Introduction: One major factor that influences the heterogeneity of Alzheimer's disease (AD) is age: younger AD patients more frequently exhibit atypical forms of AD. We propose that this age-related heterogeneity can be understood better by considering age-related differences in atrophy in the context of large-scale brain networks subserving cognitive functions that contribute to memory. Methods: We examined data from 75 patients with mild AD dementia from Alzheimer's Disease Neuroimaging Initiative. These individuals were chosen because they have cerebrospinal fluid amyloid and p-tau levels in the range suggesting the presence of AD neuropathology, and because they were either younger than age 65 years early-onset AD (EOAD) or age 80 years or older late-onset AD (LOAD). Results: In the EOAD group, the most prominent atrophy was present in the posterior cingulate cortex, whereas in the LOAD group, atrophy was most prominent in the medial temporal lobe. Structural covariance analysis showed that the magnitude of atrophy in these epicenters is strongly correlated with a distributed atrophy pattern similar to distinct intrinsic connectivity networks in the healthy brain. An examination of memory performance in EOAD dementia versus LOAD dementia demonstrated relatively more prominent impairment in encoding in the EOAD group than in the LOAD group, with similar performance in memory storage in LOAD and EOAD but greater impairment in semantic memory in LOAD than in EOAD. Discussion The observations provide novel insights about age as a major factor contributing to the heterogeneity in the topography of AD-related cortical atrophy
