There are no effective drugs to prevent, delay or treat Alzheimer’s disease (AD). The 5 million Americans currently diagnosed with AD is projected to increase to 11-16 million within two decades in the absence of effective therapies. We propose to develop for use in humans, plasma based exosome biomarker assays specifically reflecting the real-time biochemical state present in brain neurons and astrocytes. This advance will allow investigators real time assessments of AD neuropathology and opportunities to monitor drug effects. (-)-Phenserine tartrate is both a proven probe able to affect AD neuropathology that is considered important in progression to dementia, and a potential therapeutic operating independently from the AD pathology targeted over the last 30 years. Anatomical and biochemical evidence from preclinical transgenic AD models and wild type mice and rats in traumatic brain injury (TBI) and anoxia models support the translation of phenserine protection of neurons from preprogrammed cell death (PPCD) unexplained by other activities of phenserine. We have developed an extended controlled release formulation of phenserine tartrate to insure successful determination of optimal dosing that maximizes preservation of neurons and expected prevention of dementia. Based on a foundation of preclinical discovery, translational research (TBI and AD trials), clinical development at NIA, and FDA assessment, we propose a phase 1b ascending dose clinical trial of four phenserine doses given daily for 12 weeks to establish a safe and tolerated dose, to characterize biomarker responses, and to interpret their significance for cellular functioning. This dose-response evaluation prepares for advancement to a phase 2 proof of concept trial. Two specific aims are proposed to achieve this goal: Aim 1 to assess the performance of the exosome biomarkers, their ability to distinguish AD pathology from not impaired, their reproducibility, and precision in older populations; Aim 2 to conduct a phase 1b ascending dose trial of phenserine in early AD. Primary safety objectives are to define a maximally tolerated dose, and determine treatment emergent adverse events. Biomarker objectives are to enable the deployment of exosomes assays as measures of AD neuropathology and phenserine’s effects on pathology. Secondary objectives are to: 1) assess potential short-term effects of phenserine on cognition; 2) inform an ensuing phase 2 proof of concept trial with exosome biomarkers, i.e., PPCD, synaptic arborization, etc. A multi- disciplinary investigator team with expertise in drug development, biomarkers of cognitive impairment, aging, and translational research for Alzheimer therapeutics is committed to the project. Outcomes will provide: 1) an estimated safe, well-tolerated phenserine dose; 2) parameter estimates for the exosome biomarkers; and 3) parameter estimates for cognitive efficacy to advance to phase 2. The proposal meets objectives of NIA PAR- 18-175, Pilot C...