Epigenetic regulation, which modulates gene expression without altering the DNA sequence, is crucial for maintaining cellular function and facilitating responses to various influences such as aging, sex differences, and neurodegenerative diseases. In the brain, epigenetic modifications, including DNA methylation, histone modifications, and chromatin accessibility, play pivotal roles in establishing and maintaining diverse cell type identities throughout the lifespan. Although DNA methylation typically occurs at CpG dinucleotides, it is also prevalent at non-CpG sites in neurons, underlying a genome-wide reconfiguration of the DNA methylation landscape in early childhood and adolescence. Traditional analysis of bulk tissues obscures cell-type-specific changes, whereas recent single-cell sequencing technologies provide more precise insights into specific excitatory and inhibitory neuron types as well as glia. However, significant gaps remain in our understanding of how human brain epigenetic modifications, such as DNA methylation (mC) and hydroxymethylation (hmC), regulate transcriptomes and influence brain function. This dissertation addresses these gaps through advanced cell-type-specific multi-omics studies of human cortical neurons. We used these technologies to investigate age-related changes, sex differences, and mechanisms underlying neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The findings offer a comprehensive view of cell-type-specific epigenomic and transcriptomic alterations, providing critical insights for the development of targeted therapies. Chapter 1 investigates the impact of aging and sex differences on human prefrontal cortical neurons through single-nucleus multi-omics RNA and DNA methylome sequencing. Key findings include synaptic gene downregulation, increased DNA methylation, age-related telomere shortening, and cell-type-specific X-inactivation escape genes. Chapter 2 examines the dynamics of DNA methylation and hydroxymethylation in the human prefrontal cortex across the lifespan. The study reveals changes in mC and hmC levels, and distinct regulatory roles of mC and hmC in transcriptomic changes with aging. Chapter 3 focuses on the molecular mechanisms of ALS and FTD associated with the C9orf72 mutation. Single-nucleus RNA and ATAC sequencing identify profound transcriptomic and epigenomic alterations in excitatory neurons and astrocytes in ALS, and in glial cells in FTD.