Year: 2026
Type: article
Abstract: BACKGROUND AND OBJECTIVES: Blood-based biomarkers are strongly correlated with amyloid positivity in research settings, but their long-term performance in heterogeneous populations remains unclear. Our aim was to determine their long-term prediction accuracy for incident all-cause dementia on their own and when used alongside known risk factors in community-dwelling older adults. METHODS: This was a retrospective study based on the UK Whitehall II longitudinal, population-based cohort study established in 1985 among civil servants that includes a clinical examination every 4-5 years. Blood samples stored at the 2013-2013 wave were assayed in 2024 for measures of amyloid-beta (Aβ) 42 and 40, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau protein 217 (p-tau217). Incident all-cause dementia, from 2012 to 2013 to 2025, was ascertained from linked medical records, and Cox regression was used to examine associations of biomarkers with dementia, followed by estimation of prediction statistics. RESULTS: Of the 5,225 (27.2% female) participants (mean age in 2012-2013, 69.4 ± 5.7 years), 516 (30.0% female) had a dementia diagnosis over a 12.2-year median follow-up. Participants with values in the worst quartile of amyloid-beta 42 (Aβ42)/40 ratio (hazard ratio [HR] 1.88; 95% CI 1.57-2.24), p-tau217 (HR 3.74; 95% CI 3.12-4.50), NfL (HR 1.88; 95% CI 1.56-2.28), and GFAP (HR 2.25; 95% CI 1.87-2.72) had higher risk of dementia. The C-index for predicting dementia was highest for p-tau217 (0.693; 95% CI 0.672-0.714), lowest for Aβ42/40 ratio (0.587; 95% CI 0.566-0.608), and was 0.760 (0.738, 0.781) for all biomarkers together. Sensitivity (between 41.7% and 59.5%) and positive predictive value (between 16.4% and 23.5%) of all biomarkers were modest, but specificity (between 76.8% and 78.8%) and negative predictive value (92.3%-94.7%) were good. A second approach to prediction modeling showed a model containing sociodemographic, behavioral, and health-related risk factors to have a C-index of 0.765 (95% CI 0.746-0.785); adding all biomarkers to this model led to a C-index of 0.813 (95% CI 0.795-0.830). DISCUSSION: The long-term predictive ability of blood-based biomarkers for incident dementia in community-dwelling older adults was modest due to poor sensitivity and similar to that of a model containing known risk factors.
Source: Neurology
Institutions: Inserm, Université Paris Cité, Equipe de Recherche en Epidémiologie Nutritionnelle, Centre de Recherche Épidémiologie et Statistique, University College London, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University of Wisconsin–Madison, Sahlgrenska University Hospital, UK Dementia Research Institute, Indian Institute of Science Bangalore, University of Gothenburg
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Wellcome Trust, Stiftelsen för Gamla Tjänarinnor, Fondation Vaincre Alzheimer, National Institute for Health and Care Research, University College London, European Commission, Hjärnfonden, Vetenskapsrådet, FONDATION ALZHEIMER, UK Dementia Research Institute, National Institutes of Health, Medical Research Council, National Institute on Aging
Awards: G1787587971, G1806953437, G3091909500, G4298122870, Education, socioeconomic status and Aging: transitions from multimorbidity to functional limitations and mortality, Taking the long view: Identification of plasma protein biomarkers for dementia risk, Taking the long view: Identification of plasma protein biomarkers for dementia risk, G5001906568, G5093253901, G6874814778, G7645227262, The role of hepatic type cell polarity during Plasmodium liver stage infection, G84288707, G8583839118, G8668278034
OpenAlex ID: W7223276843