Abstract INTRODUCTION Agents targeting metabolic/vascular disorders are promising candidates to treat Alzheimer's disease (AD) and enhance safety and efficacy of other therapies. METHODS In a 2×2 factorial double‐blinded randomized trial, participants with mild cognitive impairment (MCI), early AD, or who were amyloid positive received intranasal insulin (INI; 40 IU q.i.d.), the sodium–glucose cotransporter‐2 inhibitor empagliflozin (10 mg q.d. oral tablet), both, or placebo for 4 weeks. The primary outcome was treatment‐related adverse events (TRAEs). Secondary outcomes included the modified Preclinical Alzheimer's Cognitive Composite‐5 (mPACC5), fluid biomarkers, cerebral blood flow (CBF), and fractional anisotropy (FA). RESULTS TRAEs were mild and similar for all groups. INI increased mPACC5, modulated FA and CBF, and reduced plasma glial fibrillary acidic protein. Empagliflozin lowered cerebrospinal fluid tau and modulated CBF. Both agents moderated immune/inflammatory/neurovascular markers. DISCUSSION INI and empagliflozin treatment was safe with promising effects on cognition, fluid, and imaging biomarkers. A longer and larger trial is needed to confirm these results. CLINICAL TRIAL REGISTRATION NCT05081219 Highlights Agents targeting metabolic or vascular disorders are promising candidates to prevent or treat Alzheimer's disease (AD). Intranasal insulin and empagliflozin were safe alone or in combination for mild cognitive impairment/AD. Insulin improved cognition and markers of inflammation and immune function. Empagliflozin reduced markers of vascular injury and neurodegeneration. A longer, larger trial is needed to validate these results.
Erichsen et al. (2025) studied this question.