Assessing the Association Between Lead Pollution and Risk of Alzheimer’s Disease by Integrating Multigenomics

Abstract

Alzheimer’s disease (AD) is a life-threatening neurodegenerative disease of the elderly. In recent observations, exposure to heavy metals environmental may increase the risk of AD. However, there are few studies on the causal relationship between heavy metal exposure and AD. In this study, we integrated two large-scale summaries of AD genome-wide association study (GWAS) datasets and a blood lead level GWAS dataset and performed the two-sample Mendelian randomization analysis to assess the causality of blood lead level and AD risk. The results showed that there is a significantly positive causality between blood lead level and AD risk both in the inverse-variance weighted (IVW) model and the weighted median estimator (WME) model. An independent additional verification also reached a consistent conclusion. These findings further confirm the conclusions of previous studies and improve the understanding of the relationship between AD pathogenesis and the toxicity of lead in environmental pollution.

Metals in Alzheimer’s Disease

“…Pb interacts with Aβ [ 31 ] and increases Aβ production [ 45 , 164 ] and aggregation [ 31 ], increases tau hyperphosphorylation [ 165 ], compromises the BBB [ 36 ], induces epigenetic modifications by altering the expression of AD-related genes [ 166 , 167 ], disrupts intracellular cation homeostasis by interfering with Ca homeostasis and replacing Zn ions in Zn enzymes [ 168 ], and induces oxidative stress [ 169 ]. In human studies, there was a decrease or no difference in the Pb levels between the AD patients and control subjects ( Table 1 ), whereas a recent MR study found that higher blood Pb levels were a risk factor for AD [ 170 ].…”