Serum unsaturated phosphatidylcholines predict longitudinal basal forebrain degeneration in Alzheimer’s disease
Abstract
Basal forebrain cholinergic neurons are among the first cell types affected by Alzheimer’s disease pathology, but the cause of their early vulnerability is unknown. The lipid phosphatidylcholine is an essential component of the cell membrane, and phosphatidylcholine levels have been shown to be abnormal in the blood and brain of Alzheimer’s disease patients. We hypothesized that disease-related changes in phosphatidylcholine metabolism may disproportionately affect basal forebrain cholinergic neurons due to their extremely large size, plasticity in adulthood and unique reliance on phosphatidylcholine for acetylcholine synthesis. To test this hypothesis, we examined whether serum phosphatidylcholine levels predicted longitudinal basal forebrain degeneration in Alzheimer’s disease. All data were collected by the Alzheimer’s Disease Neuroimaging Initiative. Participants were divided into a normal CSF group (controls; n = 77) and an abnormal CSF group (preclinical and clinical Alzheimer’s disease; n = 236) based on their CSF ratios of phosphorylated tau and amyloid beta at baseline. Groups were age-matched (t = 0.89, P > 0.1). Serum lipidomics data collected at baseline were clustered by chemical similarity, and enrichment analyses were used to determine whether serum levels of any lipid clusters differed between the normal and abnormal CSF groups. In a subset of patients with longitudinal structural MRI (normal CSF n = 62, abnormal CSF n = 161), two timepoints of MRI data were used to calculate grey matter annual percent change for each participant. Multivariate partial least squares analyses tested for relationships between neuroimaging and lipidomics data which are moderated by CSF pathology. Our clustering analyses produced 23 serum lipid clusters. Of these clusters, six were altered in the abnormal CSF group, including a cluster of unsaturated phosphatidylcholines. In the subset of participants with longitudinal structural MRI data, a priori nucleus basalis of Meynert partial least squares analyses detected a relationship between unsaturated phosphatidylcholines and degeneration in the nucleus basalis which is moderated by Alzheimer’s disease CSF pathology (P = 0.0008). Whole-brain grey matter partial least squares analyses of all 23 lipid clusters revealed that only unsaturated phosphatidylcholines and unsaturated acylcarnitines exhibited an Alzheimer’s disease-dependent relationship with longitudinal degeneration (P = 0.0022 and P = 0.0018, respectively). Only the unsaturated phosphatidylcholines predicted basal forebrain degeneration in the whole-brain analyses.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 02, 2022
- Source ID
- 10.1093/braincomms/fcac318
Entities
People
- Dinesh K Barupal
- For The Alzheimer’s Disease Neuroimaging Initiative*
- Hayley R C Shanks
- Kate M Onuska
- Taylor W Schmitz
- The Alzheimer's Disease Metabolomics Consortium
Organizations
- Alzheimer's Association
- Alzheimer's Disease Neuroimaging Initiative
- Alzheimer's Drug Discovery Foundation
- BioClinica
- Biogen
- Canadian Institutes of Health Research
- Chiron Corporation
- Eli Lilly and Company
- Foundation for the National Institutes of Health
- GE HealthCare
- Hoffmann-La Roche
- Icahn School of Medicine at Mount Sinai
- Johnson & Johnson Pharmaceutical Research and Development
- Laboratoires Servier
- Merck & Co.
- Meso Scale Diagnostics (United States)
- National Institute of Biomedical Imaging and Bioengineering
- National Institute on Aging
- National Institutes of Health
- Northern California Institute for Research and Education
- Pfizer
- Roche (United States)
- St. Joseph's Health Centre
- Takeda Pharmaceutical Company
- United States Department of Defense
- Western University