Despite advances in understanding the pathophysiology of Alzheimer’s disease (AD), its therapy remains
largely symptomatic and supportive. Acetylcholinesterase inhibitors - the first-line drugs used today do not
prevent and treat AD. So far, over 90 Phase 3 trials of AD have been unsuccessful with 99.0% failure rate. There is,
therefore, an urgent need to find effective new therapies for AD. Owing to the multifactorial nature of AD pathogenesis,
polypharmacy with drugs that target heterogeneous pathophysiological pathways, needs to be considered.
Fortunately, several drugs used currently in clinical use as monotherapies can be exploited in AD. This article,
therefore, presents a novel pharmacological treatment paradigm and recommends the use of valuable diseasemodifying
approved drugs, viz. melatonin, minocycline, modafinil, and memantine (the “M” Drugs). Melatonin - a
neuroprotector is an antioxidant and anti-inflammatory. Minocycline is also neuroprotective, it reduces neuroinflammation
and CNS pathology and prevents cell death. Sleep deprivation leads to decreased hippocampal neurogenesis, increased amyloid
beta generation, and causes memory dysfunction. Modafinil - a wake-promoting agent is approved for use in narcolepsy and obstructive
sleep apnea. It improves global mental status, hippocampal neurogenesis, attention, and cognition. Memantine is an uncompetitive
N-methyl-d-aspartic acid receptor antagonist and is approved for the management of moderate-to-severe AD. The paramount possible
beneficial effects of the M-drugs may include significant memory and cognitive enhancement in aging, mild cognitive impairment, and
AD. The M drugs-centric pharmacotherapy strategy is comprehensive and pragmatic and is meant to combat multiple pathological targets
and ameliorate cognitive dysfunction/AD.