Leading determinants of incident dementia among individuals with and without the apolipoprotein E ε4 genotype: a retrospective cohort study.

Background: Little is known regarding the leading risk factors for dementia/Alzheimer's disease (AD) in individuals with and without APOE4. The identification of key risk factors for dementia/Alzheimer's disease (AD) in individuals with and without the APOE4 gene is of significant importance in global health.

Methods: Our analysis included 110,354 APOE4 carriers and 220,708 age- and sex-matched controls aged 40-73 years at baseline (between 2006-2010) from UK Biobank. Incident dementia was ascertained using hospital inpatient, or death records until January 2021. Individuals of non-European ancestry were excluded. Furthermore, individuals without medical record linkage were excluded from the analysis. Moderation analysis was tested for 134 individual factors.

Results: During a median follow-up of 11.9 years, 4,764 cases of incident all-cause dementia and 2065 incident AD cases were documented. Hazard ratios (95% CIs) for all-cause dementia and AD associated with APOE4 were 2.70(2.55-2.85) and 3.72(3.40-4.07), respectively. In APOE4 carriers, the leading risk factors for all-cause dementia included low self-rated overall health, low household income, high multimorbidity risk score, long-term illness, high neutrophil percentage, and high nitrogen dioxide air pollution. In non-APOE4 carriers, the leading risk factors included high multimorbidity risk score, low overall self-rated health, low household income, long-term illness, high microalbumin in urine, high neutrophil count, and low greenspace percentage. Population attributable risk for these individual risk factors combined was 65.1%, and 85.8% in APOE4 and non-APOE4 carriers, respectively. For 20 risk factors including multimorbidity risk score, unhealthy lifestyle habits, and particulate matter air pollutants, their associations with incident dementia were stronger in non-APOE4 carriers. For only 2 risk factors (mother's history of dementia, low C-reactive protein), their associations with incident all-cause dementia were stronger in APOE4 carriers.

Conclusions: Our findings provide evidence for personalized preventative approaches to dementia/AD in APOE4 and non-APOE4 carriers. A mother's history of dementia and low levels of C-reactive protein were more important risk factors of dementia in APOE4 carriers whereas leading risk factors including unhealthy lifestyle habits, multimorbidity risk score, inflammation and immune-related markers were more predictive of dementia in non-APOE4 carriers.