In this longitudinal study of 181 older adults, APOE4 genotype significantly modified the association between incident CIND and educational attainment, hypertension, elevated depressive symptoms, hearing loss, vision impairment, smoking, and obesity. Given the increasing number of older adults with dementia, detection of early risk factors for cognitive decline and identifying sub-groups for whom early risk factors are most relevant are important research priorities [1,2,3, 5]. Our results suggest that those with both genetic (e.g., APOE4) and modifiable risk factors may be at particularly high risk for cognitive decline. It is possible that such individuals could benefit from closer monitoring or earlier interventions to slow the progression of cognitive decline (e.g., more intensive cardiovascular risk factor control, exercise, cognitive training, etc.) [5].
Some prior studies have reported interactions between modifiable (e.g., smoking, [8] depression, [9] sleep disordered breathing [23]) and genetic risk for dementia or cognitive decline, while other studies have reported no interaction [10,11,12]. For example, the interaction between smoking and APOE4 status has been associated with incident dementia in the UK Biobank [8]. On the other hand, no significant interaction between polygenic risk score (excluding the APOE4 allele) and smoking was found in the UK Biobank cohort [8]. As such, it is possible that APOE4 genotype is a stronger modifier of the impact of modifiable risk factors on cognitive health as compared to other gene loci. Further research is needed to determine if there are significant interactions between modifiable dementia or cognitive impairment risk factors and other individual gene loci.
In the present study, there was so significant joint effect between T2DM and APOE4 status. Prior cohort study data have provided mixed epidemiologic evidence for an association between diabetes and cognitive impairment, with some reporting no association [3, 24] while others suggest a significant association [25,26,27]. As such, it is possible that the lack of a significant joint effect between diabetes and APOE4 status in the present study may be attributable to a lack of association between diabetes and CIND among this study population. Studies with longer follow-up, larger sample size, and assessment of duration of time lived with diabetes, will be important for elucidating the association of T2DM with CIND. Moreover, once one reaches CIND, risk factor interactions could become less important because the risk of progression from CIND to dementia may be high regardless of the presence of other risk factors [2, 3, 20].
The present study assesses risk factors from throughout the life course. For example, educational attainment is more readily modifiable in young adulthood and tends to remain unchanged as participants progress through mid-life and older adulthood, when cognitive impairment and dementia is more prevalent. The Lancet Commission’s 2020 Report on Dementia Prevention, Intervention, and Care recommends using a life course framework for understanding risk factors for cognitive decline and dementia [5]. In turn, studies assessing dementia risk factors have typically included risk factors from throughout participants’ life course [8,9,10,11,12]. While some risk factors may no longer be modifiable once individuals reach older-adulthood, early life interventions (e.g. education programs, smoking cessation, diabetes control, etc.) may result in later-life benefits for cognitive health, though considerable interventional research is needed to test this [5]. Further research is also needed to determine whether APOE4 genotype may modulate the effectiveness of early interventions to prevent cognitive decline [28].
The present study has several strengths compared to prior studies, including longitudinal follow up (median 5.0 years), consensus panel diagnoses of cognitive status, genotyping of all subjects, robust covariate adjustment, inclusion of 8 key CIND risk factors, and use of CIND as an outcome, which may have a stronger association with APOE4 than dementia [14]. Prior studies reporting no interaction differed from the present study based on lack of robust cognitive status assessment and/or assessment of polygenic risk rather than APOE4 status.