This proposal examines Alzheimer’s disease (AD) from the perspective of the basic biology of memory. Work spanning the past ~20 years indicates that successful memory requires a sequence of events that are mediated by a set of rapidly expressed genes that function at connections between neurons in brain. One of these genes, termed NPTX2, mediates critical step of memory formation by enhancing connections between excitatory and inhibitory neurons to re-establish brain homeostasis. In AD brain, NPTX2 expression is prominently reduced compared to age-matched controls. Interestingly, in brain of individuals that meet pathological criteria of AD but who were cognitively normal prior to death (asymptomatic AD) NPTX2 expression is normal. This “natural experiment” first suggested that preventing NPTX2 reduction can prevent memory failure in AD. Toward this goal, we have developed a compound that markedly increases NPTX2 expression in rodent brain and in human neurons. This compound, termed a target site blocker (TSB), can be rapidly translated for human therapeutics. Here we propose studies to optimize the action of TSBs for human neurons that model AD and establish this approach as a rational therapy that can be developed to slow, prevent, or reverse memory failure in AD.