DOWN SYNDROME and ALZHEIMER’S DISEASE

Down syndrome is the most common chromosomal abnormality associated with mental retardation. Down syndrome occurs in approximately 1 in every 800-1,000 live births and in all racial and socioeconomic groups. It is caused by complete or partial triplication of human chromosome 21, leading to three copies of chromosome 21. Advances in medical care have led to a dramatic extension of life expectancy for individuals with Down syndrome. In 1983, average life expectancy for individuals with Down syndrome was 25 years. In the current birth cohort, over 55% of individuals with DS are expected to survive into their fifties and 13.5% may still be alive at 68 years old. 

Aging of adults with Down syndrome has become of great concern because of the high risk of Alzheimer’s disease in this rapidly growing population. Three neuropathological findings are characteristic of Alzheimer’s disease: (a) neuritic plaques, consisting of extracellular deposits of beta amyloid peptides; (b) neurofibrillary tangles in which abnormal filaments containing the protein tau accumulate within neurons, and (c) loss of brain cells and brain mass. Several lines of evidence suggest that deposition of beta amyloid peptides in the brain is a primary event in the development of Alzheimer’s disease. Individuals with Down syndrome are at high risk for this Alzheimer’s disease neuropathology at least in part because the gene for beta amyloid precursor protein, from which the beta amyloid peptides are derived, is located on chromosome 21. Individuals with Down syndrome have three copies of the gene for amyloid precursor protein, instead of the normal two copies, and they produce excess beta amyloid from the earliest ages.

Virtually all adults with Down syndrome over 35 to 40 years of age exhibit many of the key features of Alzheimer’s disease neuropathology, and many of these individuals will develop dementia by the time they reach 60 to 70 years of age. The chart shows the prevalence of dementia among adults with Down syndrome of different ages.

In addition to increased risk of AD from overproduction of beta amyloid peptides, middle-aged individuals with Down syndrome show many age-related changes in health and functional status suggestive of premature or accelerated aging, which may also increase their risk for Alzheimer’s disease. These changes include early menopause in women with DS, early onset of senile cataracts and other sensory impairment, hypothyroidism, and old-age associated declines in functional ability.

Thus, accelerated aging and increased risk for AD are characteristic of individuals with Down syndrome and it is important to understand the factors that contribute to these risks. Despite the nearly universal occurrence of AD pathology in the brain by middle age, there is wide variation in age at onset of dementia and not all adults with Down syndrome develop dementia. There are large individual differences in the level of many risk factors for Alzheimer’s disease and these differences modify risk. Factors that increase beta amyloid burden in the brain, such as the presence of the apolipoprotein e4 allele, high levels of beta amyloid peptides in the blood, oxidative stress, high cholesterol, and early menopause or low levels of estrogen in women are associated with earlier onset of AD. In contrast, atypical forms of Down syndrome, such as mosaicism for chromosome 21 and the presence of the apolipoprotein e2 allele, promote longevity without cognitive decline. Better understanding of the factors that modify age at onset of dementia can lead to the identification of critical pathogenic pathways and provide the basis for targeted therapeutic intervention or prevention.

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