We evaluated the association between alterations in routine blood parameters and cognitive impairment among 8,025 elderly patients. Decreased LMR, PCV, and PLT, and increased monocyte count and MCHC were associated with cognitive impairment among the elderly participants, and may be useful for the early evaluation and diagnosis of AD.
Platelets play important roles in neurodegenerative, cardiovascular, and psychiatric diseases, and have been widely used as a peripheral model to study the molecular mechanisms of AD [8, 9]. Platelets are the primary source of circulating amyloid precursor protein (APP), and APP may represent the major source of Aβ (the cleavage product of APP) detected in the whole blood [10]. It has been demonstrated that APP is expressed at similar levels in the platelets and brain [11]. Previous studies have suggested that platelet APP metabolism may promote Aβ accumulation in the brain [12]. A recent study identified the essential functions of the APP family with regard to normal hippocampal function and circuits during development [13]. One study showed that the platelet level was statistically lower in patients with AD, which is consistent with our findings [9]. Some studies have also shown that platelets can accumulate and release neurotransmitters, such as serotonin, glutamate, and dopamine. Glutamate is a pivotal excitatory neurotransmitter in the central nervous system, which is related to cognitive function [14]. It has also been verified that the tau protein, another important pathophysiological component of AD, is present in platelets [15, 16]. In addition, it has been shown that platelet size reflects platelet activity, which is related to a variety of proinflammatory diseases. MPV, the most commonly used measure of platelet size, is an early marker of activated platelets, and has different trends in different diseases [17]. PDW, another platelet index, can also indicate variations in the platelet size. Although some previous studies have indicated that MPV and PDW were decreased in MCI and AD patients [18, 19], we did not find significant differences in MPV and PDW levels between these two groups (Table 1).
In our study, there were significant differences in the monocyte count and LMR between the two groups (Table 1). The inflammatory response is known to be a key factor in the generation of Aβ plaques and neurofibrillary tangles, which initially execute protective functions but eventually lead to neural degeneration and the manifestations of AD [20]. Blood-derived leukocyte subpopulations, including lymphocytes, monocytes, and neutrophils, have been identified in the brains of patients with AD and in corresponding animal models. Monocytes can reflect the innate immune inflammatory status, and chronic inflammation might cause an increase in the monocytes circulating in the blood. Subsequently, high monocyte levels may activate glial cells to secrete cytokines such as IL-1 and TNF-α that damage the integrity of the blood-brain barrier (BBB), which is critical in the pathogenesis of AD [21]. Increasing evidence has shown that the serum levels of neopterin, which is produced by activated monocytes, are related to their capacity to release reactive oxygen species; these are higher in AD patients than in age-matched healthy controls [22–24]. In line with several studies, decreased lymphocyte count in the cognitive impairment group was observed compared to the normal cognitive function group, although the difference was not significant in our study[4, 21, 25]. The decrease in the lymphocyte count, as part of the immune regulatory barrier, could reflect the body's stress response. TNF-α, released by microglia, is able to recruit lymphocytes from the peripheral circulation across the BBB into the central nervous system, which leads to a reduction in their numbers in the peripheral circulation. Furthermore, it has been shown that increased telomerase activity in lymphocytes can result in reduced lymphocyte proliferation in patients with AD[26, 27]. With regard to neutrophils, the increased neutrophil count is usually related to the occurrence, progression, and severity of inflammation. The depletion or inhibition of neutrophils reduces the pathogenesis and cognitive impairment of AD in mouse models of cognitive dysfunction[28]. In recent years, an increasing number of studies have focused on NLR, a combined inflammatory biomarker that could have an advantage over a single leukocyte subtype and relatively higher clinical significance. The potential role of NLR in AD was first investigated by Kuyumcu et al., who found that NLR was significantly higher in AD patients compared to controls[29]. Several studies have also reported that elderly people with AD have a higher NLR than healthy controls, although we did not find a significant difference in the present study[4, 29, 30]. In summary, it was thought that the NLR was not specific enough to be used as a definitive diagnostic tool for AD or MCI[20].
According to our results, the PCV (Hct) level was decreased in the cognitive impairment group, which is consistent with a previous study [7]. PCV is viewed as a simple indicator of the number and volume of RBCs, which is an important indicator for diagnosing anemia. Although the erythrocyte count (4.55 vs 4.56) and hemoglobin level (137 vs 138) were not significantly different between the two groups, they were lower than those in the normal cognitive function group. AD is a complex multifactorial disease, and anemia is known to be associated with AD. Studies have suggested that lower hemoglobin levels are associated with poor cognition [31, 32]. Several mechanisms might explain this phenomenon. Hemoglobin is a heme-containing protein that binds to oxygen, carbon monoxide, and nitric oxide. Erythrocytes are the most common location of hemoglobin. It is well known that the brain oxygen supply is mainly derived from the oxygen carried by RBCs. Numerous studies have revealed that exposure to hypoxia induces amyloidogenic processing of APP, leading to the accumulation of amyloid-β peptides in the brain [33, 34]. Notably, in AD, microglia defend the neurons by surrounding senile plaques to protect the brain and decrease damage. It has been demonstrated that hypoxia compromises the mitochondrial metabolism of microglia via hypoxia inducible factor 1 (HIF1) in AD [35]. One more possible explanation is that iron, an important component of hemoglobin which is involved in the transport of oxygen, accumulates in tissue stores and is not adequately mobilized in AD [36, 37]. Faux et al. found significantly greater prevalence of abnormally high serum ferritin together with lower plasma iron levels and transferrin saturation in AD, which is in line with studies that showed that iron metabolism was disrupted in cortical neurons in mouse models [7]. Additionally, studies have indicated that hemoglobin is a normal component of nerve cells, and plays a role in intraneural oxygen homeostasis. Moreover, decreased hemoglobin levels were associated with decreased cortical thickness in the frontal, temporal, parietal, and occipital regions, which are vital areas related to cognitive function [38]. Besides hemoglobin, it has been suggested that complement/complement receptor 1 (CR1) mediation is the predominant mechanism of Aβ capture by erythrocytes [39].
We found that the MCHC level in the cognitive impairment group was higher than that in the normal group (1.28 [0.90,1.81] vs. 1.38 [0.98,1.98], p = 0.003), which is consistent with the results of a previous study [18]. MCHC indicates the amount of hemoglobin per unit volume, and correlates the hemoglobin content with the volume of the cell. In fact, MCHC levels have always been controversial among different studies, and several studies have demonstrated that decreased MCHC is related to cognitive impairment, while others have claimed that MCHC levels were not correlated with memory and cognitive abilities [40]. Therefore, it is difficult to explain the elevation of MCHC according to the current literature.