Association Between Slow-Wave Sleep Loss and Incident Dementia

Abstract

Importance: Slow-wave sleep (SWS) supports the aging brain in many ways, including facilitating the glymphatic clearance of proteins that aggregate in Alzheimer disease. However, the role of SWS in the development of dementia remains equivocal.

Objective: To determine whether SWS loss with aging is associated with the risk of incident dementia and examine whether Alzheimer disease genetic risk or hippocampal volumes suggestive of early neurodegeneration were associated with SWS loss.

Design, setting, and participants: This prospective cohort study included participants in the Framingham Heart Study who completed 2 overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 2001 to 2003. Additional criteria for individuals in this study sample were an age of 60 years or older and no dementia at the time of the second overnight PSG. Data analysis was performed from January 2020 to August 2023.

Exposure: Changes in SWS percentage measured across repeated overnight sleep studies over a mean of 5.2 years apart (range, 4.8-7.1 years).

Main outcome: Risk of incident all-cause dementia adjudicated over 17 years of follow-up from the second PSG.

Results: From the 868 Framingham Heart Study participants who returned for a second PSG, this cohort included 346 participants with a mean age of 69 years (range, 60-87 years); 179 (52%) were female. Aging was associated with SWS loss across repeated overnight sleep studies (mean [SD] change, -0.6 [1.5%] per year; P < .001). Over the next 17 years of follow-up, there were 52 cases of incident dementia. In Cox regression models adjusted for age, sex, cohort, positivity for at least 1 APOE ε4 allele, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% CI, 1.06-1.54; P = .01). SWS loss with aging was accelerated in the presence of Alzheimer disease genetic risk (ie, APOE ε4 allele) but not hippocampal volumes measured proximal to the first PSG.

Conclusions and relevance: This cohort study found that slow-wave sleep percentage declined with aging and Alzheimer disease genetic risk, with greater reductions associated with the risk of incident dementia. These findings suggest that SWS loss may be a modifiable dementia risk factor.

Figure 1.. Overview of the Study Time Points

Exposure variables are shown in light blue and outcomes in medium blue. A, Aim 1 investigates annualized changes in percentage of slow-wave sleep (SWS) measured between the first and second polysomnography (PSG) in association with the risk of incident dementia over the next 17 years of follow-up (n = 347 with 52 incident dementia cases). B, Aim 2 investigates the association between genetic risk of Alzheimer disease dementia and annualized change in SWS percentage (n = 345). C, Aim 2 also investigates if low hippocampal volumes were associated with annualized changes in SWS percentage between the 2 PSG studies (n = 237). Brain magnetic resonance imaging (MRI) was performed once between 1999 and 2003 but before the second PSG. The mean (SD) time interval between the brain MRI and second PSG was 2.23 (0.80) years (maximum, 4.0 years).

Figure 2.. Changes in Sleep and Risk of Dementia

A, Median (IQR) percentage change in each sleep stage per year (N = 346). B, Median (IQR) change in slow-wave sleep (SWS) by 5-year age increments. Results are shown for changes in SWS measured as a percentage of total sleep time (TST) and minutes. Sample sizes are 109 (age 60-65 years), 86 (>65-70 years), 79 (>70-75 years), 61 (>75-80 years), and 15 (>80 years). C, Association between annualized change in each sleep stage and incident all-cause dementia risk, adjusting for age, sex, and cohort (N = 346). For comparison across sleep stage, hazard ratios (HRs) are expressed per percentage increase in each sleep stage per year. Elsewhere, HRs for SWS are expressed per percentage decrease in SWS per year. D, Changes in each sleep stage stratified by individuals who eventually developed dementia (n = 52) and those who did not (n = 295) on follow-up. E, Individual slopes of change in SWS, stratified by individuals who eventually developed dementia (n = 52) and those who did not (n = 295) on follow-up. Participants were classified as having stable SWS if they demonstrated less than a 2.5% change from their baseline value. Otherwise, participants were categorized as increasing or decreasing. F, Cumulative incidence of all-cause dementia by changes in SWS percentage (n = 347). For illustrative purposes, we compare persons who demonstrated a decline in SWS percentage over time vs those whose SWS percentage remained stable or increased. Changes in sleep were measured between the 2 polysomnography studies over a maximum of 7.1 years (mean [SD], 4.8 [0.4] years). Dementia follow-up commenced at the time of the second polysomnography and continued for a maximum of 17 years (mean, 12 years). REM indicates rapid eye movement.

Figure 3.. Changes in Slow-Wave Sleep (SWS) by APOE Allele Status and Hippocampal Volume

A, Median (IQR) annualized change in SWS percentage stratified by APOE allele status, including ε3 homozygotes (n = 232), ε3/ε2 or ε2/ε2 carriers (n = 37), and ε4 allele carriers (ε4/ε4, ε4/ε2, or ε4/ε3; n = 76). B, Median (IQR) annualized change in SWS percentage stratified by low (quintile 1 [n = 49]) and normal (quintiles 2-5 [n = 192]) hippocampal volume on magnetic resonance imaging. Changes in sleep were measured between the 2 polysomnography studies over a maximum of 7.1 years (mean [SD], 5.2 [0.4] years). All values are unadjusted.