DHA, found in fish and other seafood, is crucial for nervous system function, and its deficiency can impair vision, cognition, and behavior. However, scientists have suggested that DHA supplements have limited benefits for people who already have cognitive disorders like Alzheimer's disease (AD).
A recent study suggests that a "cocktail" of common nutrients, including DHA, may slow cognitive decline in people with mild Alzheimer's disease. Tobias Hartmann, Director of Experimental Neurology at the Medical Faculty of Saarland University in Homburg, Germany, and Director of the German Center for Neurodegenerative Diseases, reported these findings at the AD/PD Conference 2024 in Lisbon, Portugal, from March 5-9, 2024. The research was published in The Journal of Prevention of Alzheimer Disease in March 2024.
In this three-year study, researchers randomly assigned 153 people with mild Alzheimer's disease to receive a combination nutritional supplement containing fish oil (DHA, EPA), vitamins C, E, B12, B6, choline, uridine (uridine monophosphate), folate, and selenium. Another 158 patients received a placebo to compare changes in their cognition and brain structure.
Ultimately, 81 participants (45 in the experimental group and 36 in the control group) completed the trial and underwent examinations. The researchers found that the group taking the supplements experienced a slower decline in cognition compared to the placebo group. Their Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores declined 45% slower, and their hippocampi, a brain region strongly linked to cognitive decline, shrank 33% less.
"Our calculations show that for every year of intervention, disease progression slows down by six months if the intervention starts after three years of disease duration. The exact number varies slightly depending on individual patients," Hartmann told Science and Technology.
He also noted that in this study, the nutrients were only effective in early Alzheimer's disease. "(Participants) were not yet at a severe level of dementia, and they could still live independently at home. We have a subsequent study that targets patients with more severe disease. Multiple nutrient interventions may be less effective in them."
This study is part of LipiDiDiet, a research project involving multiple institutions in several European countries. LipiDiDiet began in 2007 with funding from the European Union and several companies to investigate the effects of nutritional lipids on aging, Alzheimer's disease, and vascular dementia. It uses a proprietary nutrient formula called Fortasyn Connect (marketed as Souvenaid). Since 2017, the project's interim results have been published in journals such as The Lancet Neurology and Alzheimer's & Dementia.
Fish Oil Supplement Conundrum
Despite the hype surrounding fish oil's DHA content for brain health in nutritional supplement advertisements, no clinical trials have definitively proven that DHA supplements alone have significant therapeutic effects on Alzheimer's disease.
Alzheimer's disease, commonly known as dementia, is a neurodegenerative disease with an insidious onset and a long course. In the brains of patients, neurofibrillary tangles and amyloid plaques form, leading to neuronal death. Over several years or decades of illness, patients gradually develop cognitive impairments, memory loss, physical dysfunction, and ultimately become unable to care for themselves until they die.
As the global population ages, the number of people with Alzheimer's disease is rising. In China, for example, a recent nationwide cross-sectional study found that there are 15.07 million people with cognitive impairment aged 60 and over, of which nearly 10 million have Alzheimer's disease. Dementia is not exclusively a disease of the elderly, and there is a trend toward a younger age of onset; currently, approximately 12.5% of those affected are between 40 and 60 years old.
There are currently no drugs that can cure Alzheimer's disease, but studies have indicated that a healthy lifestyle and specific dietary habits can help reduce the risk of developing it. Among these, DHA, which is abundant in fish oil, has been a promising candidate.
DHA (docosahexaenoic acid) is an Omega-3 unsaturated fatty acid that is essential for neurodevelopment and cognitive function but has a low synthesis efficiency in the body and must be obtained through diet. Researchers have found that specific dietary regimens rich in DHA have some preventive effects against Alzheimer's disease, such as the so-called "Mediterranean diet." DHA and Alzheimer's Disease: A Complex Relationship
In 2016, a meta-analysis published in The American Journal of Clinical Nutrition indicated that every 0.1 grams of DHA consumed daily was associated with a 37% reduction in Alzheimer's disease (AD) risk when comparing diets from different countries.
Through pathological studies, scientists have discovered that DHA is involved in several physiological processes closely related to AD. DHA can directly affect amyloid plaque formation both in vivo and in vitro, and it can influence and improve neuronal signal transduction and learning ability, and promote neuronal differentiation and development in the hippocampus. Moreover, DHA can modulate cell death and injury size after hypoxic-ischemic injury and suppress neuroinflammatory signaling.
Although DHA has shown various benefits against AD in dietary meta-analyses and pathological studies, researchers often find disappointing results when attempting to manipulate dietary DHA content through supplementation in controlled trials. Multiple studies have found that despite supplementation increasing blood DHA levels, its effects on mitigating cognitive decline and dementia are minimal. In 2016, a study published in JAMA even found that eating one serving of seafood per week was more effective in delaying AD progression than daily DHA supplementation.
