INTRODUCTION:

•   Alzheimer's disease (AD) is characterized by the pathological accumulation of Aβ and tau proteins, detectable decades before cognitive symptoms emerge¹, granting a critical window for prevention strategies.

 •   The glymphatic system plays a key role in clearing these proteins, a process that occurs primarily during slow-wave sleep (SWS)², which is also the sleep stage during which memory consolidation takes place³. Therefore, SWS emerges as a potential modifiable risk factor in AD pathophysiology.

 •   However, whether objective SWS quality associates with glymphatic and cognitive function over time in cognitively healthy adults at elevated AD risk remains poorly understood.

 •   Given that AD disproportionately affects women, it is also unknown whether these associations differ by sex, a gap that could help explain women's unequal vulnerability to the disease.

AIM:

To test wheter SWS parameters are related to glymphatic function and cognitive trajectories in a cohort of healthy older adults at increased risk of AD.

METHODS:

Cohort:

The study comprised 76 cognitively unimpaired ALFA+ cohort participants (65.09 ± 4.56 years, 57.9% women, 65.8 APOE-ε4 carriers) followed every 3 years for 2-4 visits. (Table 1)

PSG: 

Polysomnography was performed at visit 2, when participants were free of sleep medication. Individuals presenting severe sleep apnea (AHI>30) were excluded.

SWS parameters:

 •   PSG time during lights off was classified into sleep stages. Only deep non rapid eye movement (NREM) sleep periods (N2 and N3) were considered.

 •   EEG signals from the frontal channels (F3 and F4) were used to compute the power spectral density at different frequency ranges:

   - Slow oscillation (SO, 0.5-1Hz),

   - delta (1-4Hz), and

   - slow-wave activity (SWA, 0.5-4Hz)

 •   Slow waves (SW) were detected following the YASA⁴ algorithm. Average SW slope and peak-to-peak (PTP) amplitude (Figure 1) were measured for each individual.

Glymphatic function:

Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS)⁵ was measured as a proxy for the glymphatic function in each available visit (mean 2.8 visits, range 6.30 ± 0.59 years)

 Cognitive performance:

 Cognitive performance was evaluated with the Preclinical Alzheimer Cognitive Composite (PACC) in each available visit (mean 3.1 visits, range 6.60 ± 0.87 years).

 Statistics:

 •   Linear mixed-effects models were used to test associations between sleep metrics and DTI-ALPS and between sleep metrics and PACC.

 •   Models were adjusted for age, sex, and APOE-ɛ4 status, and for education for cognitive outcomes.

 •   Stratified analyses were performed to test sex differences in these associations.

RESULTS:

 •   Delta power was significantly associated with higher DTI-ALPS values, without significant effects over time.

 •   SW slope and PTP amplitude were associated with better PACC over time.

 •   Results were driven by men (no significant associations for the women subsample):

      •  SO power and SW PTP amplitude were associated with higher DTI-ALPS values

      •  power of SO, delta and SWA, and SW slope and PTP amplitude were associated with better PACC over time.

CONCLUSIONS: