The Einstein Aging Study – Stress – Risk of Dementia
According to a recent report published in the journal Alzheimer Disease & Associated Disorders stress may increase up to 30% the risk of developing amnestic mild cognitive impairment (aMCI) or dementia.
Cognitive impairment and dementia are major causes of morbidity and mortality and contribute substantially to health-care expenditures for older adults worldwide. As the population ages, the prevalence of Alzheimer’s dementia (AD) and the pre-dementia states which precede it, such as amnestic mild cognitive impairment (aMCI), are expected to rise.
Mild cognitive impairment is a significant risk factor for the development of dementia and Alzheimer’s disease. Moreover, among all MCI subtypes, patients with amnestic MCI are at greatest risk (A Levey et al., Clin Ther, 2006, 28:991).
Of note, MCI is now considered an intermediate clinical and neuropathological state between the cognitive changes of aging and the very earliest features of Alzheimer’s disease (Ronald C. Petersen, Curr Alzheimer Res, 2009, 6: 324).
Previous research indicates that stress is linked to the pathogenesis of Alzheimer’s disease and that a higher number of psychosocial stressors, particularly in middle-aged women are associated with increased risk of dementia and Alzheimer’s.
Work in animal models have demonstrated that chronic stress plays an important role in Alzheimer’s related neuropathology, including hippocampal vulnerability, accumulation and sustained elevations in tau phosphorylation. This implies that stress measures reflecting chronic influences will exhibit stronger relationships with cognitive outcomes than measures which reflect the frequency of stressful events which may be transient.
In the Alzheimer Disease & Associated Disorders study, a research group from the Albert Einstein College of Medicine, NY and the Pennsylvania State University, PA assessed 507 participants (≥ 70 yrs old) enrolled in the Einstein Aging Study (EAS). All subjects were free of aMCI and dementia at baseline. Stress was assessed using the Perceived Stress Scale (PSS).
The authors used the Perceived Stress Scale (PSS) to measure global life stress during a 30 day period. The PSS was an instrument designed to be sensitive to chronic stress resulting from ongoing life circumstances, possible future events, as well as events not typically listed on event check-lists.
The PSS is a widely used index of psychological stress that is robustly associated with a broad range of biological outcomes hypothesized to be influenced by chronic stress, such as compromised immune function and dysregulated endocrine function.
The authors report that the stress level correlated with the participants’ risk for developing aMCI. Subjects in the highest-stress quintile had an almost 2.5-times greater risk of developing aMCI as compared to those in the remaining four quintiles combined.
Interestingly, the study’s participants in the high-stress group were more likely to be female with higher levels of depression, but depression did not appear to interfere with the effect of stress on aMCI.
The results suggest that the effects of PSS on aMCI onset are independent of demographic features, depression and APOE ε4 allele status.
The magnitude of the hazard ratios, the consistency of results after adjusting for multiple covariates and the stability of results when perceived stress is modeled as either a categorical or continuous variable suggests that these findings are robust.
There have been few longitudinal, community-based studies that have focused on perceived stress as a risk factor for incident aMCI or dementia. None have examined perceived stress in relation to the incidence of aMCI.
As a modifiable risk factor, perceived stress should be considered to be targeted in preventive interventions including mindfulness-based stress reduction, cognitive–behavioral therapies, and pharmacologic interventions that aim to reduce cognitive decline.
Effect of stress on cognition may be mediated through multiple physiological pathways involving the central nervous, neuroendocrine, immune and cardiovascular systems. Neuroendocrine effects are thought to be primarily mediated through the activation of the HPA axis, marked by increased levels of corticotrophin releasing factor (CRF), adrenocorticotropic hormone (ACTH) and glucocorticoids.
These neuroendocrine changes lead to alteration of brain structure and function in the prefrontal cortex and hippocampus, among other brain regions.
Source: Alzheimer Dis Assoc Disord. 2015 Dec 10.
Updates
2017
A 2017 study by Julie M Jiang et al. tested the internal consistency, one-year retest stability, concurrent validity, and predictive validity of evaluating the Perceived Stress Scale (PSS) as separate subscale scores in older adults.
The objective of the study was to evaluate the internal consistency, test-retest reliability, and the concurrent and predictive validity for development of amnestic mild cognitive impairment (aMCI) of the positively-worded (PSS-PW) and negatively-worded (PSS-NW) subscale scores of the PSS in older adults.
Background: The Perceived Stress Scale (PSS) is made up of two subscales but is typically used as a single summary measure. However, research has shown that the two subscales may have differential properties in older adults. Perceived stress occurs when environmental demands exceed an individual’s ability to cope with them. One of the most frequently used measures of perceived stress is Cohen’s Perceived Stress Scale (PSS). High scores on the PSS have been associated with a variety of adverse outcomes including but not limited to cognitive decline, depression, pain and poor wound healing.
The authors reported that the PSS-PW (α = 0.85) and PSS-NW (α = 0.83) showed good internal consistency reliability in older adults. Both subscales correlated with depressive symptoms, neuroticism, negative affect, and baseline cognitive status. Only the PSS-PW correlated with positive affect; only the PSS-NW correlated with anxiety.
Also, the PSS-PW, but not the PSS-NW, significantly predicted incident aMCI (HR=1.27; 95% CI:1.06–1.52; p=0.009 for a 5-point change in PSS-PW) after adjusting for age, sex, white race, years of education, depressive symptoms, and baseline cognitive status. These results were robust and were significant when viewing the PSS-PW as both a continuous and dichotomous variable.
