Basic Science and Pathogenesis.

Background: Apolipoprotein E (ApoE) is the primary cholesterol and lipid transporting apolipoprotein in the central nervous system (CNS) and is the greatest genetic risk factor for Alzheimer's Disease (AD). There are three main isoforms differing by single amino acid changes: ε3 is "neutral", ε4 is "risk" (Cys112Arg), and ε2 is "resilience" (Arg158Cys). Rare forms (Christchurch, Jacksonville) have also been proposed as resilience alleles, while an ε4-like allele (with Arg61Thr) is present in non-human primates without AD risk.

Basic Science and Pathogenesis.

Background: Microglia have been implicated as a key aspect of the pathology of Alzheimer's disease (AD). However, high microglial heterogeneities, including disease-associated microglia (DAM), tau microglia (tau-pathology related), and neuroinflammation-like microglia (NIM), hinder the development of microglia-targeted treatment.

Method: In this study, we integrated ∼0.

Basic Science and Pathogenesis.

Background: Although high-throughput DNA/RNA sequencing technologies have generated massive genetic and genomic data in human disease, translation of these findings into new patient treatment has not materialized by lack of effective approaches, such as Artificial Intelligence (AL) and Machine Learning (ML) tools.

Method: To address this problem, we have used AI/ML approaches, Mendelian randomization (MR), and large patient's genetic and functional genomic data to evaluate druggable targets using Alzheimer's disease (AD) as a prototypical example. We utilized the genomic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets across five human brain regions from three biobanks.

Basic Science and Pathogenesis.

Background: Emerging evidence links Alzheimer's disease (AD) to dysfunction of the primary cilium, a historically overlooked organelle that serves as the neuron's antenna. All neurons harbor a single primary cilium that projects from the membrane to sense changes in the extracellular environment. Primary cilia dysfunction leads to a group of diseases called 'ciliopathies', which are associated with reduced hippocampal and cortical mass, as well as neurocognitive impairment.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) risk variants APOE4 and TREM2-R47H have been shown to impact glial cell functions and transcriptional profiles. We hypothesize that TREM2-APOE may have synergistic effects in driving pathogenesis and disease progression of AD in a cell type-specific manner.

Methods: We investigated cell-type specific transcriptional changes associated with APOE4- and TREM2-R47H-carrier status.