Source: King’s College London.

A new study published in PLOS Medicine’s Special Issue on Dementia has found that the metabolism of omega-3 and omega-6 unsaturated fatty acids in the brain are associated with the progression of Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative disorder, which causes impaired memory, executive function and language. It accounts for 60 – 80% of total dementia cases worldwide, with over 46 million people suffering from the disease worldwide. The number of patients is estimated to rise to 131.5 million by 2050.

Currently it is thought that the main reason for developing memory problems in dementia is the presence of two big molecules in the brain called tau and amyloid proteins. These proteins have been extensively studied and have been shown to start accumulating in the brain up to 20 years prior to the onset of the disease. However, there is limited information on how small molecule metabolism in the brain is associated with the development and progression of Alzheimer’s disease.

In this study, researchers from King’s College London and the National Institute on Aging in the United States looked at brain tissue samples from 43 people ranging in age from 57 to 95 years old. They compared the differences in hundreds of small molecules in three groups: 14 people with healthy brains, 15 that had high levels of tau and amyloid but didn’t show memory problems and 14 clinically diagnosed Alzheimer’s patients.

They also looked at three different areas in the brain, one that usually shows little tau and amyloid, one that shows more tau and another that shows more amyloid. The main molecules that were different were six small fats, including omegas, which changed in abundance in different regions of the brain.

They found that unsaturated fatty acids were significantly decreased in Alzheimer’s brains when compared to brains from healthy patients.

Co-lead author of the study, Dr Cristina Legido Quigley from King’s College London said: “While this was a small study, our results show a potentially crucial and unexpected role for fats in the onset of dementia. Most surprisingly we found that a supposedly beneficial omega3, DHA, actually increased with the progression of the disease.

“It is now important for us to build on and replicate these findings in a larger study and see whether it corroborates our initial findings.”

Funding: This study was made possible thanks to the generous donation of volunteers from the Baltimore Longitudinal Study of Aging.

Source: Tanya Wood – King’s College London
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study” by Stuart G. Snowden, Amera A. Ebshiana, Abdul Hye, Yang An, Olga Pletnikova, Richard O’Brien, John Troncoso, Cristina Legido-Quigley, and Madhav Thambisetty in PLOS Medicine. Published online March 21 2017 doi:10.1371/journal.pmed.1002266

Abstract

Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study

Background

The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain.

Methods and findings

We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and “asymptomatic Alzheimer’s disease” (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA).

We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10−8, FC = 0.52, q = 1.03 x 10−6), linolenic acid (p = 2.5 x 10−4, FC = 0.84, q = 4.03 x 10−4), docosahexaenoic acid (p = 1.7 x 10−7, FC = 1.45, q = 1.24 x 10−6), eicosapentaenoic acid (p = 4.4 x 10−4, FC = 0.16, q = 6.48 x 10−4), oleic acid (p = 3.3 x 10−7, FC = 0.34, q = 1.46 x 10−6), and arachidonic acid (p = 2.98 x 10−5, FC = 0.75, q = 7.95 x 10−5).

These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life.

Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA.

Conclusions

The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.

“Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study” by Stuart G. Snowden, Amera A. Ebshiana, Abdul Hye, Yang An, Olga Pletnikova, Richard O’Brien, John Troncoso, Cristina Legido-Quigley, and Madhav Thambisetty in PLOS Medicine. Published online March 21 2017 doi:10.1371/journal.pmed.1002266