PROJECT SUMMARY
Stress is theorized to be involved in Alzheimer’s disease (AD) pathogenesis and progression. In animal
models, stress hormones can induce states similar to those seen in AD, such as impaired glucose metabolism,
inflammation of the brain, and increased ¿-amyloid (A¿) and hyperphosphorylated tau in the brain.
Unfortunately, the effect of stress on AD pathogenesis in humans is more difficult to establish. Currently, the
relationship between stress and AD in humans is limited to correlational studies. For instance, individuals with
mild cognitive impairment and AD have higher stress hormone (cortisol) levels throughout the day and do not
efficiently shut down the stress response. Other work suggests that greater stress system dysfunction is
associated with more rapid disease progression. Still other research suggests that veterans with a history of
post-traumatic stress disorder had a two-fold increase in AD development, while a series of studies in women
suggests that stress in midlife is related to an increased risk of AD diagnosis later in life. These studies suggest
there is a long-term and possibly cumulative effect of stress exposure on later AD outcomes, however, these
observational studies do not sufficiently address potential mechanisms connecting stress exposure to AD risk.
In particular, we lack information about whether stressors influence A¿ levels in humans. This proposal targets
this gap by asking, “does acute stress increase A¿ levels in humans?” We will achieve this by measuring the
plasma A¿ response to an acute laboratory stressor, the socially evaluated cold pressor test. Thirty-eight
women and men aged 18-65 will complete a laboratory stressor involving holding their hand in ice water for an
amount of time unknown to the participant while their reactions to the stressor are videotaped. Participants will
also complete a non-stressful task in lieu of the stressor in a separate session. At both sessions, stress
activation will be measured using changes in salivary free cortisol levels and in heart rate variability, and blood
samples will be collected for measuring the A¿ response to stress. We predict that cortisol and plasma A¿
levels will increase, and heart rate variability will decrease, during the stress session but not during the control
session. We further predict that the magnitude of change in salivary free cortisol and heart rate variability in
response to stress will be related to the magnitude of change of plasma A¿ in response to stress.
Understanding how stress may trigger AD-related processes is an important step in understanding how stress
contributes to AD development and progression in people. This proposal will address this important gap in the
stress-AD literature by translating the effects of acute stress on A¿ production observed in animal models to
humans. Findings from this study will help develop a mechanistic pathway for how repeated or cumulative
stress increases AD risk and pathogenesis later in life and drive future avenues of research in AD development
and AD treatment options, especially during the prodromal stage of the disease when decreasing stress-
related A¿ production might protect against AD-pathogenesis and progression.