Down syndrome is the most common chromosomal abnormality leading to intellectual disabilities, and results from any one of four different karyotypes. The first, and most common, is free trisomy 21, where three full copies of the 21 chromosome are present (∼95% of cases).
The second is mosaic Down syndrome (∼1% of cases), where some but not all cells are trisomic for chromosome 21. The degree of mosaicism can range from less than 1% through 99%.
The third is translocation Down syndrome, where extra critical regions of chromosome 21 are attached to chromosome 13, 14, 21, or 22 (∼4% of cases). The fourth type is nonclassical Down syndrome (0.8% of cases) (Al-Awadi et al., 1990, 1991).
The region at the end of the long arm of chromosome 21, including portions of bands 21q22.2 and 21q22.3, represents the ‘Down syndrome critical region’, the region generally believed to be responsible for much, but not all, of the Down syndrome phenotype. The presence, in triplicate, of the genes within this region is associated with many of the neuropathological and clinical features of Down syndrome (Robakis et al., 1987; Korenberg et al., 1994), although recent results from studies of mouse models indicate a more complex genotype–phenotype relationship (Olson et al., 2007).
In the early 20th century, the mean survival for children with Down syndrome was ∼9 years (Penrose, 1949) and during the second half of that century, placement of affected individuals in large institutional settings became an accepted practice (Lakin and Stancliffe, 2007).
Since then, disability advocacy groups and other proponents of rights for individuals with disabilities have been effective in expanding support that has led to significant improvements in quality of life. However, issues related to aging into late adulthood were largely ignored until quite recently, probably because of the abbreviated life span that characterized previous generations (Carter and Jancar, 1983).
In fact, it was not until 1985 that research focused on aging-related changes in the health status and cognition of adults with intellectual disabilities, and in particular those with Down syndrome, began in earnest. The first book focusing on aging of adults with intellectual/developmental disabilities appeared in 1985 (Janicki and Wisniewski, 1985), and since then, a wealth of information on the aging process in individuals with intellectual disabilities has been generated. One topic, the association between Down syndrome and Alzheimer’s disease, has perhaps received more attention than any other aspect of aging among adults with intellectual/developmental disabilities.
Presenile dementia in adults with Down syndrome was first recognized over 130 years ago (Fraser and Mitchell, 1876), and the development of some aspects of neuropathology characteristic of Alzheimer’s disease was noted in several classic studies (Jervis, 1948; Malamud, 1972).
Late onset or sporadic Alzheimer’s disease is the major cause of dementia among older individuals and currently affects over 26 million individuals worldwide (Brookmeyer et al., 2007).
Clinically, Alzheimer’s disease is characterized by a mid-life to late life onset of progressive deterioration in cognitive and functional abilities, with considerable variability in behavioral manifestation. It affects parts of the brain that control thought, memory, and language abilities during its earlier stages and progresses to other areas over time, causing serious declines in an affected individual’s ability to carry out all aspects of daily activities (Victor and Ropper, 2001).
Alzheimer’s disease has now become a major public health concern because of ever-increasing longevity and the resulting increase in the proportion of the world’s population over the age of 60 years [10% in 2005 vs. an estimated 22% in 2050 (World Health Organization, 2005].
Annual costs in the USA have been estimated to exceed $148 billion in 2005 and are projected to increase to over $189 billion by 2015 (Alzheimer’s Association, 2007).
A considerable increase in life expectancy for patients with Down syndrome during recent decades can be linked to both societal and medical factors.
The institutionalization of individuals with intellectual/developmental disabilities underwent a radical transition beginning in the 1960s, resulting in the depopulation and closing of many of the nation’s institutions that continues to this day (Landesman-Dwyer, 1981).
Medical factors included the availability of corrective surgery for congenital cardiac problems (Glasson et al., 2002), common in children with Down syndrome (Yang et al., 2002), and all the other general advances in medical care, nutrition, and public health practices that have resulted in extensions of life expectancy for all Down syndrome cases (Silverman et al., 1998).
Despite improved survival rates, adults with Down syndrome continue to experience atypical life span development, with increased mortality rates because of anatomic, immunologic, neurological, endocrine, and metabolic disorders characteristic of their phenotype, compared with other individuals with intellectual disabilities. Whether, and when, life expectancy for patients with Down syndrome will equal that of the typically developing population remains an open question, but the outlook continues to improve (Miniño et al., 2006).
Causes of increased mortality rates early in life are still primarily because of the increased incidence of congenital defects and leukemia, whereas higher mortality rates later in life may be because of a number of factors, two of which are an increased risk for dementia as a result of Alzheimer’s disease and an apparent tendency toward premature aging (Yang et al., 2002).
Dementia is defined by the (American Psychiatric Association, 1994) as the development of multiple cognitive deficits, involving memory, and aphasia (language impairment), apraxia (motor impairment), agnosia (perceptual impairment), or disturbance in executive functioning. In addition, it is characterized by considerable declines in adaptive abilities and significant functional impairment. Progressive deterioration also occurs in the ability to perform coordinated movements, and affected individuals can eventually no longer walk, show severe signs of disorientation, and lose all self-care skills (Reisberg et al., 1986).
McKhann et al. (2011) and his group proposed the following terminology for the classification of individuals with dementia caused by AD: (a) probable AD dementia, (b) possible AD dementia, and (c) probable or possible AD dementia with evidence of the AD pathophysiological process. The first two are intended for use in all clinical settings. The third is currently intended for research purposes.
Neuropathology of Alzheimer disease
Essentially, all individuals with DS (trisomy 21) develop the neuropathologic hallmarks of AD after the age of 40 years. More than half of individuals with DS also show, if carefully observed or tested, clinical evidence of cognitive decline. The presumed reason for this association is the lifelong overexpression of the APP gene on chromosome 21 encoding the amyloid precursor protein and the resultant overproduction of β-amyloid in the brains of individuals who are trisomic for this gene. The amyloid-β deposition in the brain may begin in the first decade of life in individuals with DS (Leverenz and Raskind, 1998). AD was not noted clinically or pathologically in a 78-year-old woman with partial trisomy 21 who did not have an extra copy of the APP gene (Prasher et al., 1998).
Two studies have found no association of the apolipoprotein E (APOE) genotype with age of onset of dementia in DS (Lai et al., 1999, Margallo-Lana et al., 2004), but one study did find an association of age of onset with a polymorphism in the APP gene (Margallo-Lana et al., 2004).
Schupf et al. (2001) found an unexplained increased risk for AD in mothers who gave birth to children with DS before the age of 35 years.
Three lesions are particularly characteristic of Alzheimer’s disease:
- neuritic plaques, extracellular deposits of fibrillar β-amyloid surrounded by degenerating neuronal processes and terminals.
- intraneuronal neurofibrillary tangles, primarily composed of abnormally hyperphospholated tau protein.
- vascular β-amyloidosis associated with fibrillar amyloid deposition within the vascular wall (Victor and Ropper, 2001).
Over time, these pathological processes contribute toward synaptic and neuronal loss, deterioration of neuronal networks, brain atrophy, and dementia (Victor and Ropper, 2001).
Classification and diagnosis
In the general population, there is a baseline level of ability that can be reasonably assumed. When these abilities are lost, it is clear that dementia is present, and the true task is to determine its etiology. Adults with Down syndrome, however, have substantial lifelong cognitive impairments of varying degrees that complicate the diagnosis of dementia.
Clinical presentation can be atypical, both for Alzheimer’s disease and for other conditions causing dementia, and even illnesses completely unrelated to central nervous system function can present as a pseudodementia (either because of secondary symptoms of the condition itself or the atypical side effects of medications used to treat the primary concern). Given this situation, the optimal method of diagnosing dementia in adults with Down syndrome is to document substantial decline from previous status. Unfortunately, appropriate baseline premorbid data are unlikely to be available and, even if they are, they may be of uncertain quality/validity.
These issues could be addressed by the development of practical dementia assessment methods targeting the population with intellectual disabilities with specific classification criteria anchored to premorbid levels of intellectual ability (e.g. measured against available full-scale intelligence quotient test scores).
Other methods can be used such as the Dementia Questionnaire for Mentally Retarded Persons (DMR) as an informant-based measure of dementia status developed by Evenhuis (1992, 1996), and IBREMS, a direct assessment of cognitive status on the basis of the mini mental state exam, which was modified by Wisniewski and Hill (1985) to be used with adults who have intellectual anomalies.
The DMR generates two scores: the Sum of Cognitive Scores (reflecting cognitive abilities) and the Sum of Social Scores (reflecting social skills). By plotting the Sum of Cognitive Score against full-scale intelligence quotients, Silverman et al. (2004) were able to generate a function that differentiated adults with dementia from those without dementia. The use of more than one scale of assessment increases the sensitivity of the results up to 85%.
The cumulative incidence of significant decline in adaptive behavior for adults with Down syndrome increased from less than 4% at the age of 50 years to 67% by the age of 72 years, whereas the cumulative incidence of significant decline in adaptive behavior for adults with intellectual disabilities without Down syndrome increased from less than 2% at the age of 50 years to 52% at the age of 88 years.
The rates of dementia in adults with intellectual disabilities without Down syndrome were equivalent to the general population rate of Alzheimer’s disease [i.e. ≅47% affected over the age of 85 years (Evans et al., 1989)].
The risk factors associated with Alzheimer’s disease within the population of adults with Down syndrome are defined simply as factors that either increase or decrease that risk. The heterogeneity in the clinical expression of Alzheimer’s disease observed within the population of adults with Down syndrome may be because of the additive and/or the interactive effects of a number of these risk factors, including, but not limited to, genotypic variation, sex, age, health activity, and diet (Chace et al., 2007).
