This is the first clinical study to evaluate the relationship between multiple serum metal levels and cognitive decline in healthy participants as well as those with aMCI or AD. The plasma concentrations of “B”, “Bi”, “Th”, and “U” decreased with an increase in the disease severity. Moreover, “B”, “Bi”, “Th”, and “U” levels were significantly different between patients with aMCI as well as AD and the healthy controls. The ROC analyses revealed that the plasma concentrations of “B”, “Hg”, and “Th” could differentiate between the disease groups (aMCI vs. control; AD vs. control; and AD vs. aMCI). “B” demonstrated high AUCs for aMCI versus the controls (97.6%, cut-off value: ≤73.1 ug/l) and AD versus the controls (100%, cut-off value: ≤47.1 ug/l). “Hg” revealed the highest AUC to differentiate AD from aMCI (79.9%, cut-off value: ≤1.02 ug/l). Following an adjustment for the potential confounding factors in the aMCI group, while higher baseline levels of “Ca” were associated with a smaller cognitive decline, those of “B”, “Zr”, and “Th” were associated with a rapid cognitive decline. In contrast, higher baseline levels of “Mn” were associated with a rapid cognitive decline in the AD group.
“B” levels were negatively associated with aMCI and AD. “B” is an essential trace element, abundant in fruits, vegetables, walnuts, and pulses. Recent animal and human studies have reported that long-term dietary supplementation with walnuts may reduce the risk or delay the progression of aMCI and AD [19, 20]. There is increasing evidence for the beneficial effects of “B” on human health, particularly in promoting hormone and immune response, inflammation, oxidative stress regulation, and central nervous system function [21]. Furthermore, “B” deprivation leads to poor performance in tasks, such as movement speed and flexibility, attention, and short-term memory in older adults [22]. In other words, the aforementioned studies highlight an association between “B” levels and cognitive function. In addition, “B” plays an important role in human brain function and cognitive protection.
The plasma “Th” levels were negatively associated with aMCI and AD. Moreover, higher baseline levels of “Th” were associated with a faster cognitive decline. An animal study reported that “Th”-treated mice demonstrated impaired learning and memory performance, similar to our results [23]. Furthermore, it resulted in the activation of acetylcholinesterase in mouse brain [23]. This necessitates further research on humans to reveal the underlying association between “Th” and cognitive function.
The plasma “U” concentrations were negatively associated with aMCI and AD. Daily dietary intake as well as water consumption are the most common ways of ingesting “U”. Root crops, such as potatoes and sweet potatoes contribute the highest “U” content in the diet [24]. Moreover, sweet potato anthocyanins can enhance memory and improve cognitive deficits, which in turn may be related to its antioxidant properties [25, 26].
Higher baseline levels of “Ca” were associated with less cognitive decline in patients with aMCI. A longitudinal population-based study from Sweden revealed that women receiving “Ca” supplements are at higher risk of developing dementia (odds ratio, 2.10; p = 0.046) [27]. Moreover, according to the unadjusted trend analysis in mixed-gender groups, “Ca” levels were lowest in the healthy control group and highest in the aMCI and AD groups. Recent studies have reported on the association between the disruption of intracellular Ca2 + homeostasis and the neuropathology of AD, memory loss, and cognitive dysfunction [28, 29]. Increased intracellular “Ca” in the endoplasmic reticulum (ER) is the possible mechanism by which presenilin mutations disrupt intracellular “Ca” signaling. Furthermore, preclinical studies have revealed that excess ER Ca2 + release through the inositol 1,4,5-trisphosphate receptor or the ryanodine receptor is related to tau and amyloid pathology, and contributes to memory and learning deficits [30, 31]. Therefore, calcium dyshomeostasis plays a critical role in the pathogenesis of AD.
We observed an inverse association between “Hg” levels and both aMCI and AD. There are three major groups of “Hg” compounds, namely elemental, inorganic, and organic. “Hg” is converted to methylmercury by bacteria, which enters the food chain and bioaccumulates in predatory fish [32]. Fish consumption is the primary source of methylmercury exposure [32]. Seafood, including shellfish and finfish is the largest contributor to organic “Hg” exposure in the human population. A systemic review mentioned that long-chain omega-3 fatty acids in a high-fish diet can delay cognitive decline in elderly individuals, without dementia [33]. The serum “Hg” levels of our subjects was within the normal range, thus indicating a normal dietary intake (normal value: <20µg/L for women aged ≥ 50 years and men aged > 18 years) [34]. Nonetheless, ICP-MS can only detect total “Hg” and fails to distinguish between the organic and inorganic forms. However, patients with aMCI or AD may likely reduce their seafood intake, thereby reducing organic methylmercury exposure, compared to healthy controls. We did not use a detailed food frequency questionnaire, including the types, frequency, and amount of seafood intake. This made it difficult to explain the inverse correlation between “Hg” levels and aMCI and AD, thus necessitating further investigation.
Our study established an association between higher baseline levels of “Mn” and rapid annual cognitive decline in patients with AD. “Mn” is an essential metal that maintains the normal functions of the human body. However, increased “Mn” levels in the brain are associated with impaired motor coordination, memory deficits, psychiatric disorders, and Parkinson’s disease [35–37]. An animal study reported that the overexpression of Aβ in transgenic mice lead to “Mn” accumulation in the brain, thus suggesting the role of Aβ may in “Mn” homeostasis and neurotoxicity [38]. A study conducted in China further mentioned that people with higher plasma “Mn” concentrations were associated with higher plasma Aβ peptides levels, similar to our results [39]. The aforementioned evidences suggested a relationship between “Mn” and AD, and the presence of shared pathophysiological mechanisms.
The strengths of our study include the robust statistical analysis, detailed cognitive examinations, prospective design, and large response rate at follow-up. However, our study had some limitations, which should be considered while interpreting the findings. First, the NIA-AA research framework defines AD as a biological construct rather a clinical diagnosis. However, AD diagnosis focuses on the biomarkers of brain Aβ deposition, pathologic tau, and neurodegeneration [8]. Our study population was limited to clinically evaluated patients with positive results for the cognitive tests. Moreover, we did not obtain amyloid and Tau positron emission tomography scans nor any CSF biomarkers. Second, cognitive decline is closely related to neurodegenerative biomarkers, such as hippocampal atrophy [40]. The pathophysiological link between the trace metals and neurodegenerative biomarkers remains to be determined. Third, the participants were recruited in a tertiary medical center. Therefore, our results may not be generalized to other populations, such as elderly people living in the community. However, there was also some strength of the single-center design, which made it possible to systematically and uniformly collect all the data of all participants. In addition, the cognitive assessment conducted by the board-certified clinical psychologist, making information bias less likely. Fourth, our sample size was small. Therefore, our findings need to be verified by large-scale studies in future. Fifth, we only measured the metals at a single time point, which may reflect a short period of exposure. Therefore, long-term serial measurements of trace metals may help researchers explore their relationship with cognitive decline.