Constantine Kaniklidis

  • Designation: No Surrender Breast Cancer Foundation (NSBCF)
  • Country: USA
  • Title: Melatonin in Neurodegenerative Disease: Review of Benefits in Alzheimer’s Disease and Mild Cognitive Impairment (MCI)


The author, Constantine Kaniklidis, currently serves as Research Director of the No Surrender Breast  Cancer  Foundation (NSBCF), and is a member of Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART), and of the Society for Integrative Oncology (SIO), exploring the frontier edge of oncology and neurology, as suggested in his recent publication “The Role of Melatonin in COVID-19 Treatment and in Neurocognitive Health - Commentary and Call to Action” [Cur Practice  Med Sci, 2022], following up his earlier paper on Melatonin at the Crossroads [Integr Cancer Sci Therap, 2020].


Alzheimer’s disease (AD) and related dementias remain an under-recognized but critically urgent public health crisis, often devastating in personal and societal impact, and with aggregate costs of $405 billion, projected to rise to $3.3 trillion in 2060, currently affecting 6.9 million older U.S. citizens, 13.8 million in 2060, almost two thirds being women, with Blacks and Hispanics disproportionately affected, and with a lifetime risk of development of 1 in 5. Globally, someone develops dementia every 3 seconds, and these statistics are known to be in fact underestimations.

 It is against this bleak context that this review examines the promising potential role of the chronobiotic agent melatonin in widening the spectrum of treatment options for AD and related dementias. Melatonin represents an element of what we call “integrative neurology” along with such other non-pharmacological interventions as exercise, diet, and the normalization of sleep patterns, and one moreover that, unlike conventional agents, shows high tolerability, safety and affordability. 

 As we demonstrate, melatonin functions as a neuroprotective agent against the pathogenesis of AD. Multiple studies have shown that melatonin can diminish beta-amyloid generation, inhibiting its assembly, and ultimately reducing the risk of the neurodegenerative process, and also improving cognitive function and sleep quality in AD patients.  These benefits stem, as we show, largely from melatonin’s well-documented anti-inflammatory, antioxidant, anti-fibrillogenic, anti-hyperphosphorylating, anti-amyloidogenic activities, and mitochondrial modulatory effects, as well as its powerful immunomodulatory activity against pro-inflammatory molecules. Thus one recent systematic review and network meta-analysis compared over a short term (12+ weeks) the efficacy on cognitive function of supplemental melatonin with donanemab (N3pG), lecanemab (Leqembi), and aducanumab (Aduhelm) in those with mild AD and mild cognitive impairment (MCI), finding that melatonin was significantly more effective than all three agents, and placebo, suggesting that melatonin may be a superior potential disease-modifying therapy against cognitive decline in mild AD and MCI, as also concluded by multiple other studies, reviews, and meta-analyses. In contrast, given continued debate about whether lecanemab’s statistically significant benefit of reduction in cognitive decline is in fact a clinically meaningful one, coupled with a narrow benefit/harm ratio given the small but non-trivial risk of brain swelling and bleeding and its high cost has led the American Geriatrics Society to recommend caution in it’s deployment, reflected in the drug’s slow uptake among clinicians.

 We discuss these developments here in our own review in the context of melatonin’s contribution to this urgent public health crisis, critically surveying the current state of knowledge and assessing the strength of the aggregated evidence to date. We close by examining some exciting developments on the forward horizon, with new synergies, and some promising clinical trials at or nearing completion.

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