Summary HIV-associated neurocognitive disorders and substance abuse comorbidity remain prevalent despite combination antiretroviral therapy (cART). The scientific literature as well as gene expression results from our group suggest a degree of pathogenic similarity and possibly overlap between neurodegeneration in neuroHIV and Alzheimer’s Disease (AD). Trophic factors are beneficial in animal and in vitro models of neuroAIDS. However, neurotrophic factors and other growth factors are unsuitable neuropharmaceuticals because of their peptidic nature that limits needed drug-like properties, including oral absorption, plasma stability, and brain penetration. The innovative hypothesis behind the parent grant is that small molecules can be identified that can reverse trophic deficits that characterize HANDs and manifest as synaptodendritic and mitochondrial injury and can effectively prevent or ameliorate cognitive decline in HIV and compulsive drug taking. To test this hypothesis, studies under the parent grant performed a high-throughput screening campaign (HTS) to identify inducers of a gene regulatory mechanism that broadly regulates trophic support and mitochondrial biogenesis in key cortical and hippocampal neuronal populations and that we found to be downregulated in both neuroAIDS and substance dependence. Deficient trophic support involving reduced activity of neurotrophins has also been implicated in AD neurodegeneration. Consistent with these findings, delivery of neurotrophins proved beneficial in AD animal models. Here we propose to test the small molecules identified in the parent grant for neuroAIDS in rodent models of AD as candidate therapeutics to promote improved neuronal trophic support. To this end we will test the ability of the lead compounds identified to prevent or ameliorate cognitive impairment in two transgenic rodent models of AD, the McGill-R-Thy1-APP rats (hAβPPswe,ind) and the triple transgenic AD (3xTg-AD) mice (Tg(APPSwe,tauP301L)1Lfa). We will explore the ability of the new compounds identified under the parent grant to delay or prevent AD progression and to revert the gene expression signatures associated with AD in the animal models under study. Ultimately, the proposed therapeutic strategy is expected to make neurons more resilient through improved tropic support by means of small molecules, resulting in reduced neuronal injury and improved cognitive performance in AD. The parent grant does not propose AD animal models, nor any AD-focused experiments and the PI has no AD-related funds. The results of the present Administrative Supplement will lay the foundations for a new R01 proposal aimed at further advancing the development of a series of compounds currently being established for neuroAIDS for the prevention and treatment of AD.