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Background: Identifying independent and interactive associations of a wide range of diseases and multimorbidity and apolipoprotein E4 (APOE4) with dementia may help promote cognitive health. The main aim of the present study was to investigate associations of such diseases and their multimorbidity with incident dementia., Methods: In this retrospective cohort study, we included 471,485 individuals of European ancestry from the UK Biobank, aged 38-73 years at baseline (2006-10). Dementia was identified using inpatient records and death registers. The follow-up period was between March 16, 2006, and Jan 31, 2021., Findings: During a median follow-up of 11·9 years, 6189 cases of incident all-cause dementia (503 young-onset cases, 5686 late-onset cases) were documented. In multivariable-adjusted analysis, 33 out of 63 major diseases were associated with an increased risk of dementia. The hazard ratio (HR [95% CI]) ranged from 1·12 (1·06-1·19) for obesity to 14·22 (12·33-16·18) for Parkinson's disease. In addition to conventional diseases, respiratory disorders, musculoskeletal disorders, digestive disorders, painful conditions, and chronic kidney disease were associated with increased dementia risk. A larger HR for dementia was observed for a larger number of diseases (3·97 [3·51-4·48] for ≥6 diseases versus no disease). These individual diseases and multimorbidity were more predictive of young-onset dementia than of late-onset dementia. Dementia risk score incorporating multimorbidity, age, and APOE4 status had strong prediction performance (area under the curve [95% CI]: 82·2% [81·7-82·7%]). APOE4 was more predictive of late-onset dementia (HR [95% CI]: 2·90 [2·75-3·06]) than of young-onset dementia (1·26 [1·03-1·54]). Associations of painful conditions, depression, obesity, diabetes, stroke, Parkinson's disease, high cholesterol, and their multimorbidity with incident dementia were stronger among non-APOE4 carriers., Interpretation: Besides conventional diseases, numerous diseases are associated with an increased risk of dementia. These individual diseases and multimorbidity are more predictive of young-onset dementia, whereas APOE4 is more predictive of late-onset dementia. Individual diseases and multimorbidity are stronger predictors of dementia in non-APOE4 carriers. Although multiple risk factors have been adjusted for in the analysis, potential confounding from unknown factors may have biased the associations., Funding: The Fundamental Research Funds of the State Key Laboratory of Ophthalmology, Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou, China (Z012014075), Science and Technology Program of Guangzhou, China (202,002,020,049)., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article., (© 2022 The Author(s).)

Background: Inflammation has been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN) as suggested in various cross-sectional studies. However, more convincing prospective studies in diabetes patients are scarce. Therefore, we aimed to evaluate whether proinflammatory cytokines could predict the incidence of DPN through a prospective study with a five-year follow-up., Methods: We followed up 315 patients with diabetes who did not have DPN, recruited from five community health centers in Shanghai in 2014, for an average of 5.06 years. Based on the integrity of blood samples, 106 patients were selected to obtain the proinflammatory cytokines. Plasma markers of proinflammatory cytokines at baseline included interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1). Neuropathy was assessed by MSNI at baseline and during follow-up., Findings: Among the 106 chosen patients, 63 developed DPN after 5.06±1.14 years of follow-up. The baseline plasma levels of TNF-α, IL-6, and ICAM-1 were higher in the neuropathic group (p<0.05). In multivariate models, increased plasma levels of TNF-α (hazard ratio, HR: 8.74 [95% confidence interval, CI: 1.05-72.68]; p <0.05) and ICAM-1 (HR 23.74 [95% CI:1.47-383.81]; p <0.05) were both associated with incident DPN, after adjusting for known DPN risk factors., Interpretation: Increased plasma levels of proinflammatory factors, especially TNF-α and ICAM-1, predicted the incidence of DPN over 5 years in Chinese diabetes patients, but larger longitudinal studies are required for confirmation., Funding: National Natural Science Foundation of China, Shanghai Talent Development Fund Program, Shanghai Shenkang Hospital Developing Center Clinical Scientific and Technological Innovation Program, Shanghai Science and Technology Committee Program, Shanghai General Hospital Program of Chinese traditional and Western medicine combination and Shanghai Municipal Commission of Health and Family Planning Clinical Research Project., Competing Interests: The authors declare that there is no conflict of interest., (© 2020 The Authors.)