Alzheimer Disease in Down Syndrome 

Alzheimer disease (AD) is the most common form of dementia.^{[1, 2]} AD 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. However, clinical differences have been observed, the main one being the early age of onset of AD in individuals with DS. These patients present with clinical symptoms in their late 40s or early 50s.^{[3, 4, 5, 6, 7]} Other studies have also shown some clinical differences that might be unique to persons with DS.

One study that compared the clinical findings in persons with dementia and DS with clinical findings in persons with dementia and intellectual disabilities due to other etiologies found that those patients with DS had a higher prevalence of mood changes, overactivity, auditory hallucinations, and disturbed sleep, as well as less aggression.^{[8, 9, 10]}

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 no 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.^[11]

Neuropathology

The neuropathology of AD in persons with DS closely resembles the pathology of AD in individuals without DS.^{[5, 12, 13, 14, 15]} Autopsy studies in persons with DS showed that almost all subjects had brain lesions meeting the criteria for AD.^{[16, 17]} As has been observed in persons without DS, the autopsies of patients with DS showed intraneural neurofibrillary tangles, extracellular neuritic plaques, amyloid angiopathy, and deposits of amyloid beta (Abeta) protein in senile plaques.^{[16, 18]} In persons with DS, the deposits of amyloid can be seen in the cerebral cortex as early as in their 30s.^{[19, 20]}

However, since these changes are superimposed on individuals that already have a 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 biological model or a replica of the AD seen in persons without DS. Even though conclusions from research studies may be interchangeable, the AD in persons with DS should be considered a different entity from the AD in persons without DS.

The reason Alzheimer disease (AD) is more frequent in individuals with Down syndrome (DS) is not known. All recognized mutations for AD are associated with increased deposition of amyloid beta, a peptide fragment that is 39-43 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^[21] 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.

Chromosomal abnormalities

The presence of an extra chromosome, along with the overexpression of the genes located in that chromosome, is considered the main reason for the development of the characteristics signs and symptoms of DS and probably play an important role in the development of AD in persons with DS. Overexpression of genes with consequent increase in activity leads to increased production of end products, which can be toxic for the individual.

Several genes that might play a role in the development of AD are found in chromosome 21. Among them are the APP and the cytoplasmic enzyme superoxide dismutase (SOD-1) genes, both of which are important in the regulation of potential toxic metabolites, the reactive oxygen species (ROSs), which are the result of the normal metabolism of O₂. These ROSs include free radicals (superoxide anions, nitric oxide, hydroxyl radical) and other nonradical metabolites (eg, hydrogen peroxide), among others. The accumulation of these ROS metabolites may result in cell death.^{[22, 23]}

SOD-1

The excess activity of SOD-1 in a variety of cells is not limited to the brain and has also been observed in erythrocytes, B- and T-lymphocytes, and fibroblasts. This increased activity results in the accumulation of hydrogen peroxide (H₂ O₂), which may reach toxic levels and may be related not only to the neuronal death observed in DS but also to carcinogenesis and the impairment of immune functions.

APP overexpression

The overexpression of the APP gene might be related to the overproduction of the major protein observed in the senile plaque, the Abeta (1-42) peptide, which is considered to be one of the important factors leading to the development of the pathology of DS with AD. Abeta peptide is generated by the cleavage of the APP by beta and gamma secretase enzymes.

Beta site APP cleaving enzyme 1 (BACE1), the most important beta secretase in vivo, is elevated in persons with DS.^[24] This peptide has been found in the brains of children with DS as young as age 8 years, and the deposits increase with age.^[25] Interestingly, in spite of the extensive deposits in the brain, there is no linear relationship with AD. There is a gap between the presence of abnormal brain pathology and the early signs of AD, suggesting that other factors (genetic or environmental) may play an important role in the development of AD.

