Relationship of cognitive reserve and cerebrospinal fluid biomarkers to clinical symptom onset in Alzheimer's disease

Alzheimer's disease is pathologically characterized by amyloid plaque and tau tangle deposition in the brain. Levels of beta -amyloid and phosphorylated tau (ptau), as measured in cerebrospinal fluid, have been shown to be associated with risk of progressing from normal cognition to onset of clinical symptoms [preceding the diagnosis of mild cognitive impairment (MCI)]. This study examined whether cognitive reserve (CR) modifies this association. CR is the notion that individual differences in lifetime experiences, such as education and cognitive activity, modify the negative effects of brain pathology on clinical expression of symptoms. Cerebrospinal fluid was obtained at baseline from 239 participants (mean age 57.2 years) who have been subsequently followed up to 17 years with annual neuropsychological and clinical assessments. A composite score based on the National Adult Reading Test (NART), WAIS-R vocabulary, and years of education at baseline was used to index CR. Using Cox regression models, we examined the interaction of baseline beta -amyloid, tau, and ptau with CR, using age of onset of clinical symptoms as the outcome. Increased risk of progressing from normal cognition to symptom onset was associated with lower baseline beta -amyloid, higher p-tau, and lower CR. There was no interaction between beta -amyloid and CR, indicating that the protective effects of higher CR are independent of beta -amyloid. In contrast, both tau and p-tau interacted with CR, such that CR was less protective with higher levels of tau and p-tau. This suggests that CR modifies clinical outcome when tau-related pathology in the brain is low but not high.