Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by memory loss and cognitive impairment. To date, there is no effective therapy for AD due to poor understanding the pathogenic mechanism of AD. Few drugs can significantly improve the symptoms of AD patients. Parkinson's disease (PD) is also a common neurodegenerative disorder. The commonly used drugs such as levodopa and other dopamine agonists are only effective at the early stages of PD, and quickly become ineffective with severe adverse effects and the deterioration of PD patients. Therefore, appropriate disease models that could mimic the pathophysiological mechanisms of the disease development due to the pathogenic factors are in urgent need. In this project, we found that ( I ) DHA could protect neurons from Aβ oligomers- induced injury both in vitro and in vivo, partly through decreasing the endoplasmic reticulum (ER) stress reaction, and preventing cell apoptosis. ( II ) A combination of the new piggyBac system and CRISPR/Cas9 could efficiently and precisely introduce heterozygous and homozygous mutations (PSENIF105C) in human iPSCs. In addition, we also used CRISPR/Cas9 to generate heterozygous and homozygous PSEN1 knockout mutations in human iPSCs. These mutant iPSCs derived neurons exhibit AD-related phenotypes such as mutation-dependent changes in amyloid precursor protein (APP) levels and amyloid-β (Aβ) 42:40 ratios compared to isogenic controls, suggesting AD-associated phenotypes could be faithfully modeled in neurons derived from human iPSCs. (III) We applied a small molecule, hydroxyurea (HU), to induce aging-related features in human iPSCs-derived dopaminergic neurons and promote the manifestations of Parkinson's disease-relevant phenotypes in sporadic PD patients- iPSCs-based models, which could promote the iPSCs-based modeling of PD. This strategy may also facilitate to model late-onset neurodegenerative disease via iPSCs. The findings of this study contribute to the development of models for late-onset neurodegenerative disease such as AD and PD, which is helpful to study the pathogenic mechanisms and perform high throughput drug screening for neurodegenerative diseases.