Disruption of the default mode network is a hallmark of
Alzheimer's disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and 1-year longitudinal changes in default mode network sub-systems in the visual and language variants of
Alzheimer's disease, in relation to age and tau. Sixty-one
amyloid-positive
Alzheimer's disease participants diagnosed with posterior cortical
atrophy (n = 33) or logopenic
progressive aphasia (n = 28) underwent structural MRI, resting-state functional MRI and [
18F]flortaucipir PET. One-hundred and twenty-two
amyloid-negative cognitively unimpaired individuals and 60
amyloid-positive individuals diagnosed with amnestic
Alzheimer's disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical
Alzheimer's disease participants, 26 amnestic
Alzheimer's disease participants and 40 cognitively unimpaired individuals had one follow-up functional MRI ∼1-2 years after the baseline scan. Default mode network connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral and anterior dorsal sub-systems derived from independent component analysis. A global measure of default mode network connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic
Alzheimer's disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in
Alzheimer's disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger
Alzheimer's disease participants had lower connectivity than the older ones, particularly in the ventral default mode network. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral default mode network connectivity in atypical
Alzheimer's disease. Connectivity in the ventral default mode network declined over time in atypical
Alzheimer's disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal default mode network connectivity, lower posterior and ventral default mode network connectivity and decline in ventral default mode network connectivity over time in atypical
Alzheimer's disease. Visuospatial symptoms were associated with default mode network connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic
Alzheimer's disease variants, and discriminated
Alzheimer's disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity and with disruption more pronounced in younger participants. The ventral default mode network declined over time in atypical
Alzheimer's disease, suggesting a shift in default mode network connectivity likely related to tau pathology.