Data-driven identification of health conditions associated with incident Alzheimer's disease dementia risk: a 15 years follow-up cohort from electronic health records in France and the United Kingdom

Background: The identification of modifiable risk factors for Alzheimer’s disease (AD) is paramount for early prevention and the targeting of new interventions. We aimed to assess the associations between health conditions diagnosed in primary care and the risk of incident AD over time, up to 15 years before a first AD diagnosis. Methods: Data for 20,214 AD patients from the United Kingdom and 19,458 AD patients from France were extracted from The Health Improvement Network (THIN) database. For each AD case, a control was randomly assigned after matching for sex and age at dementia diagnosis.  We agnostically tested the associations between 123 different ICD10 diagnoses extracted from health records and AD dementia, by conditional logistic regression. We focused on two time periods: 2 to 10 years vs. 0 to 2 years before the diagnosis of AD, to separate risk factors from early symptoms/comorbidities. Findings: We report odds ratios (ORs) for the association of AD with the various health conditions were calculated after Bonferroni correction for multiple comparisons. Ten health conditions were significantly associated  with high odds ratios for AD when diagnosed 2 to 10 years before AD, in the British and French samples: major depressive disorder (OR 95% confidence interval (UK):1.23-1.46)), anxiety (1.25-1.47), reaction to severe stress (1.24-1.59), hearing loss (1.11-1.28), constipation (1.22-1.41), spondylosis (1.14-1.39), abnormal weight loss (1.33-1.63), malaise and fatigue (1.14-1.32), memory loss (6.65-8.76) and syncope and collapse (1.1-1.37). Depression was the first comorbid condition associated with AD, appearing at least nine years before the first clinical diagnosis of AD, followed by, anxiety, constipation and abnormal weight loss. Interpretation: These results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer’s disease. These results could guide new dementia prevention strategies. Funding: Grants ANR-10-IAIHU-06 and ANR-19-P3IA-0001. Declaration of Interest: SE reports personal fees from Biogen, Eisai, Roche, and GE Healthcare, for presentations or participation to advisory boards. FM, LG and BE are full time employees of Cegedim. Other authors declare no competing interests. Ethical Approval: The French database obtained approval for data collection from the French National Data Protection Authority (CNIL) in 2002. For the UK database, ethical approval was granted by the NHS South-East Multicentre Research Ethics Committee in 2003 (ref: 03/01/073) for establishment of the THIN database, and it was updated in 2011. The study was a retrospective analysis of secondary anonymised patient data only.