Mutations in the amyloid precursor protein (APP) gene are associated with familial Alzheimer Disease. Here we report the neuropathological findings observed in the brain of an affected carrier of the V717L APP mutation. The proband presented with short-term memory loss and mild behavioral changes at age 35. He died at age 44, following a 9 years disease duration. His family history is remarkable for his father who died of heart attack at age 42 after having experienced memory loss and depression, and a sister who developed similar symptoms at age 38 and died at age 51. The proband's brain was processed for histology and immunohistochemistry (IHC). Aβ IHC was carried out using antibodies recognizing Aβ3–7, AβN3pE, Aβ10–16, Aβ17–24, AβN-40 and AβN-42. IHC for α-synuclein was also carried out. The brain (approximately 1183 grams) displayed moderate atrophy of the frontal lobe, mild atrophy of the remaining lobes, and extensive atrophy of the hippocampus and parahippocampal gyrus. Neuritic plaques (CERAD stage C) were abundant in the intermediate neocortical layers. Abundant diffuse Aβ deposits were observed in the remaining cortical layers as well as in the subpial zone. Mild amyloid angiopathy was seen, predominantly in penetrating vessels. Braak VI-tau pathology was observed, particularly affecting layer V and VI. Neuritic plaques were immunoreactive against the full panel of Aβ antibodies except for the anti-AβN-40. Diffuse deposits contained AβN-42 species but did not react with antibodies recognizing epitopes located before position 11. In the cerebellum, a few Aβ-immunoreactive diffuse deposits were seen. Occasional neuritic plaques were observed in the brainstem. IHC for α-synuclein was negative in all the examined sections. The proband's ApoE genotype was ϵ3/ϵ3. Our data suggest a heterogeneous involvement of the cortical layers by the deposition of Aβ species with specific immunohistochemical pattern. They also suggest that diffuse deposits, in the upper and lower cortical layers, are composed by N-terminally truncated Aβ species. Supported by AG10133 and Alzheimer's Association.