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Published March 31, 2023 | Version v1
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Changes in Plasma Neutral and Ether-Linked Lipids Are Associated with The Pathology and Progression of Alzheimer?s Disease

Authors/Creators

  • 1. Hosp Univ Santa Maria, Unitat Trastorns Cognitius, Clin Neurosci Res, IRBLleida, Lleida, Spain
  • 2. Univ Lleida, Dept Expt Med, IRBLleida, Lleida, Spain
  • 3. Univ Lleida, Dept Expt Med, IRBLleida, Lleida, Spain; Inst Catala Salut, Lleida, Spain; Fundacio Inst Univ Recerca Atencio Primaria Salut, Res Support Unit Lleida, Lleida, Spain

Description

Aberrant lipid metabolism has been strongly linked to Alzheimer's disease (AD) pathogenesis. However, the role of lipids in the pathophysiological processes of AD and their clinical progression is unclear. We hypothesized that plasma lipids are associated with the pathological hallmarks of AD, progression from mild cognitive impairment (MCI) to AD, and the rate of cognitive decline in MCI patients. To evaluate our hypotheses, we analysed the plasma lipidome profile by liquid chromatography coupled to mass spectrometry in an LC-ESIQTOF-MS/MS platform for 213 subjects recruited consecutively: 104 AD, 89 MCI, and 20 control subjects. Forty-seven (52.8%) MCI patients progressed to AD during follow-up (58 +/- 12.5 months). We found that higher plasma levels of sphingomyelin SM(36:0) and diglyceride DG(44:3) were associated with an increased risk of amyloid beta 42 (A beta 42) positivity in CSF, while levels of SM(40:1) were associated with a reduced risk. Higher plasma levels of ether-linked triglyceride TG(O-60:10) were negatively associated with pathological levels of phosphorylated tau in CSF. Plasma levels of fatty acid ester of hydroxy fatty acid FAHFA(34:0) and ether-linked phosphatidylcholine PC(O-36:1) were positively associated with pathological levels of total tau in CSF. Regarding the plasma lipids most associated with progression from MCI to AD, our analysis detected phosphatidylethanolamine plasmalogen PE(P-36:4), TG(59:12), TG(46:0), and TG(O-62:7). Furthermore, TG(O-62:7) was the lipid that was most strongly associated with the rate of progression. In conclusion, our results indicate that neutral and ether-linked lipids are involved in the pathophysiological processes of AD and the progression from MCI to AD dementia, suggesting the involvement of lipid-mediated antioxidant mechanisms in AD.

Notes

We would like to express our sincere gratitude to all of the patients and all of the members of the dementia unit at the Hospital Universitari Santa Maria. Mariona Jove is a Serra-Hunter Fellow. Farida Dakterzada was supported by the Agency for Management of University and Research Grants and the European Social Fund (FI_B100153).; The Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (PI22/01687) and Agency for Management of University and Research Grants (2021SGR00761) to Gerard Piol-Ripoll. The Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovacin y Universidades) (grant RTI2018-099200-B-I00 and PID2022-143140-OB-I00) , the IRBLleida-Diputaci de Lleida (PP10605-PIRS2021) , and the Government of Catalonia: Agency for Management of University and Research Grants (2021SGR00990) to Reinald Pamplona. This study was co-financed by FEDER funds from the European Union 'A way to build Europe'. IRBLleida is a CERCA Program of the Government of Catalonia.

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