The window between normal aging and dementia represents a critical intervention point where strategic medication management could alter cognitive trajectories for millions of adults. With 5-15% of people with mild cognitive impairment progressing to dementia annually, identifying effective pharmaceutical approaches has become increasingly urgent as populations age globally. This comprehensive analysis of 25 years of clinical evidence reveals a surprising hierarchy of therapeutic effectiveness that challenges common assumptions about cognitive enhancement. Traditional cognitive enhancers like cholinesterase inhibitors showed limited benefit in MCI patients, despite their established role in dementia treatment. Instead, the most promising interventions emerged from systematic medication optimization: reducing anticholinergic burden from common medications, eliminating unnecessary sedatives, and preventing iatrogenic complications like excessive blood pressure lowering or hypoglycemia. Disease-modifying approaches targeting amyloid or tau proteins largely failed to demonstrate clinically meaningful improvements, while vascular risk management through individualized blood pressure control and diabetes management showed more consistent cognitive protection. The review identified nootropic compounds and adjuvant formulations as areas requiring better-designed trials, noting that current evidence remains insufficient for routine clinical use. This evidence synthesis suggests that the most effective pharmacological strategy for MCI may be subtractive rather than additive—systematically removing cognitive threats from existing medication regimens while carefully managing cardiovascular risk factors. The approach represents a paradigm shift from seeking new cognitive enhancers toward optimizing the pharmaceutical environment in which aging brains operate, potentially offering more immediate and practical benefits for the growing population at cognitive risk.