Soluble amyloid precursor protein-alpha (sAPPα) plays critical roles in healthy brain functions, including cognition, suggesting that it may be a useful therapeutic for the treatment of neurological disorders such as Alzheimer’s disease (AD). Recombinant adeno-associated viruses (AAV) carrying therapeutic transgenes may provide a therapeutically useful delivery strategy. Recently, modified AAV capsids have been designed that cross the blood-brain barrier (BBB) of mice and transduce cells throughout the brain. We investigated if one such capsid, AAV-PHP.eB, could deliver either the human sAPPα transgene or the transgene for its bioactive 16 amino acid C-terminal domain, CTα16, across the mouse BBB to alleviate AD-like symptoms in an APP/PS1 mouse model of AD. Six-month-old wildtype (WT) and transgenic (Tg) female mice received, by tail vein injection, either 1x1011 viral genomes (vg) of the vector containing the TdTomato fluorescent protein transgene alone, or in conjunction with 1x1011 vg carrying either the sAPPα or CTα16 transgene under a ubiquitous promoter. Three months after injection, brain-wide intracellular TdTomato fluorescence and high levels of sAPPα expression demonstrated robust cellular transduction, particularly of neurons in the CNS. In Tg mice, both sAPPα and CTα16 treatments completely rescued long-term potentiation in hippocampal area CA1 and significantly reduced hippocampal and cortical amyloid plaque loads. No adverse effects of sAPPα overexpression on LTP were observed in WT mice. These findings further support the potential of a peripheral viral vector-based sAPPα or CTα16 gene delivery approach as a minimally invasive therapeutic strategy for the treatment of AD and potentially other neurological disorders.