Alzheimer Disease in Down Syndrome

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Alzheimer disease (AD) is the most common progressive degenerative form of dementia, strongly associated with advancing age. Although AD is strongly associated with advancing age, it should not be considered a normal aging process. Instead, AD is characterized by the continuous progression of the symptoms and associated neuropathological changes. Almost all adults with Down syndrome (DS)  develop neuropathological AD changes by 40 years of age. The leading cause of death in individuals with DS is AD and its complications.

DS was recognized as a unique form of developmental disability in 1866 by Dr. John Landon Down, and early aging was already identified by 1876. In 1948, G.A Jervis reported the dementia course and neuropathological changes in DS were similar to AD in individuals without DS. (Jervis 1948) Further research has confirmed premature aging and clinical deterioration, and the presence of neuropathological changes in AD.

Individuals with DS or trisomy 21 develop a clinical syndrome of dementia with clinical and neuropathologic characteristics almost identical to those of AD as described in individuals without DS.

Accelerated aging in DS is not confined to the central nervous system (CNS) and occurs in various other systems. The recognition that DS is associated with trisomy 21 helped in understanding the genetic basis of this association.

The neuropathology of AD in persons with DS closely resembles that of AD in persons without DS. Autopsy studies in persons with DS showed that almost all had brain lesions meeting the criteria for AD.

However, these changes are superimposed in individuals with reduced brain volume, especially in the hippocampus, and other developmental abnormalities, such as reduced dendritic arborizations, decreased number of spines, spine atrophy, and abnormalities of spine orientation in pyramidal neurons. This form of AD is not an exact biologic model or a replica of the AD seen in individuals without DS. Therefore, although conclusions from research studies may be interchangeable, AD in persons with DS should be considered different from AD without DS.

Clinical differences have been observed, mainly in the early age of onset of AD in individuals with DS. These patients present with clinical symptoms in their late 40s or early 50s.

A longitudinal study that followed babies with DS from age six weeks up to age 45 years found that the mean IQ in verbal and nonverbal tasks changed little between ages 21 and 45 years. However, in this study, tests for dementia given to persons older than 30 years showed some performance decline from 40 to 45 years.

Besides age, other studies have also shown some clinical differences that might be unique to persons with DS.

One study compared the clinical findings in individuals with DS and dementia with those with dementia and intellectual disabilities. The study reported that patients with DS had a higher prevalence of mood changes, overactivity, auditory hallucinations, disturbed sleep, and less aggression due to other etiologies.

Temple and Konstantareas found that persons with DS and AD have less severe psychotic behaviors, fewer hallucinations, and fewer delusions and were more likely to engage in physical movements than those with AD only. In this study, 66% of the persons with AD and without DS were taking rivastigmine or donepezil, and only 26% of persons with AD and DS were on those medications. The differences observed might have been related more to the use of the medications than to the disease itself.

The prognosis is poor as no treatment is available for the primary disease. AD is responsible for the sharp decline in survival in persons with DS older than 45 years. Only about 25% of persons with DS live more than 60 years, and most have AD.



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