Alzheimer Disease in Individuals With Down Syndrome

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.

Clinical
History

* This progressive neurodegenerative disorder affects multiple components of the central nervous system (CNS). The clinical signs and symptoms are an expression of continuous progressive neuronal dysfunction and death.
* One of the most sensitive and specific symptoms of Alzheimer disease (AD) in people without Down syndrome (DS) is a decline in the patient's ability to perform cognitive tasks related to employment, shopping, or household finance. When individuals with DS are employed or performing complex tasks with certain degree of personal autonomy, noticing early signs of the disease might not be difficult. Because most individuals with DS have mental retardation, a history of decline in high level premorbid cognitive abilities is usually difficult to document.
* On average, approximately 1-2 years elapse between the early signs of the disease and the confirmation of the diagnosis.
* In the author's research, typically the first symptoms, most often identified retrospectively, are observed when the patient is aged 50 years (range 36-62.5 y), and the diagnosis is confirmed at age 52.6 years (range 37-62 y). Death occurs at a mean age of 60.11 years (range 46.7-69.8 y). The author's research has also shown that the duration of the disorder from first symptoms to death is 9.10 years (range 6.9-11.10 y), and duration from diagnosis to death is 8.2 years (range 5-12.4 y).
* The main symptoms are confusion, disorientation, and wandering. In most instances, these early signs are not recognized and commonly are misdiagnosed.
* Longitudinal studies showed a progression of cognitive decline with subtle memory loss as early symptoms, which are associated with deficits in visuospatial organization.
* Behavioral changes
o In the early stage of the disease, behavioral changes are the most common sign. These changes are usually considered an exaggeration of long-standing behavioral traits. For example, refusal to follow certain orders or to do chores at home may be perceived as stubbornness.
o Since the early changes are subtle, only those familiar with the individual recognize these changes. Such changes include change in daily routine, change in sleeping or eating habits, inability to make clothing decisions, getting lost in familiar environments, and inability to remember the names of familiar people.
o One of the potentially early signs of AD in highly functional DS individuals is the inability to perform job duties.
* Visual deficiencies
o Impairment in visual perception as a consequence of central processing dysfunction has been described in the early stage of AD in individuals with DS who have a relatively high level of intelligence.
o Central processing dysfunction is more difficult to delineate in patients with DS who have severe mental retardation.
o These central changes are magnified by peripheral visual disorders (eg, cataracts, myopia, astigmatism), which frequently are present in people with DS.
o The visual deficiencies may be responsible for individuals getting lost in familiar environments, not being able to perform activities that require visuomotor coordination, increased frequency of accidents and falls, and difficulty in learning new tasks.
* Impaired learning ability is usually present in the early stages of the disease but is difficult to demonstrate in people with a moderate (or more severe) degree of mental retardation.
* Other indications of early deterioration include loss of language and other communication skills, impairment of social and adaptive skills, and progressive loss of activities of daily living (ADL) (eg, personal hygiene, dining skills, bathroom skills).
* Middle stage
o ADL markedly deteriorate. The patient may depend totally on others for activities such as dressing, eating, walking, and toilet needs.
o Communication skills are reduced markedly. Speech and language, if present, are not used efficiently.
o Behavioral problems are exaggerated, and psychotic behavior may be displayed. Social activities are reduced to a minimum.
* Advanced stage
o Patients are almost at a vegetative level.
o They totally depend on others and interact minimally with the environment.

Physical

The clinical evolution of physical symptoms is similar to that observed in individuals with AD but without DS.

