Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy
of posterior brain regions. With the majority of cases attributable to Alzheimer’s disease and recent evidence for genetic risk factors
specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and
phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease
progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer’s disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer’s disease were recruited from three
centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical
Alzheimer’s disease using differential equation models. We compared and contrasted the order in which regional brain volumes
become abnormal within posterior cortical atrophy and typical Alzheimer’s disease using event-based models. We also examined
trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models.
Temporally aligned trajectories for eight regions of interest revealed distinct (P5 0.002) patterns of progression in posterior
cortical atrophy and typical Alzheimer’s disease. Patients with posterior cortical atrophy showed early occipital and parietal
atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable
extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent
of posterior cortical involvement. Patients with typical Alzheimer’s disease showed early hippocampal atrophy, with subsequent
higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction
declined earlier in posterior cortical atrophy than typical Alzheimer’s disease whilst tests sensitive to working memory impairment
declined earlier in typical Alzheimer’s disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy
and typical Alzheimer’s disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering
of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy