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: A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear.

Method: We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model.

Basic Science and Pathogenesis.

Background: T-cell infiltration into the brain parenchyma is associated with hyperphosphorylated tau (p-tau) accumulation in neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy caused by exposure to repetitive head impacts (RHI). CTE is defined by the perivascular accumulation of p-tau at the cortical sulcal depths and can be stratified into mild and severe pathological stages.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is characterized by the aggregation and accumulation of proteins including amyloid-β and tau. We previously compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and found that mice with tauopathy but not amyloid developed a unique adaptive immune response with markedly increased activated T cells in areas with tau pathology. T cell depletion blocked tau-mediated neurodegeneration.

Basic Science and Pathogenesis.

Background: Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and primary tauopathies. We have previously shown that APOE4, the strongest genetic risk factor for AD, directly influences the severity of key pathological hallmarks of neurodegeneration including tau deposition, microglial reactivity and brain atrophy. Sleep loss influences tau accumulation and microglial reactivity in both mice and humans, suggesting that sleep loss may contribute to neurodegeneration not only by influencing protein aggregation, but also through an immune mechanism.