Studies have consistently found that the overall risk of dementia increases considerably beginning in the late 40s or early 50s, some 20 years earlier than it does within the general population. However, it is clear that individuals vary considerably in their age at onset. A small minority of adults with Down syndrome begin to experience considerable declines in cognition before the age of 50 years; yet, another minority is able to mature well into their late 60s or early 70s without experiencing the signs or symptoms of Alzheimer’s disease. Thus, there must be risk factors in addition to the presence of Down syndrome that contribute toward this heterogeneity (Schupf, 2002).
No firm conclusions on the influence of sex can be made. Nevertheless, several lines of evidence support the hypothesis that postmenopausal estrogen deficiency contributes toward decreased cholinergic function as well as increased β-amyloid deposition that, over time, leads to Alzheimer’s disease among women with Down syndrome (Schupf, 2002).
There is evidence from case studies of adults with Down syndrome that atypical karyotypes, including translocations, partial trisomies, and varying degrees of mosaicism, are associated with improved survival and a decreased risk of Alzheimer’s disease (Schupf, 2002).
Apolipoprotein E and cholesterol
The APOE gene, located on chromosome 19, is the most important genetic risk factor found thus so far for late-onset Alzheimer’s disease in the typically developing population. The APOE gene, which occurs predominantly in three variants or alleles (i.e. ε2, ε3, or ε4), is involved in cholesterol transport and lipid metabolism in plasma as well as the accumulation of β-amyloid protein in the brains of typically developing elderly individuals, both with and without Alzheimer’s disease. APOE ε4 is also associated with greater deposition of β-amyloid protein in the brains of adults with and without Down syndrome, and as for the typically developing population, an increased risk for Alzheimer’s disease has been associated with the presence of a ε4 allele, which has also been related to an overall increase in the risk of mortality for adults with Down syndrome without Alzheimer’s disease, and it may be associated with intellectual decline during early adulthood. In numerous studies, participants with Alzheimer’s disease have been found to have higher frequencies of the APOE ε4 allele compared with those without other APOE genotypes, and those with the ε4 allele have an earlier age of onset of Alzheimer’s disease (Warren et al., 2008).
More positively, the presence of the least common allele, APOE ε2, has been associated with a decreased risk of Alzheimer’s disease for adults with Down syndrome, again showing an effect that parallels observations within the general population. Thus, effect of the APOE genotype on the risk for morbidity, mortality, and Alzheimer’s disease in Down syndrome suggests that future studies of the risk of Alzheimer’s disease in Down syndrome should be mindful of its potential effects (Warren et al., 2008).
Validated biomarkers for Alzheimer’s disease in adults with Down syndrome have yet to be discovered. However, a few have been investigated. These include measures of the quantity and type of β-amyloid protein found in blood plasma (Schupf et al., 2007) and telomere size in metaphase and interphase preparations as well as on individual chromosomes (Jenkins et al., 2006).
Treatment of dementia in Down syndrome
The direct treatment of the dementia itself remains controversial in Down syndrome. There has been limited research showing that donepezil, an acetylcholinesterase inhibitor, is effective in slowing the decline of functional ability in Alzheimer’s disease, but at this stage, it is uncertain whether similar gains can be achieved in Alzheimer’s disease associated with Down syndrome. There has been some evidence that these agents may be useful in this group of patients (Kishnani et al., 2001; Prasher et al., 2002), although there have also been concerns that they may be poorly tolerated (Hemingway-Eltomey and Lerner, 1999).
Strategies for future research
Individuals with Down syndrome are at a significantly increased risk for developing Alzheimer’s disease compared with typically developing individuals; this fact has been known for over 100 years. However, contrary to the generally accepted belief, as recently as 25 years ago, that cognitive decline was inevitable by middle age in this population, there is a more positive outlook for adults with Down syndrome as they age. Knowledge of biomarkers of Alzheimer’s disease is still at a rudimentary stage. Although there are some exciting advances in the use of advanced imaging techniques, such techniques might not be as useful in adults with Down syndrome, where the background level of β-amyloid deposition is considerable and neuropathological changes are superimposed on a background of variable abnormal neurodevelopment. Currently, there are no generally available biomarkers with sufficient sensitivity and specificity to predict accurately the onset of dementia or to monitor the rate of Alzheimer’s disease progression. Advances in molecular biology and neurogenetics may provide the most positive outlook for individuals with Down syndrome. However, it was only a short time ago that survival into adulthood was just a dream for most individuals with Down syndrome, and there is every reason to believe that current research will provide the foundation for further, perhaps even more impressive, future advances in prevention and treatment (Zigman et al., 2008).
Conflicts of interest
There are no conflicts of interest.
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