BackgroundAPPduplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes ofAPPduplications carriers.MethodsClinical, radiological, and neuropathological features of 43APPduplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40APP-negative CAA controls.ResultsMajor neurocognitive disorders were found in 90.2% symptomaticAPPduplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls,APPduplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%,p= 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in twoAPPduplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia.DiscussionPhenotypes associated withAPPduplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, makingAPPduplication an interesting model of CAA.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-023-01172-2.