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Impact on the Sustainable Development Goals (SDGs)

Analysis of institutional authors

Novau-Ferré, NAuthorBullo, MCorresponding Author

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January 5, 2026
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Plasma lipid dysregulation reflecting cerebrospinal fluid profile predicts Alzheimer's disease progression

Publicated to: AGE AND AGEING. 54 (12): afaf363- - 2025-12-01 54(12), DOI: 10.1093/ageing/afaf363

Authors:

Novau-Ferre, Nil; Panisello, Laura; Garcia-Gonzalez, Pablo; Mateu-Fabregat, Javier; Cantero, Jose L; Atienza, Mercedes; Boada, Merce; Ruiz, Agustin; Bullo, Monica
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Affiliations

Carlos III Hlth Inst, CIBER Neurodegenerat Dis CIBERNED - Author
Carlos III Hlth Inst, CIBER Physiol Obes & Nutr CIBEROBN - Author
Pablo de Olavide Univ UPO, Lab Funct Neurosci - Author
Univ Rovira i Virgili URV, Ctr Environm, Food & Toxicol Technol TecnATox - Author
Univ Texas Hlth Sci Ctr San Antonio, Long Sch Med, Dept Microbiol Immunol & Mol Genet - Author
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Abstract

Lipidomics offers potential for the early detection of Alzheimer's disease (AD) and for elucidating the molecular mechanisms driving the progression from mild cognitive impairment (MCI) to AD. In this study, we investigated and validated the association between 139 cerebrospinal fluid (CSF) lipids and MCI-to-AD conversion. We included 400 MCI participants from the Ace Alzheimer Center Barcelona (ACE) cohort, all free of type 2 diabetes, comprising both ATN+ and ATN- individuals. After a median follow-up of 2.1 years, 142 participants progressed to AD dementia. We identified a multi-lipid signature of 11 lipids (including phosphatidylcholines, lysophosphatidylcholines, triglycerides, phosphatidylethanolamines, lysophosphatidylethanolamines and phosphatidylinositols) in CSF, which was associated with increased AD progression (HR = 1.85, 95% CI: 1.53-2.27). This signature was validated in paired plasma samples, a less invasive biofluid (HR = 1.26, 95% CI: 1.04-1.52) and in plasma samples from an external cohort of 189 participants (149 with subjective cognitive decline, 40 with MCI; beta = 0.261, 95% CI: 0.022-0.500), demonstrating moderate-to-high predictive accuracy for MCI-to-AD progression. Counterfactual-based mediation analysis revealed that plasma phosphorylated tau-181 mediated up to 47% of the association between the lipid signature and AD dementia, highlighting glycerophospholipid metabolism as a key pathway. Exploratory Mendelian randomisation analyses suggested a potential causal association of lipid signature and AD, with two instrumental single-nucleotide polymorphisms mapped to loci implicated in neurodevelopmental and metabolic regulation (RBFOX1 and CDKAL1). In conclusion, our findings support the growing evidence of lipid metabolism dysregulation as an early marker of AD and identify plasma lipids reflecting CSF profiles that may be promising prognostic markers for AD dementia.
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Keywords

AgedAged, 80 and overAlzheimer diseaseAlzheimer's diseaseAlzheimer’s diseaseBiological markerBiomarkersBloodBrainCerebrospinal fluidCholineCognitive defectCognitive dysfunctionDeclineDiagnosisDisease exacerbationDisease progressionDocosahexaenoic acidFemaleGeneGeneticsGood health and well-beingHumanHumansLipidLipidomicsLipidsMaleMetabolismMiddle agedMild cognitive impairmentMouse modelNeurodegeneration biomarkersOlder peoplePhosphatidylcholinePredictive valuePredictive value of testsProceduresPsychologyTau proteinTau proteinsVery elderly

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal AGE AND AGEING due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2025, it was in position 5/73, thus managing to position itself as a Q1 (Primer Cuartil), in the category Geriatrics & Gerontology. Notably, the journal is positioned above the 90th percentile.

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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-05:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 8.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 8 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 7.
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Continuing with the social impact of the work, it is important to emphasize that, due to its content, it can be assigned to the area of interest of ODS 3 - Ensure healthy lives and promote well-being for all at all ages, with a probability of 73% according to the mBERT algorithm developed by Aurora University.
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Novau Ferré, Nil) and Last Author (Bulló Bonet, Mònica).

the author responsible for correspondence tasks has been Bulló Bonet, Mònica.

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Project objectives

Los objetivos perseguidos en esta aportación se centran en profundizar en la relación entre los lípidos del líquido cefalorraquídeo (LCR) y la progresión de la enfermedad de Alzheimer (EA). Se plantean: analizar la asociación entre 139 lípidos del LCR y la conversión de deterioro cognitivo leve (MCI) a EA; validar una firma multi-lipídica de 11 lípidos en muestras de plasma y en cohortes externas; evaluar la capacidad predictiva de esta firma para la progresión de MCI a EA; determinar el papel mediador de la proteína tau fosforilada-181 en plasma en la relación entre la firma lipídica y la demencia por EA; y explorar mediante análisis de aleatorización mendeliana la posible asociación causal entre la firma lipídica y la EA.
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Most relevant results

Los resultados más relevantes de este estudio incluyen: (1) la identificación de una firma multi-lípida de 11 lípidos en líquido cefalorraquídeo (LCR) asociada con una mayor progresión de Alzheimer (HR = 1.85, IC 95%: 1.53-2.27) tras un seguimiento mediano de 2.1 años en 400 participantes con deterioro cognitivo leve; (2) la validación de esta firma en muestras plasmáticas emparejadas, con un HR = 1.26 (IC 95%: 1.04-1.52), y en una cohorte externa de 189 participantes (beta = 0.261, IC 95%: 0.022-0.500); (3) el análisis de mediación que mostró que la fosforilación de tau-181 plasmático mediaba hasta el 47% de la asociación entre la firma lipídica y la demencia; y (4) análisis exploratorios de randomización mendeliana
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