The neuropathological hallmarks of Alzheimer's disease (AD) include both "positive" lesions, such as amyloid plaques and neurofibrillary tangles, and "negative" lesions, such as neuronal and synaptic loss. Postmortem studies have enabled the staging of the progression of these lesions, leading to the development of diagnostic criteria used worldwide. Clinicopathological correlation studies have been crucial in generating hypotheses about the pathophysiology of AD, establishing a continuum between normal aging and AD dementia. Amyloid plaques and neurofibrillary tangles are primarily found in the cortical mantle and limbic and association cortices, respectively. Neuronal and synaptic loss largely parallel tangle formation, although the causal relationship remains uncertain. Recent studies have expanded the concept of neurodegeneration in AD to include earlier alterations such as synaptic and dendritic injury, disturbances in adult neurogenesis, circuitry dysfunction, and aberrant innervation. The gross and microscopic features of AD brains, including cortical atrophy, amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy, are described in detail. Clinicopathological correlations have shown that the amount and distribution of neurofibrillary tangles correlate with the severity and duration of dementia, while amyloid plaques do not. The pathological diagnosis of AD relies on the presence of amyloid plaques and neurofibrillary tangles, with current criteria distinguishing three probabilistic diagnostic categories. Mild cognitive impairment (MCI) is a new clinical construct that bridges the transition between normal aging and AD dementia, often showing intermediate levels of AD pathology. Longitudinal studies in nondemented elderly individuals have revealed that up to 45% could meet AD criteria if they were demented, highlighting the spectrum of AD pathology. Understanding the resilience of some individuals to cognitive decline in the presence of AD pathology is crucial for developing new therapeutic targets.The neuropathological hallmarks of Alzheimer's disease (AD) include both "positive" lesions, such as amyloid plaques and neurofibrillary tangles, and "negative" lesions, such as neuronal and synaptic loss. Postmortem studies have enabled the staging of the progression of these lesions, leading to the development of diagnostic criteria used worldwide. Clinicopathological correlation studies have been crucial in generating hypotheses about the pathophysiology of AD, establishing a continuum between normal aging and AD dementia. Amyloid plaques and neurofibrillary tangles are primarily found in the cortical mantle and limbic and association cortices, respectively. Neuronal and synaptic loss largely parallel tangle formation, although the causal relationship remains uncertain. Recent studies have expanded the concept of neurodegeneration in AD to include earlier alterations such as synaptic and dendritic injury, disturbances in adult neurogenesis, circuitry dysfunction, and aberrant innervation. The gross and microscopic features of AD brains, including cortical atrophy, amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy, are described in detail. Clinicopathological correlations have shown that the amount and distribution of neurofibrillary tangles correlate with the severity and duration of dementia, while amyloid plaques do not. The pathological diagnosis of AD relies on the presence of amyloid plaques and neurofibrillary tangles, with current criteria distinguishing three probabilistic diagnostic categories. Mild cognitive impairment (MCI) is a new clinical construct that bridges the transition between normal aging and AD dementia, often showing intermediate levels of AD pathology. Longitudinal studies in nondemented elderly individuals have revealed that up to 45% could meet AD criteria if they were demented, highlighting the spectrum of AD pathology. Understanding the resilience of some individuals to cognitive decline in the presence of AD pathology is crucial for developing new therapeutic targets.