Oxidative stress hypothesis

An alternative hypothesis for the amyloid cascade suggests that increased oxidative stress, secondary to pathogenic factors, increase Abeta, which behaves as a redox sensor. In this alternative hypothesis, Abeta acting as a redox sensor attenuates oxidative stress. If this proves to be true, then oxidative-induced Abeta amyloid might be a brain protector.^[26]

The accumulation of ROSs also leads to abnormal lipid peroxidation metabolism that could lead to structural damage to membranes and the generation to more toxic products. ROS-related activity also leads to DNA damage.

All these findings lead to the concept that oxidative stress, defined as the lack of balance between the production and the removal of ROSs, might play an important role in the development of AD in persons with DS; however, oxidative stress alone does not explain the whole process.^[22]

The corollary of this theory is the use of antioxidants as a therapeutic tool in the treatment and prevention of AD and of AD in DS.

Brain developmental abnormalities

Several studies have shown anatomical and chemical differences in the brain of persons with DS compared to persons without DS.^{[27, 28]} Postmortem examinations showed indications of growth retardation in the brains of persons with DS. Among other differences, the brains of persons with DS showed lower weight, reduced number and depth of cerebral sulci, narrowness of the superior temporal gyrus, and a smaller cerebellum and frontal and temporal lobes.^[29]

Microscopic studies have shown the presence of developmental abnormalities such as reduced dendritic arborizations and abnormalities in the size and orientation of spines in pyramidal neurons. These abnormalities have been seen in infancy and even in fetal life.^{[15, 30]} These early changes might contribute to the early onset of AD in persons with DS. In that sense, AD in persons with DS is not a perfect model for the understanding of AD in persons without DS.

Cognitive reserve hypothesis

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 have mental retardation and have limited baseline cognitive ability, the cognitive reserve hypothesis would suggest that patients with DS are at increased risk to develop AD.

Several studies document that most, if not all, individuals with Down Syndrome (DS) develop Alzheimer disease (AD).^{[6, 7]} 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 age 40 years. Thus, the frequency of AD is likely to increase.

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. Most persons with DS may develop AD by age 60-70 years; however, some may remain free of clinical indications of dementia into their late 70s.^[23] Several studies consistently described a subset of individuals who do not appear to develop AD, even in old age.^{[31, 32]}

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. In one study, all patients older than 70 years with DS had AD.^[7]

Additional demographic features

No particular geographic distribution exists; a similar clinical picture has been described in other countries. No documentation exists that race influences prevalence.

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.^[27]

There are some indications that the onset of dementia is related to early menopause in women with DS. This might suggest some role for estrogen in the development of AD in women with DS; however, this is not enough reason to suggest hormone therapy in this population.^{[9, 33, 34]}

There is also an indication that men with DS have an earlier onset of AD than women,^[23] suggesting that other associated hormonal changes might also be important.

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.^{[32, 35, 36]}

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 a 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.^{[4, 27]}

Early disease stage

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.^{[35, 36]}

Behavioral changes include the following:

• Deficits and variability in tests of selective attention (ie, the ability to stay focused on a particular stimulus, disregarding other stimuli) might be a subtle early sign of AD that can be documented by a relatively easy test^[37]
• 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)
• Since the early changes are subtle, only those familiar with the individual would be able to recognize them (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); one of the potentially early signs of AD in highly functional DS individuals is the inability to perform job duties
• As the disease progresses, there is an increase in maladaptive behaviors such as aggression, unjustified fears, sleep problems, and social inadequate behaviors^[38]

Visual deficiencies include the following:

• 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
• Central processing dysfunction is more difficult to delineate in patients with DS who have severe mental retardation
• These central changes are magnified by peripheral visual disorders (eg, cataracts, myopia, astigmatism), which are frequently present in people with DS
• 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 disease stage

In the middle stage, the ability to perform ADLs markedly deteriorates. The patient may depend totally on others for activities such as dressing, eating, walking, and toilet needs. Communication skills are also reduced markedly; speech and language, if present, are not used efficiently. Behavioral problems are exaggerated, psychotic behavior may be displayed, and social activities are reduced to a minimum.

