Longitudinal default mode sub-networks in the language and visual variants of Alzheimer’s disease

Disruption of the default mode network (DMN) is a hallmark of Alzheimer’s disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and one-year longitudinal changes in DMN 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 fMRI approximately one to two years after the baseline scan. DMN 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 DMN 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 DMN. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral DMN connectivity in atypical Alzheimer’s disease. Connectivity in the ventral DMN 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 DMN connectivity, lower posterior and ventral DMN connectivity, and decline in ventral DMN connectivity over time in atypical Alzheimer’s disease. Visuospatial symptoms were associated with DMN 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 DMN declined over time in atypical Alzheimer’s disease, suggesting a shift in default mode network connectivity likely related to tau pathology.