Why Have the Benefits of DHA Not Been Borne Out in the Treatment and Prevention of Alzheimer’s Disease? A Narrative Review Focused on DHA Metabolism and Adipose Tissue

Abstract

Docosahexaenoic acid (DHA), an omega-3 fatty acid rich in seafood, is linked to Alzheimer’s Disease via strong epidemiological and pre-clinical evidence, yet fish oil or other DHA supplementation has not consistently shown benefit to the prevention or treatment of Alzheimer’s Disease. Furthermore, autopsy studies of Alzheimer’s Disease brain show variable DHA status, demonstrating that the relationship between DHA and neurodegeneration is complex and not fully understood. Recently, it has been suggested that the forms of DHA in the diet and plasma have specific metabolic fates that may affect brain uptake; however, the effect of DHA form on brain uptake is less pronounced in studies of longer duration. One major confounder of studies relating dietary DHA and Alzheimer’s Disease may be that adipose tissue acts as a long-term depot of DHA for the brain, but this is poorly understood in the context of neurodegeneration. Future work is required to develop biomarkers of brain DHA and better understand DHA-based therapies in the setting of altered brain DHA uptake to help determine whether brain DHA should remain an important target in the prevention of Alzheimer’s Disease.

How Alpha Linolenic Acid May Sustain Blood–Brain Barrier Integrity and Boost Brain Resilience against Alzheimer’s Disease

“…DHA supplementation has shown inconclusive results of both positive and negative effects related to BBB integrity [ 59 ] and improvement in AD symptoms [ 60 ]. This may be due to the inhibitory effects of DHA on ALA metabolism [ 55 ] and the lower formation of intermediate n-3 FA like EPA, also needed for membrane phospholipids building.…”

Advances in the study of the relationship between Alzheimer's disease and the gastrointestinal microbiome

“…Second, whether supplementation with omega‐3 FA can improve AD has not yet been determined. Some evidence currently suggests that it is only effective in mild AD, some experiments show that supplementation with omega‐3 FA does not have a significant effect, and some literature even shows that DHA does not work at all 77 . However, the use of omega‐3 FA for therapeutic purposes is now mostly in animal experiments and less in clinical trials.…”

DHA supplementation and pregnancy complications

“…For example, Colombo et al found that prenatal DHA may positively affect infants’ attention and regulation [ 21 ], whereas Gould et al observed no benefit of prenatal DHA supplementation on child behavior; on the contrary, the results of Gould et al suggest an adverse effect of DHA on behavioral functioning [ 22 ]. Clarifying the mechanism of action of DHA can help guide supplementation during pregnancy [ 23 ].…”