Advanced disease stage

In the advanced stage, patients are almost at a vegetative level, being totally dependent on others and interacting minimally with the environment.

Motor disorders

Motor disorders become obvious in the middle and advanced stage of the disease. They include a progressive gait disorder and, in some patients, a parkinsonian syndrome. In very advanced stages, the patient is confined to bed with marked rigidity and little voluntary movement.

Eating/swallowing disorders

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.^[39] Aspiration pneumonia is a frequent complication. Changes in the diet and type of food may help ameliorate the dysphagia, but in some patients, during the course of the disease, patients may need placement of gastrostomy or jejunostomy tubes for enteral feeding.

Epileptic seizures

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. Usually, generalized tonic-clonic seizures are infrequent; if present, they can typically be controlled with antiepileptic medication.

Myoclonic seizures occur 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, myoclonic seizures may be constantly present. This has been described as late-onset myoclonic epilepsy in DS^[40] or senile myoclonic epilepsy.^[41]

Personal experience

The following information, which is from the author's personal experience with institutionalized DS individuals, may help those who plan services for individuals with DS and AD:

• 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
• 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
• 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
• 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 activities was seen after an average of 4.1 years (range 1.5-6.5 y).

Illustrative case example

A male born in 1930 was admitted to an institution for individuals with mental retardation in 1939. He died in the institution in 1991, and diagnosis of DS was confirmed by chromosomal analysis. The following is the author's account of disease evolution in this individual, who was observed from disease onset, and demonstrates the complexity of the medical issues involved.

Clinical presentation before the beginning of AD was as follows:

• No behavioral problems; patient was pleasant and congenial
• Followed simple commands and understood simple orders
• Walked independently and also was independent in ADLs
• Consumed a normal diet
• Performed housework and showered well
• Had good leisure skills and an 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

The following is a yearly description of the patient’s 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 but 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

For patients with or without Down syndrome (DS), age is the most important risk factor for Alzheimer disease (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.^[42] 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.^[28]

In patients without DS, the APOE epsilon 4 allele is associated with increased risk of AD,^{[42, 43, 44]} 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 are less compelling than for patients without DS.^[28] 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 has been evaluated in individuals with DS.

Factors that may decrease (eg, Mediterranean diet, active life style) or increase (eg, cardiac and cerebrovascular disease, small head circumference) the risk of AD in patients without DS have not been evaluated in patients with DS.^{[45, 46, 47]}

See Alzheimer Disease for a discussion of risk factors for sporadic and autosomal dominant AD.

The differential diagnosis of Alzheimer disease in patients with Down syndrome include the following:

• Cortical Basal Ganglionic Degeneration
• Dementia in Motor Neuron Disease
• Frontal and Temporal Lobe Dementia
• Frontal Lobe Syndromes
• HIV-1 Associated CNS Complications (Overview)
• Normal Pressure Hydrocephalus
• Parkinson-Plus Syndromes
• Pelizaeus-Merzbacher Disease
• Pick Disease
• Subdural Hematoma
• Thyroid Disease
• Wegener Granulomatosis
• Wilson Disease

Special concerns

The term mild cognitive impairment (MCI) has been used to characterize a state of cognitive decline transitional between normal and dementia and is characterized by impairment in memory and other cognitive functions as demonstrated by standardized neuropsychological tests. A substantial percentage of patients with the amnestic form of MCI progress to AD within 4 years of diagnosis. The lack of adequate normative data for memory in DS in different age groups makes the concept of MCI impossible to operationalize in individuals with DS.

The term pseudodementia is used to describe reversible cognitive impairment associated with psychiatric disease—usually depression. With treatment and amelioration of the psychiatric disease, the cognition returns to baseline. In patients without DS, many patients who develop AD have symptoms of depression in the early stages of disease, and the depression itself can impair cognitive function. Treatment of the depression (usually with SSRIs) often improves mood and sometimes cognition. However, over the next 24-36 months, progressive cognitive impairment, not necessarily accompanied by mood disturbances, becomes clear. Data are not available on depression in patients with DS and AD.

