Sleepless and Stressed: Insomnia May Unlock Stress Link to Alzheimer’s Amyloid Buildup

A good night’s sleep has long been treated as a lifestyle luxury. A new study from Sweden suggests it may be something closer to a biological shield against Alzheimer’s disease, and that the shield weakens dramatically when stress enters the picture. Researchers at Karolinska Institutet, reporting in the Journal of Neurology, found that lifetime exposure to stressful events was associated with greater accumulation of amyloid in the brain, but only in people who also reported moderate to severe insomnia symptoms. In those sleeping well, the same level of stress left no visible molecular fingerprint.

The findings come from the Cortisol and Stress in Alzheimer’s disease cohort, known as Co-STAR, which recruited 124 patients visiting the Karolinska University Hospital memory clinic in Stockholm between 2014 and 2017. None of the participants had dementia; 56 were diagnosed with subjective cognitive impairment and 68 with mild cognitive impairment, making them a population in which the earliest biological changes of Alzheimer’s disease can be observed before overt decline. The participants averaged 61.5 years of age, and nearly 60 percent were women.

What makes the study technically distinctive is its reliance on cerebrospinal fluid, drawn by lumbar puncture as part of routine Swedish memory clinic assessment. The researchers measured three canonical Alzheimer’s biomarkers: beta-amyloid 42, the form of amyloid whose levels drop in spinal fluid as the protein is sequestered into plaques in the brain; total tau, which rises with neurodegeneration; and phosphorylated tau at position 181, which tracks the accumulation of tangled tau filaments. Samples were centrifuged, frozen at minus 80 degrees Celsius, and analyzed with sandwich ELISA, with statistical transformations applied to correct for skewness and outliers.

Stress was assessed in two complementary ways. The 10-item Perceived Stress Scale captured how overwhelmed participants felt during the previous month, while a 16-item inventory recorded stressful life events across the entire life course, from bereavements to prolonged family illness. The life-event measure was further subdivided into recent events occurring within five years, non-recent events, acute events with sudden onset, and chronic stressors of extended duration. Insomnia symptoms were scored from three items of the Karolinska Sleep Questionnaire covering difficulty falling asleep, repeated nightly awakenings, and premature morning awakening, yielding a total score from 0 to 15.

The central result was an interaction. In linear regression models adjusted for age, sex, education, sleep medication use, and depressive symptoms, insomnia and lifetime stressful life event exposure interacted significantly in relation to cerebrospinal fluid amyloid 42. Among participants with low insomnia scores, greater stressor exposure was actually associated with higher amyloid 42 levels. But among those with moderate to high insomnia, greater stress exposure tracked with lower amyloid 42 levels, the signature of greater amyloid deposition in the brain. Similar interaction patterns emerged for chronic stressors, acute stressors, and non-recent events, with the association fading again at very high insomnia scores, producing a non-linear curve that the authors mapped across the full insomnia spectrum.

Notably, the interaction appeared only for amyloid. Neither total tau nor phosphorylated tau showed any significant interplay with insomnia, a pattern consistent with prior research linking sleep disturbance to amyloid but not tau in middle-aged and older adults. Because amyloid accumulation is believed to occur earlier in the disease process than tau pathology, the authors suggest that the combined effects of stress and poor sleep may operate at the earliest stages of Alzheimer’s development, a window when prevention efforts could still alter the trajectory.

The mechanistic story the researchers assemble is a two-pronged attack on amyloid homeostasis. On the production side, animal studies indicate that chronic stress dysregulates glucocorticoid hormones, shifting the cleavage of amyloid precursor protein away from a benign pathway and toward the amyloidogenic one that generates beta-amyloid. On the clearance side, sleep is when the glymphatic system, the brain’s waste-flushing network, is most active, and insomnia impairs the removal of amyloid and tau. Stress therefore increases amyloid supply while insomnia throttles its disposal, and the combination may push amyloid availability past what either factor alone would produce.

Neuroinflammation offers a third converging pathway. Amyloid and inflammation feed each other in a vicious cycle: rising amyloid triggers inflammatory responses that in turn promote further amyloid production and plaque formation. Chronic stress, particularly through dysregulated cortisol secretion, is known to promote the release of pro-inflammatory markers, while chronic sleep deprivation in animal models increases neuroinflammatory signals that predict plaque accumulation. The authors also point to the hippocampus, a structure central to regulating the hypothalamic-pituitary-adrenal stress axis, which has been shown to shrink in chronic insomnia. A sleep-deprived hippocampus may be unusually vulnerable to stress-axis dysregulation, potentially explaining why lifetime stressor exposure, rather than current perceived stress, showed the strongest interactions.

The study also probed sex differences, given well-documented disparities in how men and women experience stress, sleep disturbance, and Alzheimer’s risk. When the analyses were stratified by sex, the direction of the interactions remained consistent in both groups, though statistical power was limited. Intriguingly, the overall association between stressful life events and amyloid 42 appeared to run in opposite directions in men and women, with greater stressor exposure tending toward higher amyloid 42 in men and lower levels in women. The authors urge caution here, but note that animal research and human imaging studies, including one finding that elevated cortisol was linked to greater amyloid deposition specifically in postmenopausal women, support the idea that sex hormones shape the physiological stress response in ways relevant to Alzheimer’s pathology.

The researchers are careful about the limits of their evidence. The design was cross-sectional, so reverse causation cannot be excluded: emerging brain pathology may itself disturb sleep and amplify perceived stress, particularly in a memory clinic population. Stress and insomnia were self-reported, leaving room for recall bias, and the sample of 124 was too small to confirm sex differences statistically. Longitudinal studies beginning before cognitive decline, ideally incorporating objective measures such as actigraphy and diurnal cortisol, are the necessary next step, though the authors caution that cortisol is itself altered by insomnia, complicating such designs. Still, the implications are striking. The 2024 Lancet Commission estimates that up to 45 percent of dementia cases could be delayed or prevented by addressing 14 modifiable risk factors, and this study adds a crucial nuance: risk factors do not act in isolation. Treating insomnia, a common and underdiagnosed condition in older adults, may matter most precisely for those carrying heavy burdens of life stress, suggesting that combination approaches to dementia prevention could outperform any single intervention.

Subject of Research: Interaction between insomnia symptoms and chronic stress exposure in relation to cerebrospinal fluid Alzheimer's disease biomarkers

Article Title: Insomnia symptoms and stress exposure interact in relation to Alzheimer’s disease biomarkers

Article References: Holleman, J., Kåreholt, I., Näsholm, M. S., Sørensen, C., Hagman, G., Aspö, M., Kivipelto, M., Solomon, A., & Sindi, S. (2026). Insomnia symptoms and stress exposure interact in relation to Alzheimer’s disease biomarkers. Journal of Neurology, 273(10), Article 560. https://doi.org/10.1007/s00415-026-14102-7

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14102-7

Keywords: Alzheimer's disease, insomnia, chronic stress, beta-amyloid, tau, cerebrospinal fluid biomarkers, glymphatic system, stressful life events, memory clinic, dementia prevention, neuroinflammation, Karolinska Institutet