We previously demonstrated 2 statistically distinct factors of degeneration in Alzheimer's disease: one strongly related to white matter damage and age interpreted as"age-and vascular-related", and the other related to cortical atrophy thought to represent"neurodegenerative changes associated with Alzheimer's disease". Those factors are now replicated in a distinct cross-sectional data set of 364 participants from the Alzheimer's Disease Neuroimaging Initiative and their interpretation is improved using correlations with CSF biomarkers. Furthermore, we now show that changes in both factors over 2 years are independently associated with decline in MinieMental State Examination score in a longitudinal subset of 116 individuals with mild cognitive impairment. Progression in the"age-and vascularrelated" factor was greater for individuals with 2 APOE epsilon 4 alleles and linked to a greater attributable change in MinieMental State Examination than the"neurodegenerative" factor. These results suggest benefits of targeting white matter and vascular health to complement interventions focused on the neurodegenerative aspect of the disease, even in individuals with little discernable vascular comorbidity. (C) 2017 Elsevier Inc. All rights reserved.