This study presents the development of a transgenic mouse model, TgCRND8, which exhibits early-onset amyloid deposition and cognitive deficits, making it a valuable tool for studying Alzheimer's disease (AD). The mice express a double mutant form of the amyloid precursor protein (APP) 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. The study shows that these mice develop thioflavine S-positive amyloid deposits as early as 3 months of age, with dense-cored plaques and neuritic pathology evident by 5 months. By 6 months, TgCRND8 mice have high levels of Aβ42 (3,200–4,600 pmol/g brain), which is associated with early cognitive impairments in spatial learning and memory, as demonstrated by the Morris water maze test. The cognitive deficits observed in young mice were mitigated by immunization against Aβ42, suggesting a pathogenic role for Aβ42 in the model. Additionally, the expression of presenilin 1 transgenes with familial Alzheimer's disease (FAD) mutations accelerated amyloid deposition, with plaques appearing as early as 1 month of age. The TgCRND8 model provides a platform for investigating AD pathogenesis, prophylaxis, and therapy within a short timeframe. The study highlights the importance of genetic background in modulating the survival and disease progression of transgenic mice, with the (C57) × (C3H/C57) genetic background showing better survival rates. The model also exhibits AD-like neuropathology, including amyloid plaques, dystrophic neurites, and neuroinflammation, but lacks neurofibrillary tangles, which are common in AD. The findings support the amyloid cascade hypothesis and suggest that TgCRND8 mice are a robust model for studying the relationship between Aβ accumulation and cognitive decline.This study presents the development of a transgenic mouse model, TgCRND8, which exhibits early-onset amyloid deposition and cognitive deficits, making it a valuable tool for studying Alzheimer's disease (AD). The mice express a double mutant form of the amyloid precursor protein (APP) 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. The study shows that these mice develop thioflavine S-positive amyloid deposits as early as 3 months of age, with dense-cored plaques and neuritic pathology evident by 5 months. By 6 months, TgCRND8 mice have high levels of Aβ42 (3,200–4,600 pmol/g brain), which is associated with early cognitive impairments in spatial learning and memory, as demonstrated by the Morris water maze test. The cognitive deficits observed in young mice were mitigated by immunization against Aβ42, suggesting a pathogenic role for Aβ42 in the model. Additionally, the expression of presenilin 1 transgenes with familial Alzheimer's disease (FAD) mutations accelerated amyloid deposition, with plaques appearing as early as 1 month of age. The TgCRND8 model provides a platform for investigating AD pathogenesis, prophylaxis, and therapy within a short timeframe. The study highlights the importance of genetic background in modulating the survival and disease progression of transgenic mice, with the (C57) × (C3H/C57) genetic background showing better survival rates. The model also exhibits AD-like neuropathology, including amyloid plaques, dystrophic neurites, and neuroinflammation, but lacks neurofibrillary tangles, which are common in AD. The findings support the amyloid cascade hypothesis and suggest that TgCRND8 mice are a robust model for studying the relationship between Aβ accumulation and cognitive decline.