* Motor disorders
o Motor disorders become obvious in the middle and advanced stage of the disease.
o Motor disorders are associated with a progressive gait disorder and in some patients, a parkinsonian syndrome.
o In very advanced stages, the patient is confined to bed with marked rigidity and little voluntary movement.
* Eating/swallowing disorders
o In the author's research, eating disorders with progressive dysphagia and frequent choking may be observed at the beginning of the disease but are more obvious in the middle stage.
o Aspiration pneumonia is a frequent complication.
o Changes in the diet and type of food may help ameliorate the dysphagia; in some patients, tube feeding may be necessary.
* Epileptic seizures
o In the author's research, epileptic seizures of the tonic-clonic type have been described. These occur approximately 2.4 years (range 7 mo to 6.1 y) after the disease presents.
o Usually generalized tonic-clonic seizures are infrequent; if present, they typically can be controlled with antiepileptic medication.
* Myoclonus occurs more frequently than tonic-clonic seizures. The myoclonus may be stimulus sensitive and can be induced by light or a simple touch. In the advanced stages, myoclonus may be constantly present.
* The following information is from the author's personal experience with institutionalized DS individuals. These data may help those who plan services for individuals with DS and AD.
o Communication/speech disorder: Early indication of the impairment was observed after an average of 1.4 years (range 0-4 y; "0" implies the presence of symptoms at the time of first evaluation), and total loss of function occurred approximately 4.5 years (range 2.5-6.8 y) after confirmation of diagnosis.
o ADL: Early indication of failure was observed at an average of 5 months (range 0-1.8 y), and total loss of function occurred 4.5 years (range 1.5-6.5 y) after confirmation of diagnosis.
o Ambulation: Early signs of deterioration were observed after 1.1 years (range 0-3.7 y), and total loss of ambulation occurred 4.6 years (range 2.5-7.4 y) after confirming the diagnosis.
o Leisure activities: Early indications of deterioration were observed after 10 months (range 0-2.9 y), and total loss of the ability to participate in leisure activitieswas seen after an average of 4.1 years (range 1.5-6.5 y).
* The following is the author's account of disease evolution in an individual who was observed from disease onset. This example demonstrates the complexity of the medical issues involved.
o A male, born in 1930, was admitted to an institution for individuals with mental retardation in 1939. He died in the institution in 1991.
o Diagnosis of DS was confirmed by chromosomal analysis.
o Clinical presentation before the beginning of AD was as follows:
+ No behavioral problems; was pleasant and congenial
+ Followed simple commands and understood simple orders
+ Walked independently and also was independent in ADL
+ Normal diet
+ Performed housework and showered well
+ Good leisure skills and active social program; participated in dances and outdoor trips and sang with the radio
+ Understood that he had to leave the building when a fire alarm sounded
+ Score on Vineland Adaptive Behavior Scale in 1975, when aged 45 years, was 4.9 years; remained the same when he was aged 49 years
o The following is a yearly description of his symptoms as he developed AD:
+ 1981 (age 51 y): First symptoms were disorientation, confusion, and behavior changes. He refused to accept that the program activity in which he was involved was over. He refused to return to his residence. He was found wandering the grounds crying and yelling in a state of confusion.
+ 1982 (age 52 y): He showed increased forgetfulness and had emotional problems and periods of agitation manifested by verbal outbursts and throwing of objects.
+ 1983 (age 53 y): ADL needed consistent prompting. He was still capable of showering and changing clothes daily. Leisure skills were unchanged. He exhibited 3 incidents of major aggression and agitation. His score on the Vineland Adaptive Behavior Scale decreased to 3 years.
+ 1984 (age 54 y): He demonstrated poor participation in social activities due to frequent sleeping; ADL needed increased assistance, although he remained independent. A choking episode was observed.
+ 1985 (age 55 y): Regression steadily continued. Disorientation, confusion, wandering, forgetfulness, and sleeping increased. Behavior deteriorated; he would undress in the dining room and at work. ADL also regressed, and he needed more help; however, he remained independent. He frequently was found wandering outside his residence and unable to find his way. Occasionally, he could not find his bedroom. The score on the Vineland Adaptive Behavior Scale decreased to 2.1 years.
+ 1986 (age 56 y): The patient exhibited photomyoclonic response; he had myoclonic seizures and difficulty walking. ADL regressed further; he still could eat and drink but had to be reminded constantly to do so. He was transferred to a safer and more restrictive environment.
+ 1987 (age 57 y): Generalized tonic-clonic seizures appeared. He became aggressive, and his gait deteriorated markedly, but he was still able to walk. He occasionally needed a wheelchair. He fed himself using adaptive equipment. Toilet training was scheduled, but a few accidents occurred.
+ 1988 (age 58 y): He became lethargic. Inappropriate behavior became frequent. He no longer was able to walk independently or feed himself. He frequently lost sphincter control. He could not tolerate bus rides into the community. He still enjoyed music and expressed pleasure by smiling and laughing.
+ 1989 (age 59 y): He developed aspiration pneumonia. He was totally dependent for ADL. He required a wheelchair, and his social interaction became very poor. He developed urinary incontinence.
+ 1990 (age 60 y): He suffered from frequent bouts of pneumonia. He no longer was able to swallow and was fed through a nasogastric tube; a feeding tube (percutaneous endoscopic gastronomy) was placed. Incontinence required the use of diapers. He had minimal interaction with his surroundings and slept most of the time. Occasionally, he conveyed pleasure and displeasure by laughing or crying.
+ 1991 (age 61 y): He showed minimal response to environmental stimulation and slept most of the time.

Causes

* For patients with or without DS, age is the most important risk factor for AD.
* See Alzheimer Disease for a discussion of risk factors for sporadic and autosomal dominant AD.
* A few case studies suggest that persons with DS and atypical karyotypes (partial trisomies, mosaicism, translocations) may have a lower risk of AD than patients with full trisomy.
* Other chromosome 21 genes, such as the gene coding for superoxide dismutase-1 (SOD-1), may be involved. The increased activity of this enzyme may result in increased production of hydroxy radicals, which may accelerate the progression of the disease. SOD-1 activity has been reported to be increased in people with DS.
* In patients without DS, the APOE epsilon 4 allele is associated with increased risk of AD, and the epsilon e2 allele may be protective. Among patients with DS, several studies have demonstrated that the epsilon e2 allele may be protective. Data that the e4 allele increases risk in patients with DS is less compelling than it is for patients without DS.
* Small head circumference, a small brain, low level of intelligence, and a history of head trauma have also been related to a higher incidence of AD. However, none of these factors have been evaluated in individuals with DS.
* Factors that may decrease risk (eg, Mediterranean diet, active life style) or increase risk (eg, cardiac and cerebrovascular disease, small head circumference) of AD in patients without DS have not been evaluated in patients with DS.