Association of Vascular Risk Factors With β-Amyloid Peptide and Tau Burdens in Cognitively Unimpaired Individuals and Its Interaction With Vascular Medication Use

Question  Does cardiovascular medication use moderate the association of vascular risk factors with Alzheimer disease pathogenesis as measured by β-amyloid peptide and tau burdens among individuals who are cognitively unimpaired?

Findings  In this cross-sectional study of 215 middle- and late-aged adults who were cognitively unimpaired, use of vascular medications moderated an association of higher lipid levels, blood pressure, and combined vascular risk scores with increased brain β-amyloid peptide burden. Regarding tau burden, use of vascular medications moderated none but the association of combined vascular risk with higher entorhinal tau deposition.

Meaning  This finding suggests that in individuals at risk for Alzheimer disease, treatment for common vascular risk factors may moderate or mask the associations of these factors with β-amyloid peptide burden.

Importance  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.

Objectives  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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.

Results  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).

Conclusions and Relevance  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.