Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study

Article type: Research Article

Authors: Jernerén, Fredrik^{a; *} | Cederholm, Tommy^{b; c} | Refsum, Helga^{d; e} | Smith, A. David^e | Turner, Cheryl^e | Palmblad, Jan^f | Eriksdotter, Maria^{c; g} | Hjorth, Erik^g | Faxen-Irving, Gerd^g | Wahlund, Lars-Olof^g | Schultzberg, Marianne^g | Basun, Hans^b | Freund-Levi, Yvonne^{g; h; i; j}

Affiliations: [a] Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden | [b] Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden | [c] Theme Ageing, Karolinska University Hospital, Stockholm, Sweden | [d] Department of Nutrition, University of Oslo, Oslo, Norway | [e] Department of Pharmacology, University of Oxford, Oxford, United Kingdom | [f] Departments of Medicine and Hematology, Karolinska University Hospital Huddinge, and the Karolinska Institutet, Stockholm, Sweden | [g] Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden | [h] Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden | [i] Department of Psychiatry in Region Örebro County and School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro | [j] Department of Old Age Psychiatry, Psychology & Neuroscience, King’s College, London, UK

Correspondence: [*] Correspondence to: Fredrik Jernerén, Department of Pharmaceutical Biosciences, Uppsala University, Husargatan 3, Box 591, 75124, Uppsala, Sweden. Tel.: +46 0 184714224; E-mail: [email protected].

Abstract: Background:Trials of supplementation with omega-3 fatty acids (ω3-FAs) in patients with mild cognitive impairment or Alzheimer’s disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and ω3-FAs in relation to brain atrophy and cognitive decline. Objective:We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of ω3-FAs supplementation on cognitive performance in moderate AD. Methods:This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE≥15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA. Results:We found significant interactions between ω3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels <11.7μmol/L, ω3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (–22.3%, 95% CI: –5.8 to –38.7%, p = 0.009) compared with placebo. Conclusion:The effect of ω3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of ω3-FA on cognition.

Keywords: Alzheimer’s disease, B vitamins, cognition, dementia, homocysteine, omega-3 fatty acids

DOI: 10.3233/JAD-181148

Journal: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 189-197, 2019