PLASMA CORTISOL, AMYLOID-B, AND COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE

Abstract

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer's disease (AD). However, little is known about the role of HPA axis dysregulation in predicting cognitive decline or in moderating the effect of high levels of amyloid-β (Aβ) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Cognitively normal older adults (n=401) enrolled in the AIBL study underwent Aβ neuroimaging at a single timepoint. Plasma cortisol levels were obtained through a fasted blood draw. Comprehensive neuropsychological evaluation yielding measure of global cognition, episodic memory, executive function, language and attention were conducted at baseline and at 18-, 36-, and 54-month follow-up assessments. High plasma cortisol levels at baseline were associated with 2.2 times the risk of Aβ+. Furthermore, high levels of cortisol were associated with greater decline in global cognition generally, and were also found to increase the effect of Aβ+ on decline in global cognition, episodic memory, and attention. Specifically, compared to Aβ+ older adults with low cortisol, Aβ+ older adults with high cortisol had significantly faster decline on these measures, with Cohen's d values of 0.69 for episodic memory, 0.42 for global cognition and 0.31 for attention. These effects were independent of age, education, premorbid intelligence, APOE and BDNF genotypes, subjective memory complaints, vascular risk factors, and depression and anxiety symptoms. In cognitively normal older adults, high plasma cortisol levels are associated with greater decline in global cognition, and accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and attention over at 54-month period. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may help mitigate cognitive decline in the preclinical phase of AD.