# APOE4 status, sleep disturbances and neuromodulatory subcortical systems in Alzheimer's disease

## TL;DR

This study finds that APOE4 carriers with Alzheimer's disease experience worse sleep and brain changes compared to non-carriers.

## Contribution

The study links APOE4 status to sleep fragmentation and subcortical brain integrity in Alzheimer's patients.

## Key findings

- APOE4 carriers showed higher sleep fragmentation and reduced total sleep time.
- APOE4 carriers had lower integrity in several neuromodulatory nuclei, including the hypothalamus.
- APOE4 carriers experienced greater verbal learning decline over one year.

## Abstract

Sleep alterations are common in Alzheimer's disease (AD) and may be related to the early degeneration of the neuromodulatory subcortical systems (NNS). The Apolipoprotein E‐ϵ4 (APOE4) allele is the major genetic risk factor of sporadic AD and has been associated with a faster rate of cognitive decline. Our aim was to study objective measures of sleep fragmentation and the NNS nuclei integrity in a sample of AD patients according to their APOE4 status.

We included 54 patients with a biomarker‐based diagnosis of AD, classified as APOE4 non‐carriers (n = 25) and carriers (n = 29). Participants underwent clinical and neuropsychological evaluation, CSF extraction, blood sampling, 2‐week actigraphy (Motion Wath 8 device; CamNTech), and magnetic resonance imaging to measure NNS integrity. Analysis of variance (ANOVA) adjusted by age were used to compare the actigraphy measures and the NNS nuclei integrity between APOE4 carriers and non‐carriers. In a subsample (n = 35), we run Repeated Measures ANOVA adjusted by age to explore longitudinal (1‐year follow‐up) neuropsychological performance among groups.

There were no significant differences between APOE4 carriers and non‐carriers in terms of age, years of education, CSF AD biomarker levels or Mini‐Mental State Examination (MMSE) score (all p>0.05; Table 1). Compared to non‐carriers, APOE4 carriers showed a higher sleep fragmentation index (F[1,41]=5.12; p <0.05), increased body movement (F[1,41]=4.61; p <0.05) and decreased total sleep time (F[1,36]=4.79; p <0.05) as measured by actigraphy (Figure 1). APOE4 carriers presented lower integrity (Figure 2) of the preoptic area and paraventricular nucleus (PVN) (F[1,40]=4.65; p <0.05), nucleus accumbens (F[1,40]=5.17; p <0.05), hypothalamus (F[1,40]=9.12; p <0.01), and the right basal forebrain (F[1,40]=6.10; p <0.05). On the contrary, APOE4 carriers showed higher locus coeruleus integrity (F[1,40]=5.12; p <0.05). While there were no between‐group differences in the neuropsychological scores at baseline, APOE4 carriers displayed a higher decline in verbal learning measures at the 1‐year follow‐up (F[1,29]=4.50; p <0.05).

APOE4 carriers present higher sleep fragmentation and a higher vulnerability of several NSS nuclei when compared with non‐carriers. Further longitudinal research is called for to assess the relevance of the current findings as prognostic markers of the disease.