Excerpt from Alzheimer Disease in Individuals With Down Syndrome

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Background

Alzheimer disease (AD) is the most common form of dementia. It is a progressive degenerative disease of the brain, strongly associated with advanced age. However, it should not be considered a part of the normal aging process. AD is characterized by a relentless progression of symptoms associated with defined neuropathologic changes.

Individuals with trisomy 21, or Down syndrome (DS), develop a clinical syndrome of dementia that has almost identical clinical and neuropathologic characteristics of AD as described in individuals without DS. The main difference is the early age of onset of AD in individuals with DS. These patients present with clinical symptoms in their late 40s or early 50s.

The neuropathology of AD in persons with DS closely resembles the pathology of AD in individuals without DS and is superimposed on developmental abnormalities such as reduced dendritic arborizations, decreased number of spines, spine atrophy, and abnormalities of spine orientation in pyramidal neurons.

Pathophysiology

The reason AD is more frequent in individuals with DS is not known. All recognized mutations for AD are associated with increased deposition of amyloid beta, a peptide fragment from 39 to 43 amino acids long, which are products of the catabolism of the amyloid precursor protein (APP) molecule. The discovery that the APP gene is on the 21st chromosome led to the hypothesis that the early and universal development of AD pathology is due to a third copy of the APP gene. Nonetheless, many steps in the amyloid cascade hypothesis remain unproven.

Epidemiologic and brain imaging studies of patients with AD without DS have led to observations that patients with limited education or diminished baseline cognitive abilities are at increased risk for AD. These data have led to the cognitive reserve hypothesis, which suggests that patients with better baseline cognitive abilities can tolerate more AD pathology and neuronal loss than patients with worse baseline cognitive abilities. Because most patients with DS are mentally retarded and have limited baseline cognitive ability, the cognitive reserve hypothesis would suggest that patients with DS are at increased risk to develop AD.

Frequency

United States

Several studies document that most if not all individuals with DS develop AD. This is unrelated to the degree of mental retardation; AD is not more prominent in individuals with mental retardation from other causes. Due to better clinical management, most persons with DS now reach the age of 40 years. Thus, the frequency of AD is likely to increase.

The percentage of people with DS and AD varies in some of the epidemiologic studies presented. A review of these studies showed that 10-25% of patients had AD when aged 40-49 years, 20-50% had AD when aged 50-59 years, and 60-75% had AD when older than 60 years.

International

No particular geographic distribution exists. A similar clinical picture has been described in other countries.

Mortality/Morbidity

The disease is responsible for the sharp decline in survival in DS patients older than 45 years.

Race

No documentation exists that race influences prevalence.

Sex

In patients without DS, the influence of sex on the incidence and prevalence of AD remains controversial. Some, but not all, studies suggest that the prevalence is higher in women than men. Few studies have evaluated the influence of sex on AD in patients with DS and the results have been contradictory.

Age

• Age and the presence of trisomy 21 are the most important factors in disease development.
• The neuropathologic findings related to AD have been described in all DS individuals older than 35 years.
• Early clinical signs and symptoms are observed at the end of the fifth decade to the beginning of the sixth decade of life. Mean age at the time of clinical diagnosis is 51 ± 6 years.

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