Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of <i>APOE4</i> Homozygotes and Non- <i>APOE4</i> Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline

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Abstract

Background:

Alzheimer’s disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD.

Objective:

To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD.

Methods:

Patients homozygous for APOE4 and non- APOE4 carriers with mild cognitive impairment (MCI; n = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ ₄₂ levels in CSF were determined by immunoassay.

Results:

APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p = 0.042), SM(d18:1/18:0) ( p = 0.026), and Aβ ₄₂ ( p < 0.001) in CSF than non- APOE4 carriers. CSF-Aβ ₄₂ correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes ( r > 0.49; p < 0.032) and with Cer(d18:1/24:1) in non- APOE4 carriers ( r = 0.50; p = 0.025). CSF-Aβ ₄₂ correlated positively with Cer(d18:1/24:0) in MCI ( p = 0.028), but negatively in SCD patients ( p = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype ( r< –0.47; p < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non- APOE4 carriers ( p = 0.048 and 0.047, respectively).

Conclusion:

The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Clifford R. Jack, David Bennett, Kaj Blennow … (2018)

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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Dementia prevention, intervention, and care

Gill Livingston, Andrew Sommerlad, Vasiliki Orgeta … (2018)

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Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

Reisa Sperling, Paul S Aisen, Laurel A. Beckett … (2011)

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious. Copyright © 2011. Published by Elsevier Inc.

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Author and article information

Journal

Journal ID (nlm-ta): J Alzheimers Dis Rep

Journal ID (iso-abbrev): J Alzheimers Dis Rep

Journal ID (publisher-id): ADR

Title: Journal of Alzheimer's Disease Reports

Publisher: IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )

ISSN (Electronic): 2542-4823

Publication date (Electronic, preprint): 14 March 2023

Publication date (Electronic, pub): 03 May 2023

Publication date (Electronic, collection): 2023

Volume: 7

Issue: 1

Pages: 339-354

Affiliations

[a ] Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands

[b ] Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam University Medical Center , Free University Amsterdam, The Netherlands

[c ] Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Center , Free University Amsterdam, The Netherlands

[d ] Department of Clinical Chemistry, The Alzheimer Center Amsterdam, and Neurochemistry Laboratory, Amsterdam Neuroscience, Amsterdam University Medical Center , Free University Amsterdam, The Netherlands

[e ] Department of Neurology, University of Bonn , Bonn, Germany

[f ] Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University , Maastricht, The Netherlands

Author notes

[* ]Correspondence to: Dr. Monique Mulder, Erasmus MC, Department of Internal Medicine, Division of Pharmacology Vascular and Metabolic Diseases, room EE800, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 70 32707; E-mail: m.t.mulder@ 123456erasmusmc.nl .

Article

Publisher ID: ADR220072

DOI: 10.3233/ADR220072

PMC ID: 10200192

SO-VID: 25075640-f8b9-4ebc-a6d1-ee7414e0214a

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non- APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline

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Abstract

Background:

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Results:

Conclusion:

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Karger: Neurology and Neuroscience

Most cited references 72

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Dementia prevention, intervention, and care

Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

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