Alzheimer’s disease (AD), a progressive neurodegenerative disorder and common cause of dementia, affects millions worldwide (Hebert et al., 2013). Characterized by accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein, AD leads to a decline in cognitive function, ultimately impairing daily life activities. Early detection and intervention are crucial for altering the course of AD, offering a window of opportunity to delay or prevent progression to overt cognitive impairment. Midlife is increasingly recognized as a crucial period for early changes in cognitive function that may lead to dementia, as research shows that molecular, cellular, and structural brain alterations—such as hippocampal shrinkage, white matter loss, and neuroinflammation—accelerate during this time, setting the stage for later cognitive decline (Deckers et al., 2015; Karlamangla et al., 2017; Dohm-Hansen et al., 2024; Won et al., 2025). Within this context, biomarkers related to the pathological hallmarks of AD have emerged as potential early predictors. Our most recent findings indicate that a lower Aβ42/40 ratio and higher phosphorylated tau181 (p-tau181) levels in midlife women are associated with accelerated cognitive decline from mid-to late life (Wang et al., 2024). These results underscore the potential of these biomarkers in signaling early changes, identifying potential risk factors, and understanding mechanisms of neurodegeneration.

The role of essential trace elements in AD has garnered increased attention, with elements such as chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), selenium (Se), and molybdenum (Mo) crucial for biological functions. Dysregulation in homeostasis of these elements is implicated in AD pathogenesis (De Benedictis et al., 2019). Cu and Zn, for example, directly bind Aβ, facilitating aggregation into insoluble fibrils and oligomers, potentially promoting development of senile plaques (Bush, 2013; Squitti et al., 2014). Fe is implicated in hyperphosphorylation of tau protein, leading to neurofibrillary tangle formation (Derry et al., 2020). Mn and Se are crucial in modulating oxidative stress, and alterations in their homeostasis can exacerbate oxidative damage and neuroinflammation (Takeda, 2003; Cardoso et al., 2015). With the exception of Se, human studies examining the potential effects of essential trace elements are relatively limited and have focused on cognitive correlates (Cheng et al., 2022; Shang et al., 2021; Gu et al., 2021). Lower levels of Se were found in AD patients compared to control groups, suggesting a potential protective role of Se against AD pathogenesis (Varikasuvu et al., 2019; Loef et al., 2011). The majority of prior research focused on older populations and to date, no study has investigated potential associations between essential trace elements and AD biomarkers in midlife.

To address this research gap, we investigated the associations between serum levels of essential trace elements (Mn, Fe, Co, Cu, Zn, Se, and Mo) and serum levels of AD biomarkers (Aβ42, the Aβ42/Aβ40 ratio, p-tau181, and total tau) in 189 midlife women from the Study of Women’s Health Across the Nation (SWAN) at the Michigan site.

This study revealed associations between serum levels of essential trace elements and AD biomarkers in midlife women. We found that higher levels of Mo were associated with higher Aβ42/40 ratio, and elevated Co levels associated positively with p-tau181 levels. Additionally, Cu showed an inverse association with the Aβ42/40 ratio, while Zn was positively associated with Aβ42/40 respectively, though associations were borderline statistically significant.

Our findings regarding the association between higher Mo and higher Aβ42/40 ratio might indicate a potential protective role of Mo against Aβ aggregation. Aβ42 is more prone to aggregation and plaque formation than Aβ40, and thus, a lower Aβ42/40 ratio is typically indicative of a shift toward a pathological state in which amyloid plaques are more likely to form in the brain (Hampel et al., 2021). This shift has been associated with accelerated cognitive decline and AD progression (Wang et al., 2024; Giudici et al., 2020; Graff-Radford et al., 2007). Notably, the Aβ42/40 ratio is considered a more sensitive marker of amyloid pathology than Aβ42 alone. Mo deficiency is rare (Novotny, 2011), and the Mo levels in our study were within the range of a previous study of healthy women (Versieck et al., 1978). An essential cofactor for enzymes including sulfite oxidase, aldehyde oxidase, and xanthine oxidase, Mo is pivotal in biological mechanisms including oxidative stress regulation, purine metabolism, and potential modulation of Aβ dynamics (Botchway et al., 2023). By facilitating the activity of antioxidant enzymes, Mo might mitigate oxidative damage to neurons (Wang et al., 2014) and influence uric acid levels (Coelho et al., 2022), a correlate of reduced risk of AD and cognitive decline (Scheepers et al., 2019; Liu et al., 2017). Thus, several potential mechanisms exist for which Mo could impact AD progression. Recent experimental model work highlighted the potential of Mo-containing compounds to directly interfere with Aβ aggregation and promote Aβ clearance (Han et al., 2019). There is a notable scarcity of human studies specifically examining the association of Mo with AD or its biomarkers. A few studies explored the relationship between Mo levels and cognitive functions, with mixed results (Smorgon et al., 2004; Xiao et al., 2021). Another study comparing trace element concentrations demonstrated that serum molybdenum levels were significantly lower in patients with AD or mild cognitive impairment compared to individuals with subjective memory complaints and cognitively normal controls (Paglia et al., 2016).

The observed association between higher Co levels and elevated p-tau181 levels in our study, with serum Co levels in the normal range (Chen and Lee, 2024), suggests a potential neurotoxic pathway that may contribute to the pathogenesis of AD. Co, vital for vitamin B12 synthesis, is implicated in neurodegeneration through pathways outside its traditional nutritional roles (Jatoi et al., 2020). This is highlighted by potential links between Co levels and Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN-1) expression. Reduced PIN-1 activity is implicated in pathologic processing of tau and amyloid precursor protein (APP). A recent murine model study demonstrated that Co exposure decreases PIN-1 expression, leading to cell cycle arrest and apoptosis in neuroglioma cells (Zheng et al., 2021). Elevated blood Co levels were associated with disrupted PIN-1 activity, increased tau phosphorylation, and neuronal loss in cerebral cortex and hippocampus. The same research group showed an inversed association between blood Co and PIN-1 levels in 30 patients with cobalt alloy hip replacements, supporting findings from animal studies (Zheng et al., 2021). Additionally, exposure to Co in mice has been shown to induce tau hyperphosphorylation, Aβ deposition, and dysregulated autophagy in the hippocampus and cortex, mediated by an increase in ROS production through the activation of hypoxia-inducible factor-1α (Tang et al., 2023). Direct research in humans investigating the cobalt-AD linkage is limited. A recent study involving over 6,000 participants with a mean age of 62 years at baseline found that baseline urinary Co concentration was associated with lower cognitive performance measured 10 years later, especially among APOE4 carriers (Domingo-Relloso et al., 2024).

Our research provides evidence for potential associations of Cu and Zn with AD biomarkers, though these findings are of marginal statistical significance. These trace elements are implicated in various neurological functions and their dysregulation may contribute to the pathogenesis of AD. Cu is crucial for brain functions such as oxygen transport, neurotransmitter synthesis, and energy metabolism (Botchway et al., 2023). Dysregulated Cu homeostasis is potentially associated with AD pathology through several mechanisms. Elevated levels of ceruloplasmin, a Cu-binding protein, in AD patients suggest altered Cu homeostasis (Wang et al., 2015; Squitti, 2012). However, ceruloplasmin is generally and non-specifically elevated in inflammatory states, which may complicate its role as a specific marker for AD-related Cu dysregulation. The role of Cu in glutamatergic neurotransmission is also linked to the glutamatergic dysfunction observed in AD (Zheng et al., 2010). Additionally, Cu may directly interact with APP, affecting amyloidogenic processing and promoting the synthesis of Aβ peptides (Jacobsen and Iverfeldt, 2009; Thinakaran and Koo, 2008). However, the therapeutic use of copper chelators in AD patients has not yielded significant results, indicating that targeting Cu through chelation alone may not be sufficient to alter disease progression (Gromadzka et al., 2020). Zn is essential for metalloenzyme activity, neurotransmission, neurogenesis, and cognitive functions such as learning and memory. In AD, disruptions in Zn homeostasis, particularly the inhibited expression of Zn transporters, may contribute to disease progression (Xu et al., 2019). Evidence on Zn supplementation is mixed. While some animal studies have reported adverse effects of Zn on Aβ and APP, which further linked to compromised memory and spatial learning (Wang et al., 2010; Yang et al., 2013), Zn supplementation has shown promise in improving cognitive function, reducing Aβ and tau pathologies, and regulating oxidative stress in other animal studies and clinical trials (Corona et al., 2010; Sandusky-Beltran et al., 2017; Hosseini et al., 2021). Together, these findings highlight the complex roles of Cu and Zn in AD and underscore the need for further research using brain-specific measures and mechanistic studies to clarify their potential as targets for intervention.

To our knowledge, this is the first investigation of relationships between essential trace elements and AD biomarkers in midlife adults. Our findings offer important considerations for approaches to AD prevention, perhaps including modulation of trace element levels as part of a broader strategy that includes lifestyle and dietary interventions. However, our findings are limited by the modest sample size drawn from the SWAN Michigan cohort, which impacts statistical power. Furthermore, the study population composition, excluding men and limited to Black and White women by design, narrows the generalizability of our findings. Moreover, our cross-sectional assessment of element levels and AD biomarkers were confined to a single time point. We encourage future investigations to incorporate repeated assessments of AD biomarkers to explore the relationship between trace elements and their longitudinal changes.

In summary, our study provides novel results on associations between serum levels of essential trace elements and AD biomarkers in midlife women. We identified significant associations of Mo and Co with AD biomarkers, with Mo potentially offering protective effects against Aβ aggregation and Co suggesting a neurotoxic pathway linked to tau phosphorylation. Our research also highlights the importance of Cu and Zn in AD biomarker profiles, despite marginal statistical significances, pointing to their roles in AD pathogenesis. A significant body of preclinical work supports different but potentially significant roles for essential trace elements in AD pathogenesis. Our results underscore the need for further investigations into the role of trace elements in AD, particularly through longitudinal studies and with larger, diverse cohorts, to validate our findings and explore their implications for early AD diagnosis and potential interventions. The introduction of trace element modulation as part of a comprehensive strategy for AD prevention opens promising avenues for future research and healthcare approaches in the management and prevention of AD.