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Review
. 2025 Aug;16(4):1121-1136.
doi: 10.1007/s41999-025-01222-y. Epub 2025 May 20.

Multimorbidity and fluid biomarkers of Alzheimer's disease: a systematic review

Martina Valletta  1 , Marco Canevelli  1   2   3 , Francesca Gasparini  1   4 , Simona Buscarnera  2 , Martina Salzillo  2 , Federico Triolo  1 , Amaia Calderón-Larrañaga  1   5 , Alessandra Marengoni  1   6 , Davide Liborio Vetrano  1   5 , Giulia Grande  7   8
Affiliations
Review

Multimorbidity and fluid biomarkers of Alzheimer's disease: a systematic review

Martina Valletta et al. Eur Geriatr Med. 2025 Aug.

Abstract

Purpose: This systematic review aimed to summarize the evidence on the association between multimorbidity and fluid biomarkers of Alzheimer's disease (AD).

Methods: We systematically searched PubMed, Web of Science, and Embase for studies investigating the association between multimorbidity-defined as the co-occurrence of multiple chronic conditions in the same individual-and levels of cerebrospinal fluid (CSF) or blood biomarkers of AD, focusing on the most established AD biomarkers (amyloid-beta, phosphorylated-tau, total-tau, neurofilament light chain, and glial fibrillary acidic protein). Studies were selected following PRISMA guidelines.

Results: Out of 3,104 records, we identified 10 cross-sectional studies. Four studies assessed CSF biomarkers in dementia-free participants with mean age between 61.8 and 66.6 years, yielding mixed findings with no consistent association between multimorbidity and CSF biomarkers. Six studies focused on blood biomarkers in participants with mean age ranging from 66.5 to 76.4 years, five of which included individuals with dementia. Most of these studies reported an association between multimorbidity and elevated blood biomarker levels.

Conclusions: This review suggests a significant association between multimorbidity and AD blood biomarkers in older populations, while the results on CSF are mixed and inconsistent. Further research is needed, particularly longitudinal studies assessing both CSF and blood biomarkers within the same populations.

Keywords: Alzheimer’s disease; Biomarkers; Blood; Cerebrospinal fluid; Chronic diseases; Multimorbidity.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no conflict of interest. Ethical approval: For the present study, no ethics committee approval was necessary. Informed consent: For this type of study, formal consent is not required.

Figures

Fig. 1
Fig. 1
Systematic review flow-chart
Fig. 2
Fig. 2
Association between multimorbidity and fluid biomarkers of Alzheimer’s disease. Bar Heights: The height of each bar represents the study’s sample size (log-transformed). Different colors are used to represent each biomarker. Biomarker Categories: Results are displayed separately for cerebrospinal fluid (CSF) biomarkers and blood biomarkers
See this image and copyright information in PMC

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