Immunohistochemical analyses of human brain sections from AD and non-AD subjects revealed that ABCA7 is expressed in neuron and microglia cells in the cerebral cortex.
Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer's Disease Assessment Scale total score, and the Clinical Dementia Rating score.
We identified 789 and 998 DEGs common to both blood and brain of AD and MCI subjects respectively, over 77% of which had the same regulation directions across tissues and disease status, including the known ABCA7, and the novel TYK2 and TCIRG1.
Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein's involvement in cholesterol metabolism and amyloid clearance at the BBB.
Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.
We show that long-read sequencing with a single Oxford Nanopore Technologies PromethION flow cell per individual achieves 30× human genome coverage and enables accurate assessment of tandem repeats including the 10,000-bp Alzheimer's disease-associated ABCA7 VNTR.
Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) cases as compared to controls: TREM2, SORL1, and ABCA7.
Several genes associated with AD risk-most notably, the ε4 allele of the apolipoprotein E (APOE) gene and several mutations in the ATP-binding cassette transporter A7 (ABCA7) gene-are linked to altered lipid metabolism, especially in AAs.
Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.
Thus, in African Americans the interactive effects of ABCA7rs3764650 and aerobic fitness likely compound overall ABCA7-related AD risk, and may contribute to health disparities whereby African Americans are at a higher risk for dementia, with double the prevalence of AD.
Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology.
While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aβ in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau-induced neuronal loss and accelerates synaptic alterations.
Our case-control study (416 AD patients and 302 controls) provides further data on the rs3752246 polymorphism in AD in the Hungarian population that has not been investigated so far regarding the ABCA7 gene variants.
Clarifying the effect of APOE-ABCA7 interactions on the default mode network and memory is critical to exploring the complex pathogenesis of Alzheimer's disease and refining a potential therapy.