Omega-3 fatty acid treatment in mild to moderate Alzheimer's disease : results from the OmegAD study

Abstract: Alzheimer's disease (AD) is a major public health concern in all countries with an increasing prevalence. It is expected to quadruple by the year 2047. AD is a progressive neurodegenerative disease with a multifactorial origin, where a body of genetic and biochemical evidence, inflammatory aspects as well as the pivotal role of soluble amyloid β peptide (Aβ) may be the proximate cause of synaptic injuries and neuronal death leading to cognitive and neuropsychiatric decline leading to suffering in both the patient and the caregiver. Today there is no cure for AD, albeit we have access to pharmacotherapy that might improve cognitive and neuropsychiatric symptoms initially in the course of the disease. However, AD continues to progress despite treatment. It is therefore of utter importance to find other pharmacological strategies that might postpone the development of AD and also slow down the cognitive and neuropsychiatric decline in manifest AD. AD patients display lower levels of the omega-3 fatty acid (n-3 FA) docosahexaenoic acid (DHA) in both plasma and brain tissues as compared to age matched controls. Furthermore, epidemiological and animal studies suggest that high intake of DHA might have preventive properties against AD. Little is known, however, of the effects of n-3 FA on AD. Therefore we have conducted the first one year long randomised placebo controlled double-blind trial with six months administration of 2.3 g/day n-3 FA (1.7 g DHA + 0.6 g EPA) or placebo (linoleic acid, LA) followed by six months administration of n-3 FA to patients with mild to moderate AD. In total 204 patients with mild to moderate AD already on stable medication with acetylcholinesterase inhibitors (AChEI) were included. One hundred and seventy four patients fulfilled the trial and the Papers I, II and IV are based on these patients. In a subgroup of these patients lumbar puncture was performed (Paper III). All patients were followed for one year with cognitive, neuropsychiatric and functional evaluations as well as blood tests. In Paper I we conclude that n-3 FA treatment did not delay the rate of cognition as measured with the Mini Mental State Examination (MMSE) and the cognitive subscale of the Alzheimer's disease Assessment Scale (ADAS-cog) nor global status measured with the Clinical Dementia Rating scale (CDR). However, positive effects on cognition were observed in a small group of patients with very mild AD (MMSE >27). Safety and tolerability was good as was compliance measured with plasma levels of DHA, EPA and LA. In Paper II we addressed the effects of supplementation of n-3 FA on the neuropsychiatric, behavioural and functional symptoms using the Neuropsychiatric Inventory (NPI) and the Montgomery Åsberg Depression Rating scale (MADRS). Disability Assessment for Dementia (DAD) and Care givers burden (CGB). The relationship with APOE genotype was assessed. There was no overall treatment effect on neuropsychiatric, behavioural and functional symptoms, but n-3 FA appeared to have positive treatment effects on depression in non-APOEε4 carriers and in agitation in APOE ε4 carriers. In Paper III inflammatory markers in plasma (hs-CRP, IL-6, TNF-α and sIL-RII) and cerebrospinal fluid (CSF, IL-6, TNF-α and sIL-RII) and biological AD markers in CSF (Aβ42, T-tau and P-tau) were analyzed in a subgroup of 35 patients. A correlation at baseline between Aβ42 and sIL-RII was detected albeit no n-3 FA treatment effects were found in neither inflammatory nor biological AD markers. In Paper IV we investigated the hypothesis that supplementation with n-3 FA would affect appetite and weight in relation to inflammatory biomarkers and to APOE ε4 carrier ship. Mean weight and Body Mass Index (BMI) increased at 6 and 12 months in the n-3 FA group. When the placebo group was administered n-3 FA for six months, the weight and BMI also increased significantly within the group. However, there was no significant treatment effect on weight and BMI between the groups. Not carrying the APOEε4 allele and increased DHA were independently associated with weight gain. Caregiver s assessed appetite improved in the n-3 FA treatment group over the treatment period. In conclusion, our study gives some evidence that supplementation with 2.3 g/day n-3 FA to patients with mild to moderate AD may have effects on cognition in the early phases of AD, may reduce depression and agitation depending on APOE ε4 status and increase body weight loss in patients with mild to moderate AD. No effect on possible neuroinflammation in subjects with AD was observed. Supplementation with n-3 FA may be a strategy to add to lifestyle prevention for postponing early cognitive symptoms in AD but more research is needed.