We propose a seamless Phase 2A-2B trial investigating benfotiamine, a prodrug of thiamine, as a first-in- class small molecule treatment for early Alzheimer's disease (AD). We call this proposed trial `Benfotiamine in early Alzheimer's disease (BEAD)”. Brain tissue thiamine deficiency causes memory deficits that are reversible with thiamine treatment in preclinical AD models and in human conditions including Wernicke Korsakoff syndrome. In animal models of mild impairment of oxidative metabolism (i.e., thiamine deficiency), neuronal loss is accompanied by changes in neurofilament light (NfL), by increased neuroinflammation (glial fibrillary acid protein GFAP), by elevation of advanced glycation end products (AGE) and by increased plaque and by tangle pathology, all of which occur in AD. Benfotiamine dramatically raises blood and brain tissue thiamine in these models, conferring behavioral benefit and reduced plaque and tangle formation. We previously conducted an early Phase 2 pilot single-site 12-month double blind placebo controlled RCT of 600 mg of benfotiamine in 71 persons with early AD. Benfotiamine was well tolerated, had encouraging pharmacokinetic (PK) and pharmacodynamic (PD) responses and showed benefits on the Clinical Dementia Rating (CDR), the ADAS-Cog, and markers of brain metabolism. There is new evidence in mice that a 1200 mg of Benfotiamine further increases thiamine levels with greater cognitive benefits. Thus, we are proposing an 18-month Phase 2A/2B randomized placebo controlled RCT of Benfotiamine testing 600 mg/day and 1200 mg/day in 400 participants early AD, including mild cognitive impairment (MCI) and mild dementia with plasma evidence of amyloid positivity. Our overarching hypothesis is that significant benefits in cognition and global function will occur with doses of Benfotiamine that are safe, well tolerated, and achieve sufficient target engagement. If this Phase 2 trial is successful we have a consolidated seamless phase 3 development plan to expedite Benfotiamine reaching patients. We will test our overarching hypothesis through the following aims:(1) To efficiently determine the highest safe and well-tolerated dose of Benfotiamine in phase 2A (600 mg or 1200 mg) that can be advanced to long term clinical endpoints at 72 weeks; (2) To evaluate the efficacy of benfotiamine in Phase 2B, to benefit (a) global function measured with the CDR sum of boxes (CDR-SB) and (b) cognition measured with ADAS-Cog13 during a treatment period of 72 weeks in early AD; (3) To evaluate the PK (serum thiamine and it's esters) and PD effects (thiamine pyrophosphate activation of transketolase and advanced glycation end-products (AGEs)) of Benfotiamine, and their relation to the primary outcomes; (4) To evaluate the downstream biological effects of treatment with Benfotiamine in early AD on measures of neurodegeneration (cortical thickness on MRI, plasma neurofilament light and total tau), neuroinflammation (glial fibrillary acid prot...