Hypothyroidism, observed in almost 30% of individuals with DS, may simulate dementia. Hypothyroidism is frequently present in people with DS and AD; however, treatment with hormone replacement does not change the course of the underlying disease.

Vitamin B-12 deficiency has been reported in several individuals with DS and AD; however, replacement therapy does not change the evolution of the underlying disease.

Persons with AD and DS present with a higher number of health comorbidities when compared with individuals with DS and no AD. The frequency of comorbidities increases as the AD becomes more severe. Among the comorbidities expected are epileptic seizures, lung diseases (mostly aspiration pneumonias), depression, visual and hearing impairment, lack of mobility, and tube feedings.

Other problems to be considered include the following:

• Depression and other psychiatric disorders
• Dementia in Parkinson disease
• Dementia in progressive supranuclear palsy
• Multi-infarct dementia

Imaging studies are useful to exclude other causes of dementia, including subdural collections, tumors, and multiple infarcts. Once the diagnosis is established, repeat imaging is indicated when the course of progression is not consistent with AD (such as very rapid deterioration). Dementia screening tests marketed to consumers are of questionable usefulness in persons without DS and of no value in patients with DS.^[48]

The workup is no different from that recommended for patients with dementia who do not have Down syndrome (DS). Excluding treatable forms of dementia is important.

Laboratory studies include the following:

• Liver function tests
• Renal function tests
• Electrolytes
• Blood glucose
• CBC
• Folic acid
• Vitamin B-12
• Possibly tests for syphilis and HIV (among patients without DS, these tests are not recommended as part of routine evaluation but only when clinically indicated)
• Thyroid-stimulating hormone (TSH) and thyroxine (T-4) levels (likely to be abnormal due to high incidence of immune-dependent hypothyroidism in patients with DS)^[49]

Although the APOE epsilon 4 allele is associated with increased risk of AD, its use as a diagnostic tool in patients without DS is generally not recommended. At present, there is no role for this testing in patients with DS.

Lumbar puncture is indicated in evaluation of dementia without DS when conditions that could be diagnosed by examination of the cerebrospinal fluid (such as fungal meningitis) are reasonable diagnostic possibilities. Most of the time, such conditions are so unlikely that lumbar puncture is rarely performed as part of routine medical care in the evaluation of dementia. These same criteria should be used when considering lumbar puncture in patients with dementia and DS.

Biomarkers potentially useful for early diagnosis

Tau protein and amyloid beta 42 peptide levels in CSF might help to differentiate AD from other dementias. Low Abeta amyloid and high tau protein might be associated with higher risk of AD.^{[50, 51]}

Plasma levels of Abeta 42 were elevated in persons with DS and dementia when compared with persons with DS and no AD.^[23] Also, higher levels of Abeta 42 peptide in nondemented persons with DS were also predictors of dementia.^[52]

More studies are needed to determine the usefulness of these measures.^[51] At present, they are not considered routine in the evaluation of persons with DS and question of AD.

CT scan studies comparing young individuals who have Down syndrome (DS) (19-34 y) with a comparable group of healthy individuals who do not have mental retardation found no significant differences between the 2 groups in white- or gray-matter volumes or ventricular volumes.

Quantitative studies with CT scanning and MRI demonstrated that young adults with DS have no ventricular dilatation, no atrophy, and no consistent malformation that could explain the mental retardation. However, small brain size was reported consistently. This is probably an expression of small stature and a small cranial vault.

Bilateral symmetric basal ganglia calcification is a frequent finding in people with DS (see the following images); in fact, it exceeds the prevalence in the general population. However, the relationship with the clinical presentation of Alzheimer disease (AD) in DS is unclear.

The results were different when people with DS and cognitive deficiencies were compared with individuals who did not have cognitive deficiencies. In individuals with DS and cognitive deficiencies, cerebral atrophy and ventricular enlargement that suggested brain atrophy were reported consistently (see the following images).

