Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most prevalent form of late-life dementia. The ε2 allele of the APOE gene encoding apolipoprotein E (APOE2) is associated with lower susceptibility to AD among the three genotypes (ε2, ε3, ε4), while APOE4 is the strongest genetic risk factor for late-onset AD. APOE plays a critical role in maintaining synaptic plasticity and neuronal function by controlling lipid homeostasis, with APOE2 having a superior function.

Brain-targeting liposome-based gene delivery exacerbates soluble amyloid-β accumulation in mice.

Alzheimer's disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The ε2 encoding apolipoprotein E () is a protective allele against AD among the three genotypes ( ε2, ε3, ε4), while is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where has a superior function compared to and .

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels.

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism.

ABCA7 loss-of-function variants are associated with increased risk of Alzheimer's disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids.

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases.