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Older adults who report more sleep problems tend to have elevated levels of the Alzheimer's disease (AD) biomarker beta-amyloid (Ab42), but the mechanisms responsible for this relationship are largely unknown. Molecular markers of sleep problems are now emerging from rodent research, yielding opportunities to generate hypotheses about the causes of the sleep-Ab42 relationship. A major molecular marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, involved in control of sleep homeostasis and also implied in Ab42 accumulation. Here, in a sample of 109 cognitively healthy middle-aged and older adults, we tested whether the relationship between cortical Ab42 accumulation and self-reported sleep quality, as well as changes in sleep quality over three years, was stronger in cortical regions with high HOMER1 mRNA expression levels. Ab42 correlated with poorer sleep quality cross-sectionally and longitudinally. This relationship was stronger in the younger (50-67 years) than the older (68-81 years) participants. Effects were mainly found in regions with high expression of HOMER1, suggesting a possible molecular pathway between sleep problems and Ab42 accumulation. The anatomical distribution of the sleep-Ab42 relationships followed closely the Ab42 accumulation pattern in 69 patients with mild cognitive impairment (MCI) or AD. Thus, the results indicate that the relationship between sleep problems and Ab42-accumulation may involve Homer1 activity in the cortical regions that harbor Ab42 in AD. Analysis of cortical gene expression patterns represent a promising avenue to unveil molecular mechanisms behind the relationship between sleep problems and AD risk.

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