In advanced cases, atrophy was generalized. However, regional differences can exist with greater involvement of the temporal horns. The relationship between enlargement of the temporal horns of the lateral ventricles and dementia in elderly DS patients has been a consistent feature.

MRI studies have shown several developmental findings in persons with Down syndrome (DS)—reduction in the whole brain volume (including cerebellum) and gray and white matter of the brain, decrease in the volume of the hippocampus, focal reductions in the volume of the frontal and occipital lobes, and relative preservation of the temporal lobe but decreased volume of the planum temporale and the superior temporal gyrus.

MRI studies might show a decrease in the volume structures of the temporal lobe (hippocampus and adjacent medial temporal lobe) in patients with DS without dementia. A significant atrophy of the corpus callosum, an indication of neocortical atrophy, more obvious in the splenium, has also been demonstrated in persons with DS before the development of AD.

MRI findings in symptomatic individuals are similar to those of CT scans and reveal progressive atrophy of the brain with enlargement of the ventricular system. Volumetric analysis of selective areas of the brain is a research tool not available from routine MR studies. Results of studies suggest that CT scan and MRI can differentiate nondemented and demented older individuals with DS.

Positron emission tomography (PET) is not considered a routine test for Alzheimer disease (AD) in individuals with Down syndrome (DS). Schapiro et al found that PET did not demonstrate any difference between healthy people with DS and individuals without mental retardation.^[53]

Studies with xenon-133 inhalation technique, which evaluates the cortical cerebral blood flow, showed no abnormalities in young, healthy people with DS. Significant differences were observed in individuals with DS and dementia; the greatest reduction occurred in the parietal-temporal association neocortex.

Patients with Down syndrome (DS) have a high baseline prevalence of seizures, and the prevalence increases further as patients develop Alzheimer disease (AD). It is prudent to obtain an EEG in the baseline evaluation of a patient with DS and dementia.

Generally, the methods used for testing the non-Down syndrome (DS) population (eg, Mini Mental Status Examination) are unreliable to diagnose dementia in persons with developmental disabilities. Additionally, many people with developmental disabilities cannot be evaluated by standard neuropsychologic tests. One serious problem in assessing cognitive decline in persons with developmental disabilities is that they already had at least a mild-to-moderate degree of cognitive deficiency before they developed Alzheimer disease (AD).^[54] Also, persons with poor education or low-to-moderate cognitive level can be wrongly diagnosed with cognitive decline because of poor performance on the standard tests.^[55]

Because of those limitations, tests using caregivers as a source of information are more reliable than tests directly involving the individual.^[56] Several tests have been designed that are more appropriate. Generally, these tests emphasize a change in function as measured by a decline in activities of daily living (ADL), such as eating, dressing, and bathing.

Two tools that have proved to be very useful^[54] are The Dementia Scale for Down Syndrome (DSDS)^{[57, 58]} and The Dementia Questionnaire for Mentally Retarded Persons.^[59]

• The DSDS was developed for the detection of cognitive deficiencies mostly in persons at the lower end of the cognitive scale; even though the test specifically refers to DS, it could be used in any person with a moderate-to-severe degree of mental retardation
• The DSDS and The Dementia Questionnaire for Mentally Retarded Persons are able to differentiate, with high specificity and, especially, with high sensitivity, between persons with DS who have AD and those who do not.^[54] There are no major differences between these 2 tests.

A simple tool developed by the Alzheimer team at Wrentham Developmental Center, in Massachusetts, is the Alzheimer Functional Assessment Tool. The information can be obtained by interviewing relatives or caregivers. This tool was designed to record key information on the status of patients with Alzheimer disease and to assist in making decisions concerning the patient's program and residential placement.

