Cortisol, Amyloid-β, and Reserve Predicts Alzheimer’s Disease Progression for Cognitively Normal Older Adults

Abstract

Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer's disease (AD), in conjunction with amyloid-␤ (A␤) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) A␤ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and A␤ 42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/A␤ 42 , reserve score and AD progression, adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal A␤ 42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/A␤ reserve interaction for clinical 1 Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.

Cognitive Reserve, Alzheimer’s Neuropathology, and Risk of Dementia: A Systematic Review and Meta-Analysis

“…Nine prospective cohort studies were included in the metaanalytic results (Hohman et al, 2016;Petkus et al, 2019;Pettigrew et al, 2017;Soldan et al, 2013Soldan et al, , 2015Udeh-Momoh et al, 2019;van Loenhoud et al, 2017van Loenhoud et al, , 2019Xu et al, 2019). In order to reduce variability between studies, we extracted the hazard ratios and corresponding confidence intervals associated with high CR at baseline after controlling for relevant structural (Petkus et al, 2019;Pettigrew et al, 2017;Soldan et al, 2015;van Loenhoud et al, 2017van Loenhoud et al, , 2019 or biomarker (Hohman et al, 2016;Soldan et al, 2013;Udeh-Momoh et al, 2019;Xu et al, 2019) covariates. Some studies examined the interaction of CR by neuropathology in addition to the main effect of CR in relation to risk of progression to dementia (Pettigrew et al, 2017;Soldan et al, 2013Soldan et al, , 2015Udeh-Momoh et al, 2019).…”

“…In order to reduce variability between studies, we extracted the hazard ratios and corresponding confidence intervals associated with high CR at baseline after controlling for relevant structural (Petkus et al, 2019;Pettigrew et al, 2017;Soldan et al, 2015;van Loenhoud et al, 2017van Loenhoud et al, , 2019 or biomarker (Hohman et al, 2016;Soldan et al, 2013;Udeh-Momoh et al, 2019;Xu et al, 2019) covariates. Some studies examined the interaction of CR by neuropathology in addition to the main effect of CR in relation to risk of progression to dementia (Pettigrew et al, 2017;Soldan et al, 2013Soldan et al, , 2015Udeh-Momoh et al, 2019). To hone in on the specific effect of CR on risk of progression, we chose to include the main effects of CR on risk of progression from these studies rather than the interaction.…”

“…Nine longitudinal cohort studies were included (Hohman et al, 2016;Petkus et al, 2019;Pettigrew et al, 2017;Soldan et al, 2013Soldan et al, , 2015Udeh-Momoh et al, 2019;van Loenhoud et al, 2017van Loenhoud et al, , 2019Xu et al, 2019). Four studies used the residual variance approach to measure CR (Hohman et al, 2016;Petkus et al, 2019;van Loenhoud et al, 2017van Loenhoud et al, , 2019, where CR was estimated from variance in cognitive performance or structural brain integrity.…”

“…Four studies used the residual variance approach to measure CR (Hohman et al, 2016;Petkus et al, 2019;van Loenhoud et al, 2017van Loenhoud et al, , 2019, where CR was estimated from variance in cognitive performance or structural brain integrity. Five of the studies used a composite proxy approach to measure CR (Pettigrew et al, 2017;Soldan et al, 2013Soldan et al, , 2015Udeh-Momoh et al, 2019;Xu et al, 2019), with the variables comprising the composite proxy including intelligence tests, years of education, occupation, intracranial volume (ICV), cognitive activities, and social activity in late life in various combinations. Markers of AD neuropathology varied somewhat across the nine studies and included measures such as gray matter volume, CSF Aβ, and cortical thickness.…”

“…They controlled for Aβ and tau present post-mortem and found that high CR was associated with a reduced relative risk of dementia progression. Finally, one study investigated whether a composite proxy of CR was associated with reduced relative risk of progression to MCI or AD-dementia from normal cognition (Udeh-Momoh et al, 2019). They controlled for Aβ and cortisol levels in their analyses but did not find that CR was significantly associated with progression to MCI and AD-dementia.…”