This study investigated the neuropathology of probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in 483 autopsied participants from two longitudinal studies. The participants were categorized into three groups: those with probable AD, those with MCI (amnestic and non-amnestic), and those without cognitive impairment. The study found that nearly 88% of participants with probable AD had pathologically confirmed AD, while 45.8% had mixed pathologies, most commonly AD with macroscopic infarcts, followed by AD with neocortical Lewy body disease. In the MCI group, 54.4% had pathologically diagnosed AD, with 19.4% having mixed pathologies. Macroscopic infarcts without AD pathology accounted for a significant portion of MCI cases. Pure neocortical Lewy body disease was rare in all groups. Mixed pathologies were common in both AD and MCI, indicating that these conditions are pathologically heterogeneous. The study also found that mixed pathologies significantly increased the likelihood of cognitive impairment and dementia. The presence of additional pathologies in individuals with probable AD and MCI has important implications for understanding the underlying causes of cognitive decline and for the development of prevention and treatment strategies. The findings suggest that mixed pathologies are a common feature in dementia and that the diagnosis of probable AD and MCI should be considered in the context of multiple pathologies. The study highlights the importance of considering mixed pathologies in the clinical evaluation of cognitive impairment and dementia.This study investigated the neuropathology of probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in 483 autopsied participants from two longitudinal studies. The participants were categorized into three groups: those with probable AD, those with MCI (amnestic and non-amnestic), and those without cognitive impairment. The study found that nearly 88% of participants with probable AD had pathologically confirmed AD, while 45.8% had mixed pathologies, most commonly AD with macroscopic infarcts, followed by AD with neocortical Lewy body disease. In the MCI group, 54.4% had pathologically diagnosed AD, with 19.4% having mixed pathologies. Macroscopic infarcts without AD pathology accounted for a significant portion of MCI cases. Pure neocortical Lewy body disease was rare in all groups. Mixed pathologies were common in both AD and MCI, indicating that these conditions are pathologically heterogeneous. The study also found that mixed pathologies significantly increased the likelihood of cognitive impairment and dementia. The presence of additional pathologies in individuals with probable AD and MCI has important implications for understanding the underlying causes of cognitive decline and for the development of prevention and treatment strategies. The findings suggest that mixed pathologies are a common feature in dementia and that the diagnosis of probable AD and MCI should be considered in the context of multiple pathologies. The study highlights the importance of considering mixed pathologies in the clinical evaluation of cognitive impairment and dementia.