Multisystem failure, tipping points, and risk of Alzheimer's disease

Abstract INTRODUCTION Medical conditions including obesity, diabetes, hyperlipidemia, and depression significantly increased risk of Alzheimer's disease (AD). However, effect of their duration, influenced by non‐modifiable factors like chromosomal sex and apolipoprotein E ( APOE ) genotype, remains unclear. METHODS Data from 5644 UKBiobank participants were analyzed using Cox regression model to identify critical tipping points based on age of onset, risk factor (RF) duration and their interaction with sex and APOE genotype. RESULTS Hypertension or diabetes before age 62 exerted greater AD risk than APOE ε4 alone. Obesity before age 62 increased AD risk by 54%, with the risk nearly tripling between ages 62–72. Hyperlipidemia and depression were associated with age‐independent risk increases of 33% and 69%, respectively. After age 72, APOE ε4 became the dominant RF. DISCUSSION Duration of AD‐risk‐factors can have a greater impact than APOE ε4. Identification of critical age‐related tipping points highlights temporal dynamics of AD progression and role of multisystem failure in AD progression. Highlights AD risk factors impact AD onset, especially diagnosed between ages 62 and 72. Later diagnoses of hypertension, diabetes, and obesity delayed AD onset. Hyperlipidemia and depression increased AD risk by 33% and 69%, age‐independent. APOEε4 carriers regardless of sex exhibited a higher risk increasing with age. Trajectories differed between APOEε4 carriers and non‐carriers across sex.