Basic Science and Pathogenesis.

Background: The recent European-ancestry based genome-wide association study (GWAS) of Alzheimer disease (AD) by Bellenguez2022 has identified 75 significant genetic loci, but only a few have been functionally mapped to effector gene level. Besides the large-scale RNA expression, protein and metabolite levels are key molecular traits bridging the genetic variants to AD risk, and thus we decided to integrate them into the genetic analysis to pinpoint key proteins and metabolites underlying AD etiology. Few studies have generated more than one layer of post-transcriptional phenotypes, limiting the scale of biological translation of disease modifying treatments.

Basic Science and Pathogenesis.

Background: Lewy body pathology (LBP) is common in autosomal dominant (ADAD) or sporadic Alzheimer disease (sAD). LBP seems to be the most frequent co-pathology in sAD and even in the relatively young ADAD population, where other co-pathologies are rare. Knowledge of neuropathological distribution patterns of LBP and associated survival and genetic characteristics in both AD variants is incomplete.

Basic Science and Pathogenesis.

Background: Apolipoprotein ε4 (APOE4) is a major risk factor for Alzheimer's disease (AD). APOE4 carriers display altered whole-body metabolism, including increased blood glucose and inuslin. Although conditions affecting whole-body metabolism like obesity and diabetes are AD risk factors, knowledge regarding the contribution of peripheral tissues to this effect is minimal.

Basic Science and Pathogenesis.

Background: Altered liver function and dysregulated metabolism are emerging risk factors for Alzheimer's disease (AD). This includes genetic variation in apolipoprotein E (APOE), which is the strongest genetic risk determinant for AD. APOE is highly secreted by hepatocytes in the liver and astrocytes in the brain and plays a significant role in lipid homeostasis and metabolic function.

Basic Science and Pathogenesis.

Background: Impaired metabolic function and mitochondrial metabolism increase risk of Alzheimer's Disease (AD) development, which is the leading form of dementia and one of the main causes of death in older adults. Altered mitochondrial function can reduce efficiency of cellular maintenance processes like mitophagy and proteostasis, leading to protein aggregation and cytotoxicity. Mitochondria differ from other organelles, as they have their own unique genetic component (mtDNA), which encodes proteins essential for mitochondrial translation and oxidative metabolism.