Interview the staff on all shifts who work directly with the patient, and find out the patient's behavior and overall activities of daily living (ADL). The patient's abilities (skills, problems, other considerations) are described in the "description of skills" section of the summary sheet. Perform this assessment at the time of diagnosis of AD and every 6 months or when a significant change in status is observed.

This tool is appropriate for the follow-up care of individuals with Down syndrome (DS) and Alzheimer disease (AD). A decline in functions documented through this tool can also be used as a diagnostic test; however, this tool was not intended to be used as a diagnostic test and has never been validated as a diagnostic tool. Serial use of this tool can also be useful to evaluate the effects of medications and to determine the support needed for these patients.

The Alzheimer Functional Assessment Tool includes the following information

• Date:
• Name:
• Activities of daily living:
• Description of skills:
• Toileting:
• Dining:
• Walking/motor:
• Bathing:
• Dressing:
• Personal/oral hygiene:
• Environmental awareness:

Toileting

Toileting is measured by the following:

• Can use bathroom in familiar and unfamiliar environments independently
• Goes to the toilet independently or asks staff to assist; may need reminders to use toilet paper and wash hands
• Has occasional toileting accidents; needs verbal reminders
• Needs staff to take to the bathroom on a schedule; remains continent 90% of the time
• Needs staff to take to the bathroom on a schedule; remains continent 50% of the time or less
• No bowel or bladder control; may require frequent changing or special clothing (eg, pads, diapers)

Dining

Dining measurement includes the following:

• Can prepare simple food (eg, sandwich, toast); can set table and clean up after meal; uses knife and fork to cut food; may or may not use adaptive equipment to eat independently
• Can use fork and spoon to eat independently but needs food to be cut
• Eats independently with the help of adaptive equipment
• Can use fork and spoon to eat independently but may need occasional prompts to start or continue eating; may finger feed; needs food to be cut
• Needs physical assistance to complete the meal
• Develops swallowing problems; needs change in consistency of food or thick drinks
• Completely dependent; may need specialized feeding program

Walking/motor

Ambulation measurement includes the following:

• Independent ambulation; able to walk steadily; able to start, stop, and change direction without falling; able to walk fast or run; ascends and descends stairs; capable of leaving premises without assistance
• Independent ambulation for short distances; walks up and down the stairs one step at a time by holding rails; able to leave premises without assistance
• Independent but cannot negotiate stairs; unable to leave premises without assistance
• Can walk without support but requires supervision; may be unsteady; requires supportive measures at times
• Needs assistance (another person to hold, walker) to walk; "cruises" around using structures such as furniture and walls as support; unable to leave premises independently
• Needs wheelchair but can move independently
• Needs an adapted wheelchair and cannot move independently; needs to be pushed

Bathing

Bathing ability is measure by the following:

• Can independently carry out an appropriate bathing routine (disrobing, washing, drying, and dressing)
• Can carry out an appropriate bathing routine with occasional reminders to do a step or wash more thoroughly
• Needs verbal prompts to initiate and/or complete some steps in the bathing process (due to subtle confusion and/or fear); continuous staff supervision at shower time not necessary; may use toiletries inappropriately
• Requires continuous staff supervision at shower time to ensure complete bathing and safety (eg, problems due to confusion and/or fear); hand-over-hand assistance may be necessary at times; alternatives to showering or a specialized program may be recommended due to fear of showering; safe use of hot and cold water needs to be monitored
• Primarily passive during bathing; requires some form of assistance for all steps; may be able to stand and move a body part when given a verbal or touch cue; fear of water may be present
• Physically and cognitively unable to participate actively in bathing process; may respond to stimulation during bathing with vocalizations or changes in facial expressions

Dressing (skills and appropriate dress)

Dressing skills are identified as follows:

