Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study

• Published in: Molecular psychiatry 2024-10, Vol.29 (10), p.3097-3105
• Main Authors: You, Jia, Guo, Yu, Wang, Yu-Jia, Zhang, Yi, Wang, Hui-Fu, Wang, Lin-Bo, Kang, Ju-Jiao, Feng, Jian-Feng, Yu, Jin-Tai, Cheng, Wei
• Format: Article
• Language: English
• Subjects: 631/378; 692/53/2422; 692/699; 9/10; Behavioral Sciences; Biological Psychology; Body weight loss; Cardiovascular disease; Clinical trials; Cognitive ability; Comorbidity; Coronary artery disease; Cystatin C; Dementia; Dementia disorders; Diabetes mellitus; Diagnosis; Drowsiness; Heart diseases; Kidney diseases; Medicine; Medicine & Public Health; Mental disorders; Neurosciences; Pharmacotherapy; Polyunsaturated fatty acids; Psychiatry
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-024-02570-0

Background Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia. Methods Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p -values under consecutive timeframes preceding the diagnosis of dementia. Findings During a median follow-up of 13.7 [Interquartile range, IQR 12.9–14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63–0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76–0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11–1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67–1.91]), stroke (OR 2.34 [2.1–1.37]), diabetes (OR 2.03 [1.89–2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3–5 year, overall time of activity, OR 0.82 [0.73–0.92]), drowsiness (3–5 year, sleep duration, OR 1.13 [1.04–1.24]) and weight loss (0–5 year, weight, OR 0.9 [0.83–0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis. Interpretation Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.