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.