Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease

Rodrigo P. Almeida, Stephanie A. Schultz, Benjamin P. Austin, Elizabeth A. Boots, N. Maritza Dowling, Carey E. Gleason, Barbara B. Bendlin, Mark Sager, Bruce P. Hermann, Henrik Zetterberg, Cindy Carlsson, Sterling Johnson, Sanjay Asthana, Ozioma C. Okonkwo

JAMA Neurology. 2015 Jun;72(6):699-706.


Importance: Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer’s disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. Objective: In this study, we investigated whether cognitive reserve modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. Design, Setting, and Participants: Cross-sectional cohort of 268 individuals (211 cognitively normal and 57 cognitively impaired) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. Additionally, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with ≥16 years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by cognitive reserve. Main outcome measures: CSF levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42. Results: There were significant age*cognitive reserve interactions for CSF t-tau (p=.019), p-tau (p=.009), t-tau/Aβ42 (p=.021), and p-tau/Aβ42 (p=.004). Specifically, with advancing age, individuals with high cognitive reserve exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low cognitive reserve. This attenuation of age effects by cognitive reserve tended to be more pronounced in the cognitively-impaired group compared with the cognitively-normal group. Lastly, there was modest evidence of a dose response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling. Conclusions and Relevance: In a sample comprised of both cognitively normal and cognitively impaired individuals, higher cognitive reserve was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which cognitive reserve might favorably alter lifetime risk for symptomatic AD.


Contributing Lab Members