Circulating oxysterols in Alzheimer’s disease: a systematic review and meta-analysis

Abstract

Despite decades of research, the cause and series of events underlying the advancement of Alzheimer’s disease (AD) has not yet been established. Lipids and especially cholesterol levels have been proposed to be implicated in AD. Several studies have been undertaken and many ongoing in different directions looking at the importance of circulating cholesterols and oxidised cholesterols in Alzheimer’s disease with inconsistent methods and results. This meta-analysis aims to systematically analyse available data describing the involvement of oxidised cholesterols in Mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We conducted a systematic literature search of 6 databases MEDLINE (PubMed), BIOSIS (Web of Science), EMBASE (Elsevier), PsycNET, Scopus and Cochrane library for studies measuring oxysterols (24-hydroxycholesterol (24OHC); 26-hydroxycholesterol (26OHC) and 7-oxycholesterols) in serum or plasma from MCI / AD patients compared to age and gender matched cognitively normal controls. Data was analysed using the inverse variance and standard mean difference with random effect analysis model at 95% confidence interval for association between oxysterols and MCI / AD in Review Manager (RevMan) software version 5.4.1. 175 studies between January 2000 and April 2022 were identified by 2 independent researchers out of which 14 met the inclusion criteria and were analysed with a total of 957 controls, 469 MCI cases and 509 AD cases. The standard mean differences between MCI / AD participants and controls did not show any difference in the oxysterol levels except for 26OHC level which were higher in AD but not statistically significant.

Plasma oxysterols are associated with serum lipids and dementia risk in older women

“…The associations between less favorable lipids and higher 24-OHC and 27-OHC are consistent with some of the literature, 6,9,19,20,21,44 although a recent meta-analysis of case-control studies reported no differences in 24-OHC between MCI (n = 260) or AD (n = 509) patients and controls (n = 438 and n = 428, respectively). 8 Higher dementia risk observed in those with a higher 24-OHC/27-OHC ratio is in agreement with the marginally significant findings of increased cognitive impairment risk reported by Hughes et al, but, in contrast, we did not observe a relationship between 24-OHC levels and dementia risk in our exclusively female sample. 45 Nonetheless, our study is the first to report significantly greater dementia risk in relation to higher 24-OHC/27-OHC, and specifically in APOE3 and APOE4+ carriers.…”

“…Nonetheless, our study is the first to report significantly greater dementia risk in relation to higher 24‐OHC/27‐OHC, and specifically in APOE 3 and APOE 4+ carriers. While this finding could reflect a protective effect of a higher 24‐OHC/27‐OHC ratio against dementia among APOE 2+ carriers, the consistent reports of the deleterious effects of altered oxysterol levels 6–10,16,17,21–24 suggest a greater likelihood that APOE ε2 allele may instead be protective against pathological effects of abnormal oxysterol levels. Nevertheless, this interaction between oxysterols and APOE in relation to cognitive impairment should be interpreted with caution given the small number of cases among APOE 2+ carriers.…”

“…6,7 The growing investigation into altered lipid metabolism as a central aspect of AD has revealed the involvement of a number of oxysterols, of which 24(S)-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC) are among the most investigated. [6][7][8][9][10] 24-OHC is produced in the brain and serves as a primary route for excess brain cholesterol to exit into the periphery. 11,12 24-OHC appears to prevent AD pathology [13][14][15][16] but may be harmful at high concentrations.…”

Redox Experimental Medicine: Linking redox research to human health and disease

“…With regard to diabetes mellitus, nutritional supplementation with redox bioactive compounds was proposed to prevent or ameliorate muscle loss (Lee et al 2022) and the improvement of mitochondrial function outlined as one of the primary targets of this syndrome's treatment (de Marañón et al 2022). Of interest in the neuropsychiatric field are the systematic check of the literature concerning the actual applicability of measuring defined oxysterols as markers of Alzheimer's disease (Ademowo and Dias 2022), and the reviews on the pathophysiological role of the redox-regulated protein DJ-1 in Parkinson's disease and other pathologies (Dash et al 2022), the potential therapeutic use of sirtuins in the treatment of Rett syndrome (Cordone et al 2022), an appropriate insight into the mechanisms by which hypoxic preconditioning actually attenuates neuronal oxidative stress and damage was afforded (Millán et al 2022). Finally, the impact of a major oxysterol of non-enzymatic origin, namely 7-ketocholesterol, in human pathophysiology, as well as in food science, was comprehensively examined (Ghzaiel et al 2022) and the essential role of selenium as a micronutrient, but also its toxicity at non physiological amounts, has been fully reported on by Saito (2022).…”