline. Conversely, not all patients with AD-NC exhibit symptomatology of Alzheimer's dementia. In addition to diagnostic plaques and tangles, other neurodegenerative, cerebrovascular, and perivascular substrates manifest through discrete tissue lesions. Factors related to energetics, neurogenetics, neuroimmunology, resilience, proteinopathies, and waste clearance are increasingly suggested to be general drivers of disease. Recognition of novel neuroimmune pathways and brain-body connections further suggest there may be broader extracranial determinants of person-specific disease.Alzheimer's dementia is a pathologically heterogeneous and biologically multilayered disease. Recent studies and exercises in nomenclature reveal shortcomings in existing terminologies. Recognizing and overcoming these limitations is required for experts to effectively communicate about and ultimately prevent and treat Alzheimer's dementia.