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

Summary

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.

Key Points

• 1Unsaturated fatty acid levels are significantly altered in Alzheimer disease patients
• 2The study includes a comparison of brain tissue from healthy controls and individuals with different levels of AD pathology
• 3Key fatty acids showed distinct trends based on cognitive performance and AD neuropathology
• 4The findings indicate that fatty acid metabolism could influence Alzheimer disease symptom expression
• 5The study has limitations due to a relatively small sample size and focus on post-mortem analysis.

Related articles

• How to Assess the Quality of Qualitative Research

  This article serves as a guide for health care practitioners, educators, and researchers on how to evaluate the quality of qualitative research. It discusses essential characteristics that make a qualitative study high-quality and trustworthy, as well as standards specific to this type of research.

• CHOLEGRAPHY Easy Visual Reviewer - Terms & Definitions Matrix Based on Module

  This document serves as an educational resource on cholegraphy, outlining procedures, indications, contraindications, and care related to the imaging of the biliary system. It is designed as a visual reviewer for learners in health sciences.

• Routine CT Procedures and Related Anatomy Visual Study Reviewer Matrix

  This document serves as a comprehensive reviewer for technologists involved in routine CT examinations, detailing essential procedures, patient preparations, and anatomical landmarks essential for accurate imaging.

• Investigating Genetic Counselors' Inclusion of Sponsored Genetic Testing Programs

  This study aims to investigate genetic counselors' awareness and attitudes toward sponsored genetic testing programs, as well as the factors influencing their decisions to offer these tests to patients. The importance of understanding these dynamics arises amid the growing availability of biopharmaceutical-sponsored genetic tests and the impact of financial considerations on patient access to care.

• Nature-Based Mindfulness: A Qualitative Study of the Experience of Support for Self-Regulation

  This qualitative study investigates how a five-day residential mindfulness program in a natural setting supports self-regulation among university students experiencing stress. Through interviews, the study explores participants' lived experiences and the perceived benefits of the mindfulness retreat.