O1‐08‐05: Apoe Gene Modifies the Link Between Type 2 Diabetes and Dementia Risk: the Memento Cohort

Type 2 diabetes mellitus is associated with dementia risk, but the underlying mechanisms remain unclear. E4 isoform of the APOE gene is the strongest genetic risk factor for sporadic, late onset Alzheimer's Disease (AD), and is also associated with risk for type 2 diabetes mellitus (T2DM). In a large clinic-based prospective cohort of participants with either isolated cognitive complaints or mild cognitive impairment, we investigated whether APOE gene modifies the association between diabetes and AD risk. The Memento cohort is a multicenter longitudinal study of the determinants of cognitive evolution (including dementia) of participants consecutively enrolled in French memory clinics and presenting either isolated cognitive complaints or light to moderate cognitive impairment. Throughout France, 2323 participants have been enrolled and are followed at least five years with yearly clinical examinations and for brain imaging (MRI) every two years. All dementia cases diagnosed during follow-up are validated by an independent events' review committee. Cox proportional hazard models were used to investigate the likelihood of progression to dementia. To assess that APOE ε4 modifies the association between diabetes and dementia, we tested for interaction (p<0.01) and performed stratified analyses. Mean baseline age was 70.4 years, 62% were female and 40% had a clinical dementia rating scale scored 0. During a mean follow-up of 2.1 years, 160 participants became demented, 112 were of Alzheimer's type. ApoE ε4 carriers were at increased risk of dementia than non-carriers [hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.83-3.90]. TD2M persons had an increased risk of incident dementia (HR=1.3, 95% CI 1.1-1.7). The highest risk of dementia was found among ε4 carriers with T2DM versus ε4 non-carriers without T2DM (HR 5.5, 95% CI 2.2-9.4). Trends were similar when all types of dementia were considered. Participants with T2DM and at least one ε4 allele had significantly smaller hippocampal volume and higher load of white matter lesions. In this large naturalistic cohort, ApoE4 increases the rate of AD or dementia in those participants with T2DM. MRI markers of brain pathology show consistent results with dementia outcomes.