ABSTRACT We propose to evaluate and optimize the portable, home-based product – the Computerized Olfactory Training Program (COT) – as a disease modifying intervention for prevention of progressive cognitive decline and progressive dementia in early Alzheimer's Disease (AD). The COT uses validated neuroprotective olfactory stimulants to intensely engage the primary and secondary olfactory cortices, with stimulation parameters that overcome olfactory habituation, paired with computerized olfactory cognitive training tasks that synergistically enhance the same brain regions; with the goal of increasing structural and functional resilience to AD progression. Phase I research and development met or exceeded stated technical milestones: COT intervention led to increased olfactory and cognitive functions 6 and 12 months later in ApoE4 carriers with mild cognitive impairment and early dementia. Among completers of 12-month follow-up visit, COT blunted trajectory in shrinkage of the entorhinal cortex and the hippocampus. Furthermore, the acute effects of odorant molecules in the COT in regulating sleep disruptions and emotional reactivity adds to a potential value of COT for treatment of behavioral dysfunctions in advanced AD. Alzheimer’s disease is a major public health crisis both in the United States and worldwide. Hitherto, no therapeutic has demonstrated significant effectiveness in modifying progression from early stages to advanced stages of AD. Most putative disease modifying therapeutics targeting various steps of amyloid biosynthesis and amyloid beta (Aβ) accumulation have either failed to reverse cognitive decline or worsened cognitive decline in Phase III clinical trials. However, neuroscience evidence that AD pathology progresses early, over several decades in the olfactory brain regions, before emergence of progressive, irreversible cognitive decline and dementia, as well as experimental and clinical findings that olfactory compromise accelerates the progression of AD, provide solid premise for targeting olfactory structure and function in the modification of AD progression. The success of use of enriched odor environment in reducing aggregation of pathological neurofilaments in animals spurred high hopes for translation of olfactory training (OT) into treatment of AD in humans. Unfortunately, lack of innovative approaches to sustain olfactory engagement sufficiently to influence functional and structural plasticity in clinical populations, hindered the translation of OT into an AD intervention. We built an innovative olfactory treatment delivery system for home use; established a proprietary regimen of safe neuroprotective plant odorant extracts and stimulation parameters that overcome odorant habituation in the primary olfactory cortex; and created a synchronized App to simultaneously administer olfactory cognitive training tasks that synergistically target the same brain regions being stimulated by the odorants. This breakthrough product...