Study Title:

Lack of DHA Linked to Alzheimer's

Study Abstract

Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P = 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P = 0.005) and mid-frontal cortex (P = 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P = 0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r = 0.78; P<0.0001), and negatively with global deterioration scale grades (P = 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P = 0.041), whereas expression of peroxisomal D-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in D-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain.

From press release:

UC Irvine researchers have discovered that markedly depleted amounts of an omega-3 fatty acid in brain tissue samples from Alzheimer's patients may be due to the liver's inability to produce the complex fat, also contained in fish-oil supplements.

Low levels of docosahexaenoic acid, or DHA, have been associated with the chronic neurodegenerative disease affecting millions of Americans, but no cause had been identified.

In postmortem liver tissue from Alzheimer's patients, the UCI team found a defect in the organ's ability to make DHA from shorter molecules present in leafy plants and other foods. Previous studies have shown that most brain DHA is manufactured in the liver.

Non-Alzheimer's livers did not have this defect, said Daniele Piomelli, the Louise Turner Arnold Chair in the Neurosciences and director of the Center for Drug Discovery at UCI, who led the research with Giuseppe Astarita, project scientist in pharmacology.

"We all know Alzheimer's is a brain disease, but our findings -- which were totally unexpected -- show that a problem with liver fat metabolism can make people more vulnerable," Piomelli said. "They also suggest a reason why clinical trials in which Alzheimer's patients are given omega-3 fatty acids to improve cognitive skills have had mixed results."

The study appears Sept. 8 in the open-access, peer-reviewed journal PLoS ONE.

DHA occurs naturally in cold-water fatty fish and seaweed. It is essential for the proper functioning of adult human brains and for the development of our nervous system and vision during the first six months of life. Omega-3 fatty acids are also part of a healthy diet that helps lower risk of heart disease.

"Additionally, we found that the greater the amount of Alzheimer's-related cognitive problems experienced in life by the patients, the lower were their liver DHA levels," Astarita said. "So we do see a connection."

Piomelli added that the results point to new diagnostic and dietary approaches to Alzheimer's: Specific blood lipid profile tests might identify at-risk persons, and dietary supplements with a chemically enhanced form of DHA may benefit early-stage patients.

"Our research isn't advocating that liver metabolism is a key to Alzheimer's," he noted. "The factors causing the disease are many and complex, but we feel this is another piece in the Alzheimer's puzzle."

Study Information

1.Giuseppe Astarita, Kwang-Mook Jung, Nicole C. Berchtold, Vinh Q. Nguyen, Daniel L. Gillen, Elizabeth Head, Carl W. Cotman, Daniele Piomelli, Silvana Gaetani.
Deficient Liver Biosynthesis of Docosahexaenoic Acid Correlates with Cognitive Impairment in Alzheimer's Disease.
PLoS ONE
2010 September
Center for Drug Discovery at UCI.

Full Study

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012538