Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer’s disease (AD). It is rapidly progressive, with a median time from diagnosis to death or nursing home admission that is half that seen in AD, with extensive burden on patients and family caregivers. There is a great unmet medical need, with no approved treatments, only AD and Parkinson’s disease (PD) drugs used off-label to partially or temporarily relieve some of its severe cognitive and motor symptoms. The proposed treatment, neflamapimod, an orally bioavailable, highly specific inhibitor of the intracellular enzyme p38 mitogen activated protein kinase alpha (p38α), is in clinical development by EIP Pharma with a phase 2a study in DLB and phase 2 studies in early AD already completed. Preclinical data indicate that neflamapimod, through inhibiting p38α, therapeutically targets specific pathogenic mechanisms underlying dysfunction and degeneration of neurons in the basal forebrain, considered to be the major pathogenic drivers of dementia in DLB, e.g., increasing the number of functioning basal forebrain cholinergic neurons in Ts2 transgenic (Down syndrome) mice that develop neurodegeneration in the basal forebrain cholinergic system. With a strong scientific rationale for neflamapimod as a disease modifying treatment for DLB, neflamapimod received Fast-Track designation by the FDA for DLB. A completed phase 2a exploratory (i.e., hypothesis-generating) clinical trial (NCT04001517) in 91 patients with mild-to-moderate DLB provided preliminary evidence of clinical efficacy of neflamapimod on various cognitive, motor, and functional aspects of the disease. The current funded project (R01AG080536) conducts a phase 2b trial to confirm and expand upon these results. The Specific Aims are to, in the context of performing a phase 2b randomized, double- blind, placebo-controlled, 16-week treatment study of neflamapimod (40mg TID) in 160 subjects with mild DLB: (Aim 1). Demonstrate that neflamapimod improves cognition and function, based on primary (Clinical Dementia Rating Scale Sum of Boxes) and secondary (Timed Up and Go test, a Neuropsychological Test Battery, The Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change) efficacy measures in patients with mild DLB; (Aim 2). Assess neuropsychiatric outcomes and safety/tolerability during neflamapimod treatment in these subjects; and (Aim 3). Assess effects of neflamapimod on electroencephalographic (EEG) measures of DLB, markers of basal forebrain cholinergic dysfunction. Newly added Aim 4 assesses a proposed biomarker of therapeutic activity in the basal forebrain by structural and functional MRI. Successful completion of this phase 2b trial will inform our pivotal phase 3 trial, advancing neflamapimod as a disease-modifying treatment for DLB and providing hope for these patients and their families.