Tau‐derived Locus coeruleus degeneration as a driver for sleep‐wake alterations and neuropsychiatric symptoms in early and late‐onset Alzheimer’s Disease

Abstract

AbstractBackgroundEarly‐onset Alzheimer’s Disease presentations (EOAD, under 65) frequently present with atypical phenotypes and a more aggressive disease course with a higher burden of neuropsychiatric symptoms than late‐onset AD (LOAD). Current treatments for sleep and behavioral disturbances are still non‐specific, causing side effects (e.g., sedation, falls). Identifying the underlying changes driving behavioral differences between EOAD and LOAD is crucial to developing tailored treatment avenues. The noradrenergic locus coeruleus (LC), one of the first sites of tau deposition in AD, has been implicated in sleep‐wake patterns and mood regulation. We aim to test the hypothesis that the LC is more affected in EOAD than LOAD by comparing LC volume (neuromelanin‐sensitive MRI) and sleep‐behavioral symptoms in biomarker‐confirmed EOAD and LOAD cohorts.MethodFifty‐four subjects with AD biomarker‐based diagnosis (20 EOAD, 34 LOAD) were recruited at the Hospital Clínic de Barcelona. All participants and informants completed the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Neuropsychiatric Inventory (NPI) questionnaires to assess the severity of sleep‐wake alterations and neuropsychiatric symptoms. In addition, they underwent a 3T turbospin‐echo MRI to measure LC volume. We compared mean values of LC volume, ESS, PSQI, and NPI between EOAD and LOAD. Furthermore, linear regression models controlling by cognitive status (MMSE) were performed.ResultEOAD and LOAD had similar cognition (MMSE 21.3±5 vs. 22.6±4, respectively), functional status (CDR 0.92±0.1 vs. 0.68±0.1), and prevalence of amnestic phenotype (57 vs. 70%). EOAD compared to LOAD, trended towards higher scores for ESS (7.4±1 vs. 5.1±1, respectively), PSQI (7.3±2 vs. 5.6±1), NPI (21.6±8 vs. 14.6±8), and caregiver distress (9.4±3 vs. 4.7±3). LC volume was lower in EOAD according to preliminary MRI data [n=18, 9 EOAD (21.8±3 mm3), 9 LOAD (29.5±3 mm3)]. Linear regression models showed that MMSE did not influence the EOAD/LOAD effect on LC volume (coef. 7.7, p=0.032).ConclusionThe current preliminary study suggests that LC degeneration is greater in EOAD than LOAD. This difference may explain the EOAD‐associated worse sleep‐wake dysfunction and neuropsychiatric symptoms. Deep phenotyping/comparison of EOAD and LOAD can inform tailored treatment strategies for these behavioral symptoms.