Contribution of amyloid and tau to cerebrospinal fluid fatty acid indices in preclinical and prodromal Alzheimer’s participants

Abstract

AbstractBackgroundSince Aβ42 derives from membrane‐bound amyloid precursor protein (APP), we propose that membrane lipid composition may influence how APP is processed. Therefore, we aim to determine if fluctuations in fatty acid metabolism accompany amyloid and tau pathology.MethodUsing neuropsychology and ELISA‐based Aβ42/T‐tau measures in CSF, we classify five groups of elderly subjects: c ognitively h ealthy with n ormal Aβ 42/T‐ t au (CH‐NAT, n=36 ), cognitively healthy with pathological Aβ42/T‐tau (CH‐PAT, n=34), and MCI participants with normal or pathological Aβ42/T‐tau (MCI‐NAT, n= 26; MCI‐PAT, n=12), and Alzheimer’s (n=25). We determined the unesterified fatty acid (UFA) levels and the fatty acid composition of CSF nanoparticulate (NP) fraction and supernatant fluid (SF) using GC/MS. We calculated the chain length, unsaturation, and peroxidation indices and the ratio of monounsaturated fatty acid (C18:1, oleic acid) to saturated fatty acid (C18:0, stearic acid) designated the stearoyl‐CoA desaturase (SCD) index.ResultUnesterified chain length, unsaturation, peroxidation, and desaturase indices are higher MCI‐NAT/PAT than in AD. In the SF fraction, fatty acid indices are higher in the prodromal MCI‐PAT state than AD. To determine if SCD could account for differences in unsaturation, we quantified the primary SCD substrate (C18:0) and product (C18:1) in CSF fractions. We found that unesterified C18:0 was lower while C18:1 was higher in MCI‐NAT than the other clinical groups. These changes in C18:0 and C18:1 levels resulted in a higher desaturase index in MCI‐NAT (0.35± 0.15) than in CH‐PAT (0.26±0.16, adjusted p‐value (q) = 0.0230) and AD (0.16±0.11, q < 0.0001). In the SF fraction, C18:0 levels are lower in MCI‐PAT than AD concomitant with a higher C18:1 in MCI‐PAT than AD. These fatty acid differences result in a significantly higher desaturase index in the prodromal MCI‐PAT (0.46±0.15) than in AD (0.28±0.11, q = 0.0067).ConclusionThese studies show an increase in the unsaturation and peroxidation indices in early AD that may result from enhanced brain desaturase activity. These data suggest that fatty acid indices are potential biomarkers of preclinical or prodromal AD. The increase in fatty acid indices followed by a decrease in dementia indicate a need for state or stage‐specific combinatorial preventive therapies.