Can non-pharmacological interventions change levels of neurofilament light in older adults at risk of dementia? A secondary analysis of the SCD-Well randomized clinical trial - 12/07/25

Doi : 10.1016/j.tjpad.2025.100299

Lehané Masebo ^1,^{^{$
These authors contributed equally to this work}}, Tim Whitfield ^1,^{^{$
These authors contributed equally to this work}}, Harriet Demnitz-King ^1,², Amanda Heslegrave ^3,⁴, Géraldine Poisnel ⁵, Antoine Lutz ⁶, Eric Frison ⁷, Miranka Wirth ⁸, Abdul Hye ⁹, Frank Jessen ^10,^11,¹², Nicholas J. Ashton ^9,^13,^14,¹⁵, Henrik Zetterberg ^3,^4,^13,^16,¹⁷, Natalie L. Marchant ^1,^⁎
¹ Division of Psychiatry, University College London, London, United Kingdom
² Centre for Psychiatry and Mental Health, Wolfson Institute of Population Health, Queen Mary University, London, UK
³ Dementia Research Institute, UCL, London, UK
⁴ Department of Neurodegenerative Disease, Institute of Neurology, London, UK
⁵ Normandie University, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", NeuroPresage Team, Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000 Caen, France
⁶ Lyon Neuroscience Research Center Inserm U1028, CNRS UMR5292, Lyon 1 University, Lyon, France
⁷ Univ. Bordeaux, INSERM, Institut Bergonié, CHU Bordeaux, CIC1401-EC, EUCLID/F-CRIN clinical trials platform, F-33000 Bordeaux, France
⁸ German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
⁹ Department of Old Age Psychiatry, King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
¹⁰ Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany
¹¹ Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany
¹² German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
¹³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
¹⁴ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
¹⁵ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, UK
¹⁶ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China
¹⁷ Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

^⁎Corresponding author: Natalie L. Marchant, Division of Psychiatry, 6th Floor Maple House, 149 Tottenham Court Road, University College London, London W1T 7NF, UK. Tel: +44 (0)20 3108 7961Division of PsychiatryUniversity College London6th Floor Maple House, 149 Tottenham Court RoadLondonW1T 7NFUK

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Abstract

Background

Older adults with subjective cognitive decline (SCD) and/or elevated neurofilament light (NfL), a neurodegeneration biomarker, are at increased risk of dementia. Non-pharmacological interventions offer a promising strategy for reducing dementia risk, yet none have utilized NfL as a marker of response in dementia prevention trials.

Objective

To investigate the effects of two non-pharmacological interventions on NfL in older adults with SCD.

Design

SCD-Well was an 8-week observer-blinded, randomized, clinical trial with 6-month follow-up, and was a part of the Horizon 2020 European Union-funded "Medit-Ageing" project. Data were analyzed from June 2022 to August 2024.

Setting

Memory clinics at four sites in France, Germany, Spain, and UK.

Participants

Participants were enrolled from March 2017 to January 2018 after fulfilling SCD research criteria and performing within the normal range on cognitive testing. Of the 147 participants enrolled, 140 were included in this secondary analysis (7 did not consent to venipuncture).

Interventions

Participants were randomly allocated to the Caring Mindfulness-Based Approach for Seniors (CMBAS) intervention or a structurally matched Health Self-Management Program (HSMP).

Measurements

Plasma NfL was measured at baseline (V1), post-intervention (V2), and 6-month follow-up (V3), using Single molecule array technology, and log-transformed for analyses.

Results

137 older adults with SCD provided NfL data (mean [SD] age: 72.7 [6.8] years; 62.0% female; CMBAS, n=70; HSMP, n=67). NfL data were available at V1 (n=136), V2 (n=119) and V3 (n=115). The visit-by-arm interaction was not statistically significant, and no significant changes in NfL were observed within the CMBAS or HSMP arms from V1 to V2. However, within the HSMP arm, NfL levels reduced from V1 to V3 (-0.10, 95% confidence interval [-0.18 to -0.02]). Modified intention-to-treat analyses, which included 140 participants, supported these findings, and additionally recorded significant reductions in the HSMP arm from V1 to V2 (n=140, -0.07 [-0.14 to -0.00]).

Conclusions

In this study, NfL levels were reduced at 6-month follow-up after a health self-management program. Future interventions with longer duration, extended follow-up and clinical endpoints will help clarify whether NfL reductions are sustained over extended timeframes and translate to lower dementia incidence.