Alzheimer’s disease (AD) remains the leading cause of dementia in the older population, and stands as the fourth highest cause of disability and death in the elderly (25). One of the major clinical features of AD is the chronic decline in cognitive function and overall poor daily living. Cognition, a major clinical feature of AD, has been linked with the delicate balance in the biochemical milieu of neurons, which is also related to neuronal oxidant/antioxidant balance (26). This study investigated the relationship between oxidant/antioxidant levels and some environmental trace and toxic metals reported to impact on the maintenance of this oxidative balance; the possible contribution of trace and toxic metals in the pathogenesis of several neurodegenerative conditions including AD in this environment was therefore examined.
Zn is one of the essential trace metals that modulate oxidative damage activities in the body. In the brain, metallothionein, the active antioxide form of Zn, is expressed as MT-3, and is a key antioxidant in the blood-brain barrier capable of binding to and preventing brain exposure to cadmium, mercury, arsenic, copper and other toxic metals. There have been several reports on the contribution of trace metals in the generation and neutralization of ROS in-vivo (27).
In this study, plasma zinc levels in AD were significantly lower than that of controls; this corroborates the findings in different studies (28, 29). The brain has been reported to be second only to the beta cells of the pancreas to contain the highest concentration of zinc (30), where it performs diverse roles in key processes such as enzymatic activity, neurotransmitter release and modulation of gated ion channels for synaptic transmission (31). However, different studies have reported the antagonistic role of Aβ protein, an established macromolecule known to facilitate the development of AD by accumulating zinc ions in different studies on AD making Zn unavailable to protect the neurons through the formation of metallothionein complex (32, 33). Hence, the low zinc levels in this study may therefore be attributed to the zinc binding ability of the Aβ protein abundant in AD subjects. In normal physiology, zinc is released from the neocortical glutamergic synapse which is readily exchangeable with plasma zinc pool (34). Mechanistically, as Aβ in AD brains continue to trap and accumulate zinc in these synapses, it creates a gradient that favors movement of zinc into the synaptic pool which in turn depletes zinc from the plasma zinc pool. This is supported by the findings of (35), where low plasma levels of zinc in AD patients returned to normal levels after treatment with zinc binding compound, Clioquinol, which also have Aβ disintegrating properties.
Also, zinc deficiency has been associated with increased levels of oxidative damage including increased lipid, protein and DNA oxidation (36). Hence, as an antioxidant, zinc at physiologic concentrations protects the body’s sulfhydrl pool directly by antagonizing other redox active metals (e.g. copper) or indirectly by serving as a cofactor for key antioxidant enzymes such as Cu/Zn-SOD (36). Although an equivocal relationship of Zn in the development of AD as reflected by its non-significant relationship with OS markers was seen in this study, this may be more in consonance with previous works that questioned the link between this micronutrient and the development of AD (30). It may also be attributed to strict compensatory mechanisms of the body that always maintain serum concentrations of trace essential metals such as copper and zinc at a given physiological ratio often expressed as copper:zinc ratio (Cu:Zn) (37). Hence, the expression of copper as a ratio to zinc towards establishing the interplay of the two micronutrients in OS pathogenesis of AD becomes important. Previous work showed evidence that an increase in Cu:Zn was associated with several chronic age-related diseases (38) and systemic OS (39). Thus the observed significantly increased Cu:Zn in AD patients in comparison to controls in this study may be worthy of note. Elevated Cu:Zn has been associated with mortality in the elderly and reflects an inflammatory response (38). Since Zn is an important element that maintains the level of metallothionein which has been severally established as a major antioxidant in the brain, a reduction in its level especially in the presence of an increase in levels of Cu and Fe may facilitate the oxidant tendencies of Cu and Fe. This may therefore largely explain the progression of AD especially with respect to increase in cognitive dysfunction. This may then be exacerbated by several other mechanisms during inflammatory conditions driving an increase in plasma concentration of copper at the expense of zinc as reported by other severally (40).
Discussions on the role of iron and copper in the pathogenesis of AD may be said to be interrelated. Studies on iron and copper in AD have shown that excess of both metals stimulates hydroxyl radical formation via the Fenton reaction, which may contribute to increased OS in AD (41). Though in this study, plasma copper levels were not significantly different in both groups, reports on the role of copper in AD pathogenesis remain largely equivocal (42, 43, 44). Also, the non-significant difference in plasma iron levels in cases and controls as seen in this study is similar to results of some meta-analyses which reported unchanged or reduced plasma iron levels in AD patients compared to controls (45, 46). Notwithstanding, the increase in Cu:Zn ratio observed may largely precipitate the toxicity of both Cu and Fe especially in advanced age as seen in participants in this study.
Lead in biological systems is a neurotoxicant and a risk factor for neurodegenerative diseases (47). The significantly elevated blood lead levels (BLL) observed in AD patients in this study was consistent with findings of a similar study (48). Environmental exposure to pollutants has been reported as veritable source of Lead contamination (49); hence, the elevated BLL observed in AD patients in this study may be attributed to the higher proportion of AD patients living in low-income residential areas/slums (88.9%) and/or with houses closer to tarred roads (50%) than in the controls. Previous works also observed that exposure to leaded gasoline in persons living near major roads was associated with an increased incidence of dementia (also a known age related neurodegenerative disease) (50).
Leaded gasoline is one of the possible sources of environmental lead exposure. This is quite veritable in Nigeria with an average lead content of 0.66 g/L of gasoline in the country (51, 49). This, in conjunction with the high proportion of poorly maintained second hand vehicles common in Nigerian cities (49), may contribute significantly to environmental pollution via release of large quantities of incompletely combusted hydrocarbons in exhaust fumes, which release high percentage of lead into the atmosphere (52). This is further supported by the evidence that distance from roadways has been found to be inversely correlated with soil lead concentrations and human BLL (53, 54). Vocational engagement has also been linked to the development of neurodegenerative diseases; a significant proportion of the AD patients (61.1%) were found to be engaged in unskilled labor, which has also been associated with an increased risk of exposure to toxic metals (Ji et al., 2014) (55).
That elevated blood cadmium levels as observed in this study may predispose subjects to AD has also been previously reported (56). This is further supported by a larger scale study conducted on a US-based population (57). Since mode of exposure of cadmium in human is similar to that of Lead, engagement in unskilled labor and living in low-income, traffic prone areas may be the plausible link between elevated blood cadmium levels and AD in this study. Previous work also reported that road traffic associated emissions of metals such as cadmium from vehicle parts (such as tyres and brake linings) remain major sources of exposure to Cd in environmental pollution (58).
However, the level of blood cadmium in AD patients in this study was much higher than that observed (1.34 ± 0.71 ug/L vs. ~0.6ug/L). Orisakwe, in a review (59), argued that Nigeria like most developing nations, is awash with heavy metals. This is backed by findings in environmental studies conducted in different parts of the country (49, 61, 62).
In this study engaging in unskilled labor, living in local residential areas/slums or closer to tarred roads were mostly associated with AD. A significant association between menial low skill occupations and AD dementia has been previously reported (63) while traffic-related air pollution has been reported to be associated with increased risk of developing AD dementia (Hazard Ratio = 1.6) (64).
Though genetics is one of the major risk factors for developing many neurological diseases, AD was not associated with family history of the disease in this study. This may indicate that the development of AD in this environment is either sporadic or may have been previously overlooked by families of affected individuals as part of the normal ageing process. In conclusion, oxidative stress may be linked as the pathogenesis of AD in participants as seen from results of this study, this might have been precipitated by the residential and vocational dispositions. However, the progression of the disease may largely be due to an increase in the Cu:Zn ratio making the brain more vulnerable to the damaging effect of the antioxidants accumulating in the process.