Abstract
Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels. Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = -0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = -0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = -0.006 [SE, 0.002]; P = .02), pulse pressure (β = -0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = -0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = -3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993]; P = .04) on Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = -0.010 [SE, 0.005]; P = .046). These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.
Highlights
The neuropathological hallmarks of Alzheimer disease (AD) include cerebral β-amyloid peptide (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles
Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by positron emission tomography (PET) was associated with higher total cholesterol level (β = −0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = −0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = −0.006 [SE, 0.002]; P = .02), pulse pressure (β = −0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = −0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications
These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. These associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials
Summary
The neuropathological hallmarks of Alzheimer disease (AD) include cerebral β-amyloid peptide (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. Cholesterol levels and blood pressure (BP) outside of reference ranges, as well as combined vascular risk scores, have been associated with increased Aβ burden in some studies,[2,3,4,5,6,7] but other studies have had conflicting results.[8,9] A few studies found direct and indirect associations of vascular risk factors with increased tau burden,[8,10,11,12] potentially moderated through Aβ burden; a 2009 study[13] did not find these associations.
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