O2‐08‐03: LIFETIME MEASURES OF RESERVE ATTENUATE CORTISOL AND β‐AMYLOID‐RELATED RISK OF ALZHEIMER'S DISEASE CLINICAL PROGRESSION FROM THE PRE‐SYMPTOMATIC PHASE

Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity evidenced by elevated glucocorticoid (GC) levels [released as cortisol in man] has emerged as a putative risk factor for accelerated cognitive decline in cognitively normal (CN) elderly individuals with cerebral amyloid abnormalities. This study aims to determine whether elevated cortisol levels predict faster Alzheimer's disease (AD) clinical progression in the presence of abnormal β-Amyloid, and whether this association can be moderated by lifetime measures of reserve. Data from 91 CN individuals with no subjective cognitive complaints at baseline, who took part in the Alzheimer's disease Neuroimaging Initiative (ADNI) study from 2004 and had available morning CSF cortisol and CSF Aβ42 information were retrospectively evaluated. Reserve was modelled as a latent variable calculated as a weighted sum of standardised proxies of brain (indexed by intracranial volume) and cognitive (indexed by premorbid intelligence/ educational/occupational attainment) reserve via exploratory factor analysis(EFA). Covariate-adjusted Cox regression models tested whether the association between GC/Aβ42 and clinical progression within the study period was modified by reserve; after adjusting for age, sex, APOE-genotype status and subclinical depression. Kaplan-Meier (KM) estimates showed that individuals with baseline abnormal Aβ and elevated cortisol levels (GC+/Aβ+) were at highest risk of progression to Mild-Cognitive-Impairment-due-to-AD (MCI-AD) and AD, compared to other biomarker-defined groups. Significant GC+*Aβ+*reserve interaction for clinical progression was noted (HR=0.15, P<0.001), after adjusting for potential confounders; suggesting a moderating effect of the reserve composite on the deleterious association between GC+/Aβ+ and the development of clinically overt cognitive decline. Significantly higher risk for transition to clinical AD state was also detected in individuals carrying at least one APOE-ε4 allele (HR=4.30, P<0.001) and high scores on the Geriatric Depression Scale (GDS), the latter suggestive of subclinical depression/low mood (HR=1.78, P<0.001). Cortisol hyper-secretion at the pre-symptomatic stage is predictive of accelerated clinical progression in cognitively intact individuals, in the presence of abnormal CSF-Aβ42. We present the first evidence for the moderating effects of reserve indicators in terms of clinical progression for pre-symptomatic individuals with both CSF amyloid abnormalities and a hyper-glucocorticoid profile. We are currently investigating the precise role of hypercortisolemia in AD-symptom development using relevant approaches including Mendelian randomization.