The authors discussed that the PSS has commonly been used to evaluate the effectiveness of stress reduction interventions in a variety of populations. Interventions designed to reduce stress include meditation, mindfulness based stress reduction, yoga, to name a few. All of these studies have used total PSS scores as a primary outcome, but is possible that it would be better to measure perceived stress as PSS-PW and PSS-NW subscales instead of a total score.
2020
A 2020 study by Megan Zuelsdorff et al. examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). The authors reported that greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory.
The authors concluded that exposure to self-reported lifetime stressful events associated negatively with cognitive test performance within both White and African American participants, though the domains affected varied by race. African Americans also reported significantly greater exposure to stressors. Cumulative stressful life events partially accounted for observable racial gaps in Speed & Flexibility. According to the authors the study contributed additional evidence that life course socio-environmental factors are important determinants of later-life cognitive trajectories and dementia risk.
2023
A 2023 study suggested an increased risk for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) if a patient with depression is additionally exposed to chronic stress, as indicated by the ‘diagnosis’ stress-induced exhaustion (SED).
Both preceding depression and SED were independently associated with increased risk for MCI and AD, but only depression was associated with increased risk for other dementia i.e., Lewy body, vascular and mixed dementia.
However, according to the authors, as there were only a few cases, this association needs confirmation. The marked additional effect of chronic stress in patients with depression for developing MCI or dementia has, as per the authors, has not been previously “presented in an epidemiological cohort study”.
Thus, the investigators concluded that their results suggest that chronic stress increased the risk of mild cognitive impairment and Alzheimer’s disease. The same was seen with depression. The novel finding is
the potential additive effect of chronic stress to depression, on risk of MCI and AD.
2024
A 2024 review by Mia Burke, Ioannis Sotiropoulos and Clarissa Waites outlined some recent findings from mechanistic studies in rodent and cellular models, wherein defined chronic stress protocols or glucocorticoids (GCs) administration have been shown to elicit Alzheimer’s disease (AD)-related pathology. The authors specifically discussed the effects of chronic stress and GCs on tau pathogenesis, including hyperphosphorylation, aggregation, and spreading, amyloid precursor protein (APP) processing and trafficking culminating in Aβ production, immune priming by proinflammatory cytokines and disease-associated molecular patterns, and alterations to glial cell and blood-brain barrier (BBB) function.
Highlights
– Chronic stress and glucocorticoids (GCs) are implicated in the tau, amyloid β (Aβ), and neuroinflammatory pathology, characteristic of Alzheimer’s disease.
– Stress and GCs activate kinases and inhibit proteostasis mechanisms, thus driving tau hyperphosphorylation, aggregation, and secretion/spreading through the brain.
– Stress and GCs promote Aβ pathology by increasing the expression and amyloidogenic processing of amyloid precursor protein (APP) and by impairing APP and Aβ clearance mechanisms.
– Stress and GCs stimulate neuroinflammation through upregulation of the inflammasome and damage-associated molecular pattern (DAMP) receptors, thereby promoting the secretion of proinflammatory cytokines.
– Stress and GCs induce aberrant glial cell functioning, leading to over-pruning of synapses, glutamate excitotoxicity, and decreased integrity of the blood–brain barrier (BBB) and glymphatic clearance systems.
2025
A 2025 review by Mary Kate P. Joyce, Stacy Uchendu and Amy F.T. Arnsten summarized the cellular mechanisms by which stress and inflammation impact the dorsolateral prefrontal cortex (dlPFC).
Background: Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC). The PFC is essential for generating and sustaining the mental representations that are foundational to working memory, abstract thought, and goal-directed (top-down) regulation of attention, action, and emotion, including flexible, high-level decision making and metacognitive functions such as insight about oneself and others.
According to the authors, we are beginning to learn about the molecular events that occur with stress and inflammation that erode the ability of the PFC to provide top-down regulation of thought, action, and emotion. New research with marmosets has begun to dissect the functional circuits that emanate from BA 25 that contribute to symptoms found in mood and stress disorders and may also begin to reveal how serotonin, NMDARs, and inflammatory mechanisms alter the activity of this key brain region.
This work is consistent with the extensive neuroanatomical tracing studies that have shown that the more recently evolved PFC circuits, e.g., in the dlPFC and frontal pole, are positioned to regulate BA 25 and the more primitive circuits that generate emotional responding. This research has provided an anatomical framework for understanding how neuro-modulatory technologies such as rTMS and deep brain stimulation can rebalance brain activity.
Another 2025 review by Paul J Lucassen et al. discussed some recent preclinical findings on putative substrates that can explain or contribute to the effects of stress early in life on the risk of developing Alzheimer’s disease (AD).
The authors concluded that various (pre)clinical lines of evidence suggest that negative experiences early in life can modulate the trajectory of cognitive decline and the onset, incidence, and progression of (aspects of) AD. This emphasizes the importance of better understanding the mechanisms by which early-life stress (ELS) can alter AD features.
This includes alterations in E/I balance, synapse function, mitochondria, lipid metabolism, neurogenesis, and neuroinflammation and may render brain cells and networks less able to adapt to AD pathology, thereby decreasing resilience and advancing AD onset.
Preclinical models have helped identify several putative substrates, but human data on similar mechanisms remain scarce. Whereas the importance of the early-life period for psychopathologies, such as depression, is generally recognized, research should also focus on this critical period for the brain in relation to AD.
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