Is DHA Transport Altered in Alzheimer's Disease?
Several reports have documented the relationship between low intakes of fish or long-chain omega-3 PUFAs (n-3 LC-PUFAs) and an increased risk of developing Alzheimer’s disease or cognitive decline. Some areas of the brain, such as the orbitofrontal cortex, may gradually lose DHA with age. In one study, patients deceased with Alzheimer’s disease had less brain DHA than non-demented controls, but another report found no differences between the two groups. Individuals with Alzheimer’s disease develop synaptic damage, intracellular neurofibrillary tangles (insoluble twisted fibers in neurons) and abnormal accumulation of amyloid plaques between neurons. DHA has been implicated in many of these symptoms. For example, dietary DHA reduced the accumulation of the abnormal protein beta-amyloid, in animal models of Alzheimer’s disease.
DHA is also linked to neuroprotective effects in models of Alzheimer’s disease through a metabolite, neuroprotectin D1 (NPD1). This docosanoid has been shown to counteract the neuroinflammation and neuronal apoptosis (programmed cell death) associated with Alzheimer’s disease and to reduce the production of Aβ42, a protein that promotes the toxic effects of the disease.
These reports might suggest that increasing dietary intake of fish, DHA or n-3 LC-PUFAs, could slow the progress of Alzheimer’s disease, but results of such interventions have been disappointing. A recent randomized controlled trial of DHA supplementation (2 g/day) in individuals with mild to moderate Alzheimer’s disease did not slow the rate of cognitive decline in these patients. Similar results were reported in a different study of patients with mild to moderate disease, but in this study, a subgroup of patients with very mild symptoms experienced a significant reduction in cognitive decline. Other studies have reported a benefit from fish oil or DHA consumption in older individuals with mild symptoms of age-related cognitive decline. However, we do not know when it is most effective to intervene and what an effective dose might be. It has been reported that fish oil supplementation is without effect on cognitive function in older adults with healthy cognition.
Another complication in human trials with n-3 LC-PUFAs or DHA and cognition is the confounding effect of the APOE4 allele. Carriers of this gene variant fail to respond to dietary n-3 LC-PUFAs or fish intake and face a higher risk of Alzheimer’s disease than non-carriers. A recent analysis of the prevalence of APOE4 carriers among those diagnosed with Alzheimer’s disease reported prevalences as high as 61% in Northern Europe and as low as 40% in Southern Europe. The prevalence was 57% in North America. Thus, the susceptibility to Alzheimer’s disease associated with the APOE4 allele varies substantially with geography and the genetic background of the population.
Even with this information, there are limited data on fatty acid profiles in older adults as they age. Do fatty acid profiles in blood change with the development of impaired cognition? Plasma phospholipids in elderly individuals contain greater concentrations of n-3 LC-PUFAs compared with younger adults. Red cell membranes also increase in n-3 LC-PUFAs with age. What happens in the brain?
These questions were the focus of researchers in the laboratory of Stephen Cunnane, Université de Sherbrooke, Québec, who studied the fatty acid profiles in the plasma phospholipids and brain tissues of deceased participants in the Memory and Aging Project. The project is a prospective cohort study on the clinical neuropathology of residents in the Chicago area retirement communities. Participants were 85 years of age on average and free of clinically diagnosed dementia at enrolment. Every year each participant underwent a structured clinical evaluation including a neurological examination and neuropsychological testing. Organs were donated at death. Thirty-six cases randomly selected before death as having normal cognition, mild cognitive impairment or Alzheimer’s disease had postmortem brain autopsies for phospholipid fatty acid analysis in 3 regions of the cortex: the superior temporal gyrus, midfrontal gyrus and angular gyrus. Plasma collected an average of one year earlier was available for 26 of the 36 cases.
Plasma free fatty acids for total, oleic, linoleic and total n-6 fatty acids were significantly and markedly decreased (range 43% to 80%) in participants with mild cognitive impairment or Alzheimer’s disease compared with cognitively normal participants. In contrast, free DHA and total n-3 PUFAs were not significantly reduced in Alzheimer’s patients.
However, in the total plasma phospholipids, DHA concentrations were 30% to 50% lower and alpha-linolenic acid concentrations 8 times higher in the Alzheimer’s participants compared with unimpaired individuals (Table). Similarly, EPA concentrations were approximately 44% lower in the Alzheimer’s patients. There were no significant differences among the groups in any n-6 PUFAs.
In the brain, the main difference in fatty acid composition among the groups was a significant decrease in DHA in the Alzheimer’s participants in the phosphatidylserine phospholipids of the mid-frontal and superior temporal cortex. Reductions varied from 12% to 14% in these regions. There were no differences in the fatty acids of the other phospholipid classes. The authors noted that DHA in the phosphatidylserine of neuronal cell membranes inhibits neuronal cell death and would be neuro-protective in Alzheimer’s disease.
When the associations between plasma and brain phospholipid fatty acid compositions were analyzed, only the percent DHA in plasma total phospholipids and brain DHA phosphatidylethanolamine in the angular gyrus of cognitively unimpaired individuals were significant. These data also suggest that plasma phospholipid fatty acids are a poor indicator of brain cortex fatty acid concentrations. However, variability in the analytical data and the relatively small sample size may have contributed to the lack of statistical significance.
These observations raise intriguing questions. The first is that DHA content in the brains of Alzheimer’s patients may not be reduced compared with cognitively unimpaired individuals as was previously reported. Another is that several plasma fatty acids differed significantly among the cognitive groups when expressed as concentrations (mg/dL) in total phospholipids, but not when expressed as percent composition. If plasma phospholipid fatty acid concentrations are not correlated with brain cortex fatty acids, is there another biomarker that better reflects cortex fatty acid concentrations? Red blood cells have been significantly correlated with cerebral cortex fatty acids previously.
The investigators suggested that the observed differences in plasma phospholipid DHA between Alzheimer’s patients and unimpaired individuals might reflect altered plasma fatty acid transport in Alzheimer’s disease. This notion is consistent with the higher uptake of DHA from supplementation in older individuals and the altered transport of DHA through plasma lipid classes as reported by this laboratory. The investigators did not examine the fatty acids in red blood cells, a possible transport mechanism for n-3 LC-PUFAs to the brain and no dietary data were available. These thought-provoking observations contradict previously reported changes in DHA metabolism in aging and Alzheimer’s disease and ensure that the quest for more detailed understanding of fatty acid metabolism in Alzheimer’s disease will continue.
Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, Morris MC. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 2012;29:691-697. PubMed
Calon F. Omega-3 polyunsaturated fatty acids in Alzheimer’s disease: key questions and partial answers. Curr Alzheimer Res 2011;8:470-478. PubMed
Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011;72:1577-1584. PubMed
Millichap JG, Yee MM. The diet factor in attention-deficit/hyperactivity disorder. [Review] Pediatr 2012;129:330-337. PubMed
Richardson AJ. Review: ω-3 fatty acids produce a small improvement in ADHD symptoms in children compared with placebo. Evid Based Ment Health 2012; Feb 18. [Epub ahead of print] PubMed