Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

Abstract

Alzheimer's disease (AD) pathology is characterized by an early and prolonged decrease in the amyloid peptide (Aβ) levels concomitant with a later increase in phosphotau concentrations in cerebrospinal fluid (CSF). We propose that changes in lipid metabolism can contribute to the abnormal processing of Aβ 42 in AD. Our aim was to determine if polyunsaturated fatty acid (PUFA) metabolism can differentiate presymptomatic AD from normal aging and symptomatic AD. Using neuropsychology measures and Aβ 42 /T-tau in cerebrospinal fluid (CSF), we classify three groups of elderly study participants: cognitively healthy with normal Aβ 42 /T-tau (CH-NAT), cognitively healthy with pathological Aβ 42 /T-tau (CH-PAT), and AD individuals. We determined the size distribution and the concentration of CSF particles using light scattering and quantified PUFA composition in the nanoparticulate (NP) fraction, supernatant fluid (SF), and unesterified PUFA levels using gas chromatography combined with mass spectrometry. Four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were enriched in NP of AD compared with CH-NAT. C20:3n-3 levels were higher in the NP fraction from AD compared with CH-PAT. When normalized to the number of NPs in CSF, PUFA levels were significantly higher in CH-NAT and CH-PAT compared with AD. In the SF fractions, only the levels of docosahexaenoic acid (DHA, C22:6n-3) differentiated all three clinical groups. Unesterified DHA was also higher in CH-NAT compared with the other clinical groups. Our studies also show that NP PUFAs in CH participants negatively correlate with CSF Aβ 42 while C20:4n-6, DHA, and n-3 PUFAs in the SF fraction positively correlate with T-tau. The profile of PUFAs in different CSF fractions that correlate with Aβ 42 or with T-tau are different for CH-NAT compared with CH-PAT. These studies show that PUFA metabolism is associated with amyloid and tau processing. Importantly, higher PUFA levels in the cognitively healthy study participants with abnormal Aβ 42 /T-tau suggest that PUFA enhances the cognitive resilience of the pre-symptomatic AD population. We propose that interventions that

Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer’s Biomarkers Precedes Lipolysis in the Dementia Stage

“…30–200 nm-sized particles that we described in CSF to have neurotransmitters, lipids, active enzymes, and signaling functions and are likely derived from brain cells via exocytosis and vesicle signaling ( Harrington et al, 2009 ). We also reported that these nanoparticles are rich in the GP class of lipids, with compartmentalization between the SF and NP fractions of CSF ( Fonteh et al, 2013 , 2015 , 2020 ). Here, we provide evidence to support this hypothesis by finding that GPs and SPs in both SF and NP fractions are higher in CH-PATs and lower in dementia.…”

“…Neither medications nor measured blood lipids differ between the CH-NAT, CH-PAT, and AD groups ( Harrington et al, 2013 ; Chew et al, 2020 ). The comprehensive dietary questionnaire was only analyzed with confidence in the CH sub-groups to avoid any bias from impaired memories in those with dementia; the dietary lipid intake did not differ between CH-NAT and CH-NAT participants ( Fonteh et al, 2020 ). These results suggest that the changes mentioned above in GPs and SPs in biochemical and dementia stages likely result from the brain pathophysiology.…”

“…We determined the number and size distribution of NPs in CSF using a NanoSight NS300 instrument (Malvern Panalytical, Inc., Westborough, MA, United States; Fonteh et al, 2020 ). Briefly, after centrifugation at 3,000 RCF for 3 min to remove cellular debris, we diluted CSF (10×) using dd-H 2 O.…”

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…AA increased in brains, erythrocytes, and CSF of AD individuals (Thomas et al, 2016;Goozee et al, 2017;Fonteh et al, 2020). LA decreased in AD brain and plasma (Snowden et al, 2017;Cunnane et al, 2012).…”

“…DHA decreased in brains, circulation, and CSF of AD individuals (Fonteh et al, 2014(Fonteh et al, , 2020de Wilde et al, 2017;Snowden et al, 2017;Hosseini et al, 2020). EPA decreased in brain and circulation of AD individuals (Hosseini et al, 2020).…”