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

Abstract

Importance: Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology.

Objective: To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD.

Design, setting, and participants: A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) 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 Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with 16 or more 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 CR. The study dates were March 5, 2010, to February 13, 2013.

Main outcomes and measures: Cerebrospinal fluid levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42.

Results: There were significant age × CR interactions for CSF t-tau (β [SE] = -6.72 [2.84], P = .02), p-tau (β [SE] = -0.71 [0.27], P = .01), t-tau/Aβ42 (β [SE] = -0.02 [0.01], P = .02), and p-tau/Aβ42 (β [SE] = -0.002 [0.001], P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was 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 composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.

Figure 1

Higher cognitive reserve is associated with a diminution of age-related alterations in CSF biomarkers of AD CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=less than 16 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 1

Higher cognitive reserve is associated with a diminution of age-related alterations in CSF biomarkers of AD CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=less than 16 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 1

Higher cognitive reserve is associated with a diminution of age-related alterations in CSF biomarkers of AD CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=less than 16 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 1

Higher cognitive reserve is associated with a diminution of age-related alterations in CSF biomarkers of AD CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=less than 16 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 1

Higher cognitive reserve is associated with a diminution of age-related alterations in CSF biomarkers of AD CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=less than 16 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 2

Dose-response in the modification of age effect on CSF biomarkers of AD by cognitive reserve CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=8 to 12 years of education; Medium=13 to 15 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 2

Dose-response in the modification of age effect on CSF biomarkers of AD by cognitive reserve CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=8 to 12 years of education; Medium=13 to 15 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 2

Dose-response in the modification of age effect on CSF biomarkers of AD by cognitive reserve CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=8 to 12 years of education; Medium=13 to 15 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 2

Dose-response in the modification of age effect on CSF biomarkers of AD by cognitive reserve CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=8 to 12 years of education; Medium=13 to 15 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).

Figure 2

Dose-response in the modification of age effect on CSF biomarkers of AD by cognitive reserve CSF=cerebrospinal fluid, AD=Alzheimer's disease, CR=cognitive reserve [Low=8 to 12 years of education; Medium=13 to 15 years of education; High=16 or more years of education], t-tau=total tau, p-tau= phosphorylated tau, Aβ42=amyloid-β 42. Panels display adjusted means and standard errors from analyses that, within the pooled sample of cognitively normal and cognitively impaired persons, modeled each CSF biomarker as a function of age, sex, apolipoprotein E4 genotype, cognitive status (i.e., cognitively normal vs. cognitively impaired), CR, and an age*CR interaction. The age*CR interaction term was the effect of primary interest in all models. Because cognitive status was adjusted for in the models, the age*CR effect is deemed to be over and above the influence of cognitive status on the CSF biomarkers. Although age was included in the analyses as a continuous variable, for the purposes of graphing the study findings we chose two anchor points to represent Younger Age (age=50 years, black bars) and Older Age (age=80 years, red bars).