title: Human Central Nervous System (CNS) ApoE Isoforms Are Increased by Age, Differentially Altered by Amyloidosis, and Relative Amounts Reversed in the CNS Compared with Plasma.
abstract: The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF β-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden.
authors: From the Departments of Neurology and.
authors: Alaina T
authors: 0000-0002-4627-6024
authors: AT
authors: Baker-Nigh
authors: From the Departments of Neurology and.
authors: Kwasi G
authors: KG
authors: Mawuenyega
authors: From the Departments of Neurology and.
authors: James G
authors: JG
authors: Bollinger
authors: From the Departments of Neurology and.
authors: Vitaliy
authors: 0000-0001-6722-4883
authors: V
authors: Ovod
authors: From the Departments of Neurology and.
authors: Tom
authors: T
authors: Kasten
authors: Pathology and Immunology.|Knight Alzheimer's Disease Research Center, and.
authors: Erin E
authors: EE
authors: Franklin
authors: From the Departments of Neurology and.
authors: Fan
authors: 0000-0003-4874-460X
authors: F
authors: Liao
authors: From the Departments of Neurology and.
authors: Hong
authors: H
authors: Jiang
authors: From the Departments of Neurology and.|Knight Alzheimer's Disease Research Center, and.|Hope Center for Neurological Disorders, Washington University, St. Louis, Missouri 63110.
authors: David
authors: 0000-0002-3400-0856
authors: D
authors: Holtzman
authors: From the Departments of Neurology and.|Pathology and Immunology.|Knight Alzheimer's Disease Research Center, and.|Hope Center for Neurological Disorders, Washington University, St. Louis, Missouri 63110.
authors: Nigel J
authors: NJ
authors: Cairns
authors: From the Departments of Neurology and.|Knight Alzheimer's Disease Research Center, and.|Hope Center for Neurological Disorders, Washington University, St. Louis, Missouri 63110.
authors: John C
authors: JC
authors: Morris
authors: From the Departments of Neurology and batemanr@wustl.edu.|Knight Alzheimer's Disease Research Center, and.|Hope Center for Neurological Disorders, Washington University, St. Louis, Missouri 63110.
authors: Randall J
authors: RJ
authors: Bateman
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis; D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D053318:Apolipoprotein E3 / Q000032:analysis*; D053327:Apolipoprotein E4 / Q000032:analysis*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis*; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003704:Dementia / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D015415:Biomarkers
keywords: Alzheimer disease; aging; apolipoprotein-E (apoE); brain; cerebrospinal fluid; mass spectrometry (MS); plasma; quantitation