Investigating the risk of cardiovascular risk factor subgroups in cognitively normal elderly on progression to AD: A latent class approach

Abstract

Individual cardiovascular risk factors (CVRFs) have been associated with neurodegenerative processes. However, CVRFs often co-occur with one another and little is known regarding the extent of their clustering, and effect on progression to Alzheimer's disease (AD). We identify classes of CVRFs in cognitively normal (CN) individuals, and investigate their risk on progression to AD.CN individuals were recruited from the National Alzheimer's Coordinator Center dataset, with follow-up. To identify CVRF classes at baseline, a latent class analysis (LCA) was conducted with five vascular (hypertension, hypercholesterolemia, heart condition, stroke, and smoking history), and two metabolic (diabetes, and high body mass index (BMI)) indicators. Separate cox regressions were conducted to investigate the risk of CVRF class on progression to clinically-diagnosed and neuropathology-confirmed AD (clinically-diagnosed AD with intermediate/high AD Neuropathologic Change). Post-hoc analyses investigated differences in non-AD related neuropathologies between CVRF classes.This study included 12,412 CN individuals (age:70.9±10.5, male:35% (N=4312), MMSE:28.9±1.4, 6% (N=788) of whom progressed to AD). The LCA identified three phenotypes of baseline CVRF classes (Figure 1). One group had low probabilities of CVRFs (N=5398 (43%)) (reference group). The second group had higher probabilities of hypertension and hypercholesterolemia (vascular-dominant class) (N=5721 (46%)). The third group had higher probabilities of hypertension, hypercholesterolemia, diabetes, and high BMI (vascular/metabolic class) (N=1293 (10%)). Compared to the reference group, the vascular-dominant class (HR:1.14, 95%CI:1.02-1.27, p=.02), and vascular/metabolic class (HR:1.33, 95%CI:1.11-1.59, p=.002) were associated with an increased risk of progression to clinically-diagnosed AD. Compared to the reference group, only the vascular dominant class was associated with an increased risk of progression to neuropathology-confirmed AD (HR:1.40, 95%CI:1.00-1.96, p=.05). Post-hoc analyses determined that compared to other classes, the vascular/metabolic class had the greatest proportion of individuals with underlying cerebrovascular disease (CVD) (46% vs. ≤28%)(X2 (2)=5.76, p=.05).Presence of vascular-dominant, or a combination of vascular/metabolic CVRFs were associated with an increased risk of progression to clinically-diagnosed AD. The fact that vascular/metabolic class was not associated with an increased risk of progression to neuropathology-confirmed AD, suggests that the development of cognitive impairment in this group is due to underlying neurobiological processes such as CVD that are not related to AD.