Blood-Based Biomarkers for Predictive Diagnosis of Cognitive Impairment in a Pakistani Population

Abstract

Numerous studies have identified an association between age-related cognitive impairment (CI) and oxidative damage, accumulation of metals, amyloid levels, tau, and deranged lipid profile. There is a concerted effort to establish the reliability of these blood-based biomarkers for predictive diagnosis of CI and its progression. We assessed the serum levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, total cholesterol, selected metals (Cu, Al, Zn, Pb, Mn, Cad), and total-tau and amyloid beta-42 protein in mild (n = 71), moderate (n = 86) and severe (n = 25) cognitively impaired patients and compared them with age-matched healthy controls (n = 90) from Pakistan. We found that a decrease in HDL cholesterol (correlation coefficient r = 0.467) and amyloid beta-42 (r = 0.451) were associated with increased severity of CI. On the other hand, an increase in cholesterol ratio (r = −0.562), LDL cholesterol (r = −0.428), triglycerides, and total-tau (r = −0.443) were associated with increased severity of CI. Increases in cholesterol ratio showed the strongest association and correlated with increases in tau concentration (r = 0.368), and increased triglycerides were associated with decreased amyloid beta-42 (r = −0.345). Increased Cu levels showed the strongest association with tau increase and increased Zn and Pb levels showed the strongest association with reduced amyloid beta-42 levels. Receiver Operating Characteristic (ROC) showed the cutoff values of blood metals (Al, Pb, Cu, Cad, Zn, and Mn), total-tau, and amyloid beta-42 with sensitivity and specificity. Our data show for the first time that blood lipids, metals (particularly Cu, Zn, Pb, and Al), serum amyloid-beta-42/tau proteins modulate each other's levels and can be collectively used as a predictive marker for CI.

A Comprehensive Investigation of the Potential Role of Lipoproteins and Metabolite Profile as Biomarkers of Alzheimer’s Disease Compared to the Known CSF Biomarkers

“…In this study, TAU showed positive correlations with cholesterol ratio (TC/HDL), TG, and LDL and a negative correlation with HDL. Furthermore, Aβ-42 showed positive correlations with TG, LDL, and cholesterol ratio and negative correlations with HDL and TC (22). In our analysis, Apo-A1 also showed a correlation with TAU and P-TAU in the negative Apo-E4 group, while Apo-B did not yield any significant result.…”

“…Similarly, another systematic review and meta-analysis reported that elevated concentration of LDL could be a potential risk factor for AD and this association is strong in patients in their 60s, which fades with advancing age (21). Other studies emphasized the other lipids and lipoproteins and reported lower serum level of HDL (22) and elevated serum level of TC (23) in the cases with AD. On contrary, some studies reported that late-life hypercholesterolemia might slow cognitive decline, particularly in combination with other cerebrovascular risk factors, possibly due to enhanced cerebral perfusion (24).…”

Plasma Lipids as Biomarkers for Alzheimer's Disease: A Systematic Review

“…They found that increased cholesterol in the plasma was leading to increased beta-amyloid production. Many other studies found the same association between cholesterol and beta-amyloid plaques in the brain [4,24]. Some studied proved that beta-amyloid isoforms 1-40, 1-42 are associated explicitly with plasma cholesterol [7,13].…”

“…The study by Iqbal et al was a systematic review showing that increased LDL-C, TC, TG were increasing beta-amyloid production. In contrast, decreased HDL-C was associated with AD [ 24 ].…”

Plasma neurofilament light chain is associated with cognitive decline in non-dementia older adults

“…Although we have adjusted the MAPT groups in our analysis, further cohort studies with baseline NfL data are needed to generalize our findings to a wider population. Moreover, besides NfL, other cognition-related blood biomarkers, such as brain-derived neurotrophic factor, 3-hydroxykynurenine, lipid levels and total-tau 14 , 15 , might also be tested as potential candidates in similar analysis to distinguish cognitive status between the NC and the MCI groups. Despite that we found associations between NfL and global cognitive functions in the MCI group, investigations using a more comprehensive assessment of cognitive functions 7 , 11 , 16 is needed to confirm our findings.…”