Summary This is an “Alzheimer’s-Focused Administrative Supplement for NIH Grants that are Not Focused on Alzheimer’s Disease” in response to NOT-AG-21-018. Emerging neuropathology findings in neuroHIV as well as gene expression results from our group suggest a degree of pathogenic similarity and possibly overlap between neuroHIV and Alzheimer’s Disease (AD). Additionally, the abuse of stimulants like cocaine and methamphetamine (METH) is believed to increase the risk of dementias including AD, but experimental evidence of the detrimental interaction of stimulants and AD are lacking. To address these knowledge gaps, we proposed to study the effects of stimulants in a rat transgenic (Tg) model of AD, the McGill-R-Thy1-APP rat that expresses human APP751 with the Swedish and Indiana mutations, under the control of the murine Thy1.2 promoter. The McGill-R-Thy1-APP rats have been extensively characterized and show age-dependent accumulation of amyloid plaques, gliosis, cholinergic synapse loss, and cognitive impairment. In particular, paralleling the studies of the parent grant, we aim to test if histories of escalated self-administration of stimulants under conditions of extended daily access that results in compulsive drug intake, will result in early onset of cognitive impairment in the McGill-R-Thy1-APP rats as we have seen with 3xTg-AD Tg mice with a history of repeated alcohol intoxication. We will also use AD/HIV double Tg rats to explore the possible interaction of AD and HIV mechanisms of pathogenesis. The proposed studies will also determine if McGill-R-Thy1-APP rats differ from wild-type rats in motivation for stimulants and propensity to escalate intake in the paradigm of extended access. The paradigm of escalated drug intake under conditions of extended daily access is highly relevant to the human substance use disorder (SUD) as it models all 7 of the criteria for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11 criteria in the DSM-V. Paralleling the parent grant, we will conduct gene expression analyses in a systems biology framework to dissect the gene regulatory networks involved in the interaction of excessive stimulant intake with AD and with AD/HIV. This systems biology strategy identifies master regulatory genes that drive the gene expression signatures associated to specific phenotypes and that will point to new testable mechanistic hypotheses and candidate therapeutic targets for the progression of neurodegeneration in AD, HIV, and stimulant abuse. 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.