An increase in fatty acid indices in cerebrospinal fluid of mild cognitive impairment precedes a decrease in Alzheimer’s

Abstract

AbstractBackgroundProcessing of membrane‐bound amyloid precursor protein (APP) may produce toxic amyloidogenic or less toxic non‐amyloidogenic amyloid (Aβ) peptides. We propose that brain membrane lipid composition and metabolism can dictate APP processing.MethodUsing neuropsychology measures, brain MRI, and consensus clinical conferencing, we classify three groups of elderly subjects: cognitively healthy (CH, n=70), mild cognitive impairment (MCI, n=40), and Alzheimer’s disease (AD, n=25). We fractionated CSF and determined the fatty acid composition of the unesterified fatty acid (UFA), the supernatant fluid (SF), and the nanoparticulate (NP) fraction using gas chromatography coupled with negative ion/chemical ionization mass spectrometry. We determined fatty acid indices for each fraction for chain length, unsaturation, peroxidation, and desaturase.ResultChain length, unsaturation, peroxidation, and desaturase indices were significantly different in the CSF fractions (p<0.0001). UFA carbon‐chain length, unsaturation, and peroxidation indices were higher in CH and MCI than in AD. In contrast, these indices did not significantly differ in the other CSF fractions. The UFA desaturase index was significantly higher in MCI (0.32±0.14) than in CH (0.26±0.2, adjusted p‐value (q) = 0.0220)) and AD (0.16±0.11, q <0.0001). In the SF and NP fractions, the desaturase index was lower in AD than MCI and CH. The changes in fatty acid indices were not associated with age, sex, BMI, and ApoE genotype.ConclusionOur studies show the compartmentalization of fatty acid metabolism in CSF fractions and changes in the AD spectrum. A higher carbon chain length, unsaturation, peroxidation, and desaturase index in MCI suggest higher lipid membrane turnover. A lower desaturase, peroxidase, and desaturase index in AD suggests enhanced lipolysis and oxidation of lipids. These data suggest that lipolysis and oxidation are features of AD pathophysiology, and monitoring fatty acid indices can help effectively monitor new therapies.