• Dresses independently or with physical assistance due to handicap; can choose appropriate clothing (for weather or activity of the day) and cares for own clothing (eg, places dirty clothes in hamper, hangs clothing, stores properly)
• Occasionally needs reminders to dress appropriately ("It's cold out today") and to care for clothes ("Remember where your dirty socks go?")
• Dresses with minimal assistance or verbal prompts
• Dresses inappropriately for weather (layers clothing and/or puts clothing on inappropriately); may undress at an inappropriate time and/or place; may benefit from adaptive clothing to retain dressing skills; makes no attempt to care for own clothing
• Needs assistance in dressing (50% or more of task) and may be resistive; may assist when compliant (eg, puts arm through sleeve)
• Lies passively during dressing; does not respond to dressing or undressing

Personal/oral hygiene (hair brushing, teeth brushing, sanitary pad, shaving)

Hygiene maintenance is measured by the following:

• Able to perform all personal hygiene tasks
• Able to perform all personal hygiene tasks within regular routines; may show difficulty in performing tasks if routine is changed (eg, hospitalized, moved)
• Able to perform all personal hygiene tasks but requires occasional reminders from staff to complete the task
• Able to perform personal hygiene tasks but requires frequent reminders from staff to complete the task; may need staff guidance (verbal and point cues) in some parts of some tasks (ie, may forget steps); may still be proficient in one area and lose ability in another area
• Requires staff supervision (verbal and point cues) to complete some personal hygiene tasks and staff assistance (light, moderate physical cues) to complete others
• May still be able to perform some steps of some personal hygiene tasks with staff assistance but depends on staff to meet other personal hygiene needs
• Depends on staff to meet all personal hygiene needs

Environmental awareness

Awareness of environment is noted by the following:

• Cognizant and responsive, in a relevant way, to familiar and unfamiliar people and other environmental stimuli
• Generally responsive to familiar and unfamiliar people and situations but seems self-absorbed and/or confused most of the time
• Cognizant and responsive in a relevant way to familiar people and situations but shows a delayed or inappropriate response to unfamiliar people and situations
• Cognizant and responsive to stimuli, but response is often inappropriate, even in familiar situations
• Mostly awake but seems self-involved, showing little or inconsistent response to the environment
• Sometimes awake but shows little interest in surroundings; sleeps at other times
• Sleeps most of the day; needs to be aroused repeatedly to maintain interaction

The medications below have been recommended or used in individuals with Alzheimer disease (AD). Donepezil and rivastigmine are the only drugs investigated in individuals with Down syndrome (DS).^{[60, 61, 62, 63]}

Acetylcholinesterase inhibitors

Four acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) have been approved by the FDA for treatment of AD in patients without DS. Tacrine is almost never used because potential liver toxicity requires frequent blood monitoring. All 4 drugs are approved for mild-to-moderate dementia. Donepezil remains the only cholinesterase inhibitor also approved for treatment of patients with severe dementia.

Memantine, a partial N -methyl-D -aspartate (NMDA) antagonist, is approved for the treatment of moderate-to-severe AD.

The efficacy of the cholinetransferase inhibitors in AD in patients without DS is modest, and data are not convincing that these drugs influence the overall progression of the disease. Nonetheless, industry-sponsored studies have shown that AD patients without DS on these medications may require nursing home placement 1 year later than patients not treated with these medications.

Choline transferase inhibitors might be expected to produce the same results in persons with DS. However, AD in patients with DS is often diagnosed at a later stage than in patients without DS. Most studies of cholinesterase inhibitors were conducted in patients with mild-to-moderate disease, and efficacy in patients with severe disease is less well established.

The efficacy of memantine is also modest. Indeed, its effect size is only half that of the cholinetransferase inhibitors. Memantine also does not slow the progression of disease. Some believe its efficacy is due to decreasing baseline noise in information processing associated with excess glutamate.

Several studies in patients without DS suggest that both the cholinesterase inhibitors and memantine may be effective in treating secondary symptoms of AD such as agitation. As both groups of medications usually have fewer side effects than neuroleptics, a trial of a cholinesterase inhibitor or memantine to control secondary symptoms of AD before neuroleptics may be warranted.

Few clinical trials of the cholinetransferase inhibitor donepezil have been performed in patients with DS