Omega-3 Fatty Acids Increase Amyloid-β Immunity, Energy, and Circadian Rhythm for Cognitive Protection of Alzheimer’s Disease Patients Beyond Cholinesterase Inhibitors

Article type: Research Article

Authors: Fiala, Milan^{a; b; *} | Lau, Yik Chai Charles^{a; b} | Aghajani, Anthony^{a; b} | Bhargava, Sneha^{a; b} | Aminpour, Eli^{a; b} | Kaczor-Urbanowicz, Karolina Elżbieta^{a; c} | Mirzoyan, Hayk^{a; b} | Nichols, India^d | Ko, Meng-Wei^a | Morselli, Marco^b | Santana, Joslyn^{a; b} | Dang, Johnny^{a; b} | Sayre, James^e | Paul, Ketema^d | Pellegrini, Matteo^b

Affiliations: [a] Division of Oral Biology and Oral Medicine, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA | [b] Department of Molecular, Cell, and Developmental Biology, UCLA School of Life Sciences, Los Angeles, CA, USA | [c] UCLA Institute for Quantitative and Computational Biosciences, Los Angeles, CA, USA | [d] Department of Integrative Biology and Physiology, UCLA School of Life Sciences, Los Angeles, CA, USA | [e] UCLA School of Public Health, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Milan Fiala, 3000C Terasaki Bldg, 610 Charles Young Dr. East, Los Angeles, CA 90095, USA. Tel.: +1 310 206 6392; Fax: +1 310246 1321; E-mail: fiala@mednet.ucla.edu.

Abstract: Background:The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer’s disease (AD) are palliative for a limited time. Objective:To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. Methods:We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients. Results:MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitro ω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. Conclusion:Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.

Keywords: Amyloid-beta, bioenergy, cell signaling, cholinesterase inhibitor, glycolysis, ω-3 fatty acids, phagocytosis, tricarboxylic cycle

DOI: 10.3233/JAD-200252

Journal: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 993-1002, 2020