Association of Sleep-Disordered Breathing and Medial Temporal Lobe Atrophy in Cognitively Unimpaired Amyloid-Positive Older Adults

Abstract

Background and objectives:Sleep-disordered breathing (SDB) has been related to amyloid deposition and increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions and episodic memory performance in cognitively unimpaired older adults.Methods:Data were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Ageing European project. Participants aged over 65 years old, free of neurological, psychiatric or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir positron emission tomography and magnetic resonance imaging, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy and episodic memory performance at baseline and at a mean follow up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status.Results:We included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aβ+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (β=-0.81, p<0.001, pη2=0.19), whole hippocampal (β=-0.61, p<0.001, pη2=0.10), subiculum (β=-0.56, p=0.002, pη2=0.08), CA1 (β=-0.55, p=0.002, pη2=0.08) and DG (β=-0.53, p=0.003, pη2=0.08) volumes, such that higher sleep apnea severity was related to lower MTL subregions volumes in amyloid-positive individuals, but not those who were amyloid-negative. In the whole cohort, lower whole hippocampal (r=0.27, p=0.005) and CA1 (r=0.28, p=0.003) volumes at baseline were associated with worse episodic memory performance at follow-up.Discussion:Overall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer’s continuum, which may increase the risk of developing memory impairment over time.Trial Registration Information:ClinicalTrials.gov Identifier:NCT02977819

Cerebrovascular pathology mediates associations between hypoxemia during rapid eye movement sleep and medial temporal lobe structure and function in older adults

“…The ERC is known to act as the major input-output structure of the hippocampal formation and nodal point in cortico-hippocampal circuits, stabilizing mnemonic content for long-term storage 128 . Consistent with the presented study findings here, these two regions of the MTL, the hippocampus and ERC, have been shown to be impacted by OSA and hypoxia more broadly in prior studies 6,14,17,20,35,129–138 . These effects are particularly apparent in older adults with subjective and objective cognitive difficulties, where ODI was associated with reduced cortical thickness in the bilateral temporal lobes which in turn was associated with reduced verbal encoding 139 .…”

“…Greater CSVD burden in the frontal region was related to reduced bilateral hippocampal volume and was particularly robust for reduced left ERC thickness, the latter of which was also associated with deficits in sleep-dependent memory. While prior studies have shown that OSA is associated with white matter lesions 21,30 , MTL atrophy 14,20 and memory impairment 19,50,92,93 , these findings indicate that the effects of OSA are potentially linked with MTL degeneration and memory impairment and are likely downstream of the effects of OSA-related hypoxemia on cerebrovascular pathology. Taken together, these data may partially explain how OSA contributes to cognitive decline associated with aging and Alzheimer's disease (AD): through cerebrovascular-mediated degeneration of MTL circuits that support memory consolidation during sleep.…”

“…Obstructive sleep apnea (OSA) is a common, though underdiagnosed, sleep disorder 1 that increases in prevalence with age 2 and is characterized by recurring episodes of complete or partial upper airway collapse during sleep 3 . OSA has been independently associated with reduced regional white matter integrity [4][5][6][7][8][9][10][11][12][13] , altered medial temporal lobe (MTL) morphometry [14][15][16][17][18][19][20] , cerebrovascular pathology [21][22][23][24][25][26][27][28][29][30][31] , and increased risk for cognitive decline [32][33][34] . The relative contributions of distinct OSA features (e.g., sleep architecture changes, hypoxemia severity) to the severity of neuropathological, neurodegenerative, and behavioral consequences remains unclear.…”

Older adults at greater risk for Alzheimer’s disease show stronger associations between sleep apnea severity in REM sleep and verbal memory

“…Future studies are needed that combine multimodal neuroimaging, sleep apnea testing, and other cognitive measures, to examine this in more detail. Regardless, it is important to state that despite the cohort being largely β-amyloid and tau negative, AD risk still remained a significant moderator of OSA-memory relationships, indicating that these effects cannot be entirely explained by and may even precede β-amyloid positivity, despite recent findings [ 26 ].…”

“…Roughly 40-80% of people with AD carry at least one APOE4 allele and older adults with APOE4 may have increased risk for SDB, although this has not been consistently reported [22,23]. Moreover, the effects of APOE4 on the associations between OSA and memory have remained unclear [24,25], though it appears that OSA's effects on memory networks may be stronger in β-amyloid positive older adults [26]. There are also sex differences in both AD and OSA risk.…”