One explanation for this discrepancy is that the amount of DHA from supplements reaching the brain is limited. When DHA supplements are ingested, they first enter the plasma, and only a small fraction crosses the blood-brain barrier into the cerebrospinal fluid (CSF). In a study published in EBioMedicine in 2020, researchers gave participants 2000 mg of DHA supplementation daily and found that while their plasma DHA levels increased by 200%, their CSF DHA levels increased by only 28%.
Furthermore, even if CSF DHA concentrations are increased, it is still unclear whether this DHA can be converted into functionally active DHA within critical brain structures affected in AD. Research suggests that different forms of DHA from diet and supplements have distinct metabolic fates in the body, influencing their uptake and utilization in the brain.
Balanced and Long-Term Nutrition as a Possible Key
While the clinical trial led by Dr. Hartmann showed promising results, the study used a multi-nutrient supplement, making it difficult to pinpoint the effects specifically to its DHA component.
Moreover, the combination supplement provided near or above the recommended daily allowance (RDA) of almost all its ingredients, such as vitamins B and E, which individually have shown weak effects in pathological studies of cognitive impairment. Dr. Hartmann explained to 澎湃科技 that the intention of this supplement was to target multiple pathological mechanisms.
"Alzheimer's disease does not only lead to one pathological phenomenon. Brain damage is not limited to one type, but causes multiple different types of damages and pathological phenomena. Therefore, we determined the nutritional elements needed based on each pathological phenomenon, and combined these nutrients. By doing so, we can gain a cumulative effect and achieve better intervention results," he said.
The study also adhered to the RDA set by the American Nutrition Society for common nutrients included in the supplement, such as 3 μg of vitamin B12 (25% above RDA) and 400 μg of folate (meeting the RDA).
Although the mechanism remains unclear, the protective effects of this multinutrient supplement on AD suggest that comprehensive and balanced nutrient intake may be more effective than single nutrient approaches. Additionally, Dr. Hartmann believes that maintaining such balanced nutrition over an extended period may also contribute to its benefits.
He stated that taking fish oil, for example, "In the short term, this nutrient does not have an immediate effect. Only long-term intake can take effect. We found that it takes half a year or longer for this nutrient to start affecting the cognitive abilities of the experimental group, and this effect increases over time."
Identifying Culturally Adapted Nutrients and Dietary Patterns
The study's multi-supplement containing fish oil showed some efficacy in slowing AD progression in a European sample. However, it is necessary to investigate whether the same formulation will be effective in Chinese patients, given the different genetic backgrounds and the dosages being based on US norms.
To address this question, 澎湃科技 interviewed Professor Liu Jun, Deputy Director of the Neurosciences Institute of Guangzhou Medical University and Director of the Department of Neurology at the Second Affiliated Hospital of Guangzhou Medical University. He believes that more research is needed to confirm the effects of these nutrients in Chinese patients but that some nutrients may have universal benefits.
"(Foreign populations) may have different genetic backgrounds. We need to verify these findings in Asian and Chinese samples, which will take time," he said. "From a nutritional perspective, lipid metabolism and similar processes may be more closely related to genetics, but omega-3 polyunsaturated fatty acids may have less of a relationship with genetic factors."
Professor Liu emphasizes the importance of early prevention and intervention for AD, given its long disease course and high care costs. "If clinical symptoms are present, it means that amyloid plaques have already accumulated in the brain for at least 20 years. Treatment at this stage is quite late," he said.
"For families with an AD patient, the average annual cost is 132,000 CNY," he added. "The latest drug, lecanemab, costs 180,000 CNY per year, bringing the total annual cost to around 300,000 CNY."
"Current medications primarily [intervene] on acetylcholine levels in the brain, rather than fundamentally protecting neurons and preventing brain nerve cell death. They treat symptoms without addressing the root cause," Professor Liu Jun told the澎湃科技 (The Paper). "Prevention and treatment of this disease should start with a healthy diet, supplemented with nutrients that have evidence-based medical evidence, in order to delay the progression of the disease."
Regarding what kinds of nutritional supplements and diets Chinese people should use to prevent and treat Alzheimer's disease, Professor Liu Jun emphasized that functional nutritional supplements must have a rigorous evidence-based medical basis. It is necessary to seek further specific advice from professional institutions and medical professionals. In terms of diet, a balanced eating style should be sought that both conforms to Chinese dietary habits and has therapeutic effects.
"The Mediterranean diet requires eating nuts, olive oil, and deep-sea fish, which contain a variety of nutrients. However, Chinese people are not used to eating the Mediterranean diet, and if you ask them to eat it every day, they definitely won't be able to tolerate it," Professor Liu Jun said. "So we are also looking to see what beneficial dietary approaches exist among the many cuisines of China's vast land and abundant resources that could be beneficial for delaying this disease. I believe that we need to continue exploring and researching."
