Abstract

Background Plasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer’s disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid‑β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer’s Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL. Methods Non‑demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer’s Disease Assessment Scale‑Cognitive subscale (ADAS‑Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6‑ or 12‑month intervals. Linear mixed‑effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity. Results Over a mean follow‑up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS‑Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p‑values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS‑Cog scores (p‑value 0.005) and hippocampal volumes (p‑value 0.004). Regarding ADAS‑Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS‑Cog scores, hippocampal volumes, and WMH volumes (all p‑values < 0.001). DM influenced the association between plasma NfL and changes in ADAS‑Cog scores (p‑value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p‑value 0.026). Conclusion This study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL‑based prognostic model for neurodegeneration in non‑demented older adults.

Document Type

Article

Publication Date

2024

Notes/Citation Information

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Digital Object Identifier (DOI)

https://doi.org/10.1186/s13195-024-01564-y

Funding Information

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‑12‑2‑0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‑Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‑La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www. fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. The Laboratory disseminates ADNI data for Neuro Imaging at the University of Southern California. This work was also supported by a general clinical research grant‑in‑aid from the Seoul Metropolitan Government Seoul National University (SMG‑SNU) Boramae Medical Center (04‑2023‑0013), the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711197743, RS‑2023‑00253694), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS‑2023‑00280087).

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