Mice expressing human amyloid precursor protein restricted to the liver (HSHA strain) and secreted as apoprotein of nascent triglyceride-rich lipoproteins develop blood-brain barrier dysfunction, neurodegeneration, cerebral amyloid deposition, and cognitive dysfunction. In this study, we developed a novel transgenic mouse strain to examine the synergistic effects of human APOE genotype in HSHA-murine APOE knock-out-human APOE knock-in mice. By having human apoE4 gene, the cognitive function in HSHA-E4 mice was significantly worse, compared to HSHA-E3 and wild-type controls. Concomitantly, the HSHA-E4 mice exhibited substantial neurovascular dysfunction and Alzheimer's-like pathophysiology, including barrier breakdown (IgG), astrogliosis (GFAP), inflammation (Iba1), oxidative stress (8OHdG) and neurodegeneration (NeuN). Furthermore, spatial whole RNA transcriptomics indicated significant alterations in lipid metabolism, inflammation and cellular survival in HSHA-E4, which are similar to clinical Alzheimer's. These findings suggest that peripheral metabolism of lipoprotein-amyloid may be a major risk factor for a neurodegenerative phenotype consistent with early Alzheimer's and may explain the present novel pathway and therapeutic target for Alzheimer's in individuals carrying apoE4 allele.