Down syndrome is associated with increased mortality rates due to congenital cardiac defects and leukemia early in life, and with Alzheimer's disease and a tendency toward premature aging later in life. Alzheimer's disease was once considered an inexorable result of growing old with Down syndrome, but recent data indicate that risk does not reach 100%. Although some individuals exhibit signs and symptoms of Alzheimer's disease in their 40s, other individuals have reached the age of 70 without developing dementia. This chapter presents a wealth of data from a longstanding longitudinal study with the overall objective of understanding and recounting the mechanisms responsible for these substantial individual differences.