Neuronal lipid metabolism genetics and Early‐Onset Alzheimer’s Disease: A systematic review and meta‐analysis of observational studies

Abstract

AbstractBackgroundEarly Onset Alzheimer’s disease (EOAD) is associated with mutations in APP, PSEN1 and PSEN 2 genes but few studies have assessed its relationship with mutations involved in lipid metabolism and the amyloid cascade. Therefore, this study seeks to determine the association of ABCA7, SORL1 and APOE mutations with EOAD.MethodThe protocol was registered in PROSPERO(CRD42022328366). We included comparative observational studies assessing the association of ABCA7, SORL1 and APOE mutations with the development of EOAD in patients younger than 65 years old. The search strategy was performed in five databases (MEDLINE, Scopus, Web of Science, EMBASE, Opengray) from their inception to May 7th,2022. Abstract and full‐text screening, data extraction and risk of bias (RoB) assessment were performed in duplicates. RoB was assessed with Newcastle‐Ottawa Scale. We performed a random effects meta‐analysis for dichotomous outcomes by using the DerSimoniain Laird method. Effect sizes were reported as odds ratio (OR) with their corresponding 95% confidence intervals (95%CI).ResultA total of 2191 studies were screened and seven studies (n = 8992) were included; one was a retrospective cohort and six were case‐control studies. Three studies had high RoB and four had low RoB. Overall, 60% were female and the mean age ranged from 33.9(SD±17.1) to 57.4(SD±5.6). Three case‐control studies (n = 5098) found a significant association of ABCA7 mutation with EOAD (OR:2.51 95%CI[1.33‐4.73]; tau‐squared = 0.20, I‐squared = 66%). Two case‐control studies (n = 3107) found that SORL1 mutation was not associated with EOAD (OR:3.65 95%CI[0.76‐17.49]; tau‐squared = 1.15, I‐squared = 89%). Two case‐control studies and one cohort study (n = 787) found that APOE4 allelic variant mutation of the APOE gene had significant association with EOAD (OR:13.21; 95%CI[3.81‐45.85]; tau‐squared = 0.90, I‐squared = 75%) and that the APOE2 allelic variant mutation was not associated with EOAD.ConclusionDespite the high heterogeneity in our results and limited number of studies, this study shows that ABCA7 and APOE mutations may be associated with an increased risk of EOAD. Larger high‐quality cohort studies are needed to address this research question.