New research suggests that, in older women with higher genetic risk for Alzheimer’s disease, sleep complaints may track with visual memory decline and early tau buildup in brain regions vulnerable to AD.
Study: Sleep complaints and genetic risk of Alzheimer’s disease in older women: associations with memory and tau deposition. Image Credit: ER Pictures / Shutterstock
Alzheimer’s disease (AD) is a chronic progressive incurable neurodegenerative disease affecting millions of people worldwide. Identifying markers of modifiable risk would help to frame preventive interventions. A recent study published in The Journal of Prevention of Alzheimer’s Disease found that poor sleep was associated with Alzheimer’s disease (AD)-related cognitive and tau changes in older women, especially if they have a higher genetic risk for the condition.
Early tau protein and sleep cycle changes in AD
Existing studies indicate that sleep disruption occurs before the observable accumulation of beta-amyloid plaque deposition characteristic of AD. Poor sleep predicts clinical symptoms and is associated with a higher risk of AD dementia.
Other research has shown that phosphorylated tau builds up earliest in brain regions that help regulate sleep-wake cycles, and is involved in disrupting sleep and normal circadian rhythms. This occurs decades before either clinical symptoms or amyloid-beta plaques appear, at the earliest stages of AD.
Thus, the evidence suggests that poor sleep is not just a consequence of tau accumulation but may also contribute to AD progression. “This bidirectional relationship creates a vicious cycle in which sleep disruption and AD pathogenesis mutually reinforce each other, contributing to progressive cognitive and functional decline.”
Women and AD risk
Women make up two-thirds of AD cases, but mild cognitive impairment (MCI) in women is more likely to be diagnosed late because of their increased verbal memory capabilities relative to men. However, once MCI sets in, verbal memory loss occurs faster in women than in men.
Visual memory tests, in contrast, show similarly robust associations with AD risk and AD brain changes and may sometimes be more sensitive than verbal memory tests, though with fewer obvious sex-specific differences. This suggests that assessing both visual and verbal memory may help identify early signs of incipient AD-related change.
Women are also more likely to complain of poor sleep but less likely to be diagnosed and treated for it. Poor sleep in women is more strongly associated with cognitive decline, hippocampal atrophy, and AD incidence. Moreover, menopause-related changes in sleep often persist into older age. All these factors, coupled with the accelerated buildup of tau in women, may put them at higher risk for AD from sleep disruption, compared to men.
APOE ε4 and genetic AD risk
One possible mechanism linking disrupted sleep and tau burden could involve the apolipoprotein E (APOE) ε4 genotype, which is postulated to accelerate tau accumulation earlier in life within sleep-regulating brain regions. Women who carry this genotype progress faster into clinically manifest AD, with faster tau buildup and memory loss, compared to either men carrying ε4 or women without this genotype.
The use of a polygenic hazard score (PHS) rather than only APOE ε4 can increase the sensitivity of estimation of genetic AD risk, predicting age of AD onset, amyloid-beta and tau accumulation, and cognitive impairment. It can predict the age of onset even in non-carriers of APOE ε4.
Exploring genetic AD risk, sleep, and cognitive impairment associations
The current study merged these areas, exploring the effect of genetic AD risk on the association between subjective sleep and memory and tau accumulation in women aged 65 or older. Tau burden was measured within composite brain regions across Braak stages of AD progression.
The participants were part of the ongoing Women Inflammation Tau Study, with an average age of 72.5 years. They were assessed for subjective sleep quality, verbal and visuospatial memory tests, and positron emission tomography (PET) imaging. Genetic risk was estimated using the polygenic hazard score (PHS), including whether or not they carried at least one apolipoprotein E (APOE) ε4 allele.
Higher genetic risk predicts sleep-associated visual memory impairment
Of the 69 participants, 26 had a higher-risk PHS and were all APOE ε4 carriers, compared with 7% among the 43 women with a lower-risk score. Unexpectedly, the higher-risk PHS group reported fewer sleep complaints.
The higher-risk group had a greater accumulation of abnormal tau than the lower-risk PHS group. Sleep disruption was associated with worse visual memory in the higher-risk PHS group. However, despite a fairly large effect size, the interaction between sleep quality and genetic risk was only marginally significant.
When stratified by PHS, the researchers found that poor sleep was associated with worse visual memory and greater tau burden in Braak regions III/IV, but only in the higher-risk group. Meanwhile, sleep quality did not interact with the PHS on verbal memory score.
The study could not clarify whether women with higher genetic AD risk are more vulnerable to poor sleep, since lower-risk women had worse subjective sleep than higher-risk women. Findings from earlier studies involving APOE ε4 carriers have been inconsistent. The researchers hypothesize that women with MCI might not accurately recall sleep quality.
The specific contribution of APOE ε4 to the association of poor subjective sleep with genetic AD risk could not be separately assessed in this study, and the role of the other PHS components remains unclear.
Study limitations
The study results may not be generalizable due to the sample's mostly White composition and the use of a genetic risk score developed primarily in White European populations. No corrections were made for multiple comparisons. The study might have been underpowered to detect interactions between subjective sleep and genetic risk, though the authors plan to repeat these analyses once data collection is complete and to assess longitudinal relationships.
Conclusion
For older women with a high genetic risk, poorer subjective sleep quality was associated with deficits in visual memory and increased tau accumulation in the regions affected in the early stages of AD. The researchers suggest that sleep disruption may be a risk factor for AD, making sleep interventions a possible strategy to support AD risk mitigation and prevention research, particularly in older women.
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