There's a triplication of chromosome 21 due to nondisjunction. This affects up to 400 genes and many regulatory microRNAs, which causes an overall increase in genes, product, and proteins. There are two, not mutually exclusive, hypotheses:

• Gene Dosage Effect Hypothesis: the disease phenotype is caused by the dosage imbalances on chromosome 21
• Amplified Developmental Instability Hypothesis: dosage imbalances in the hundreds of affected genes cause nonspecific changes in genome-wide expression

Down Syndrome arises from the result of quantitative (i.e. the amount) gene changes. In additition to these genetic changes, there are also neuroanatomical differences, such as:

• Reduced dendritic branching
• Reduced synaptic density
• Abnormalities in the layers of the cortex (layers II and IV) become apparent after the 22nd week of gestation. There’s a slight increase in dendrites at birth but by around 6 months of age that number decreases
• Decreased GABAergic inhibition in layers II and IV of the cortex - which could explain why some persons with Down Syndrome get seizures
• Altered glutamatergic synapses with larger, though fewers spines