Abstract
Background: Comorbidities such as hypertension and hypercholesterolemia are risk factors associated with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). The most significant genetic risk factor is the ε4 allele of the apolipoprotein E gene (APOE). The aim of this paper is to determine whether hypertension is the most significant but modifiable risk factor to delay AD onset. Method: A cohort of patients with MCI (N = 3052) is developed from the documented database (N = 43,999) within the National Alzheimer's Coordinating Center (NACC) during the time period from June 2005 to May 2021. Cox proportional hazard models with propensity score weights on demographic information and comorbidities at baseline are applied to examine association of hypertension and hypercholesterolemia with AD onset among MCI patients. Associations are compared to APOE genotypes and AD onset. In addition, the association of hypertension with decline rates in Mini-Mental State Examination (MMSE) scores are reported. Results: After controlling for age, sex, race, APOEε4, and reported comorbidities, the results show that MCI patients who subsequently develop hypertension within 18 months after their first diagnosis of MCI have a significantly higher risk of AD onset (HR = 2.77, 95%CI (1.66, 4.65), p value < 0.0001), compared to MCI patients with no hypertension or a late occurrence of hypertension after 18 months. This significant association is validated through a Random Forest method, a machine learning approach with bootstrap simulations. In addition, patients with early hypertension have significantly higher MMSE score declining rates compared to those without hypertension (coefficient = 0.988, p = 0.0054.). Conclusions: Hypertension is the most significant risk factor comparable to the genetic risk factor APOEε4 allele. Our finding is unique, as we did not observe a similar outcome in those with early hypercholesterolemia. Thus, among all comorbidities, hypertension is the most significant risk factor similar to the genetic risk factor APOEε4 allele.