Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) is characterized by cognitive decline due to synaptic loss and neuron death, with amyloid-β plaques and neurofibrillary tau tangles as key pathological hallmarks. Although genetics account for about 70% of AD risk, modifiable factors also significantly contribute to AD and dementia onset and AD-resilience. Utilizing the All of Us (AoU) cohort, this study explores the relationship between clinical conditions, quantitative phenotypes (including lab tests and anthropometric measurements), and AD risk, shedding light on potential preventative measures.

The relationship between 11 different polygenic longevity scores, parental lifespan, and disease diagnosis in the UK Biobank.

Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific "polygenic scores (PGS)" that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual's likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined "Polygenic Risk Scores" (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits.

Hepatic PEMT Expression Decreases with Increasing NAFLD Severity.

Choline deficiency causes hepatic fat accumulation, and is associated with a higher risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the production of phosphatidylcholine, causes steatosis, inflammation, and fibrosis in mice. In humans, common PEMT variants impair phosphatidylcholine synthesis, and are associated with NAFLD risk.