Multifactorial Analysis of a Biomarker Pool for Alzheimer Disease Risk in a North Indian Population

Abstract

Background: Alzheimer disease (AD) is a progressive neurodegenerative disease with a complex multifactorial etiology. Here, we aim to identify a biomarker pool comprised of genetic variants and blood biomarkers as predictor of AD risk. Methods: We performed a case-control study involving 108 cases and 159 non-demented healthy controls to examine the association of multiple biomarkers with AD risk. Results: The APOE genotyping revealed that ε4 allele frequency was significantly high (p value = 0.0001, OR = 2.66, 95% CI 1.58-4.46) in AD as compared to controls, whereas ε2 (p = 0.0430, OR = 0.29, CI 0.07-1.10) was overrepresented in controls. In biochemical assays, significant differences in levels of total copper, free copper, zinc, copper/zinc ratio, iron, epidermal growth factor receptor (EGFR), leptin, and albumin were also observed. The AD risk score (ADRS) as a linear combination of 6 candidate markers involving age, education status, APOE ε4 allele, levels of iron, Cu/Zn ratio, and EGFR was created using stepwise linear discriminant analysis. The area under the ROC curve of the ADRS panel for predicting AD risk was significantly high (AUC = 0.84, p < 0.0001, 95% CI 0.78-0.89, sensitivity = 70.0%, specificity = 83.8%) compared to individual parameters. Conclusion: These findings support the multifactorial etiology of AD and demonstrate the ability of a panel involving 6 biomarkers to discriminate AD cases from non-demented healthy controls.

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…According to the very recent meta-analysis, which includes a total of 35 pieces of research: eighteen report an increase, fourteen show no change, and one reports a decrease in Cu level in the serum-plasma of this disorder [ 232 ]. Subsequently, three more studies have been published, stating increased Cu 2+ ions level in Alzheimer’s compared to that in the healthy controls [ 233 , 234 , 235 ].…”

“…These recent researches have contributed considerably to the explanation of the previous controversy. In blood, a higher level of free plasma Cu, which has been identified in 50–60% of Alzheimer’s patients, can explain the higher level of serum Cu in AD [ 145 , 174 , 233 , 236 ]. Another earlier research also observed an increased concentration of serum copper ions in a special kind of AD (Alzheimer’s disease epsilon four apolipoprotein E allele carriers) [ 237 ].…”

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

“…More specifically, the large stand most recent meta-analysis (total pool of subjects analyzed: 2128 AD vs. 2889 healthy controls) includes a total of 35 studies: 18 report an increase, 14 no difference, and one a decrease in values of copper in the serum–plasma in AD compared to healthy controls ( Li et al, 2017 ). Three additional studies appeared after the publication of this consensus result ( Guan et al, 2017 ; Pu et al, 2017 ; Talwar et al, 2017 ), reporting increased concentrations of Cu 2+ in AD patients vs. controls.…”

Commentary: The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer’s Disease

“…Considering general circulation studies, two studies reported no overall differences in outcomes, while five studies show higher levels of copper in AD patients vs. controls (Table 1 ). Moreover, a recent meta-analysis ( 12 ) comparing 879 AD patients with 1712 controls has shown that the plasma copper component that circulates not bound to ceruloplasmin (non-Cp copper) is increased in AD, as confirmed by studies published after this publication ( 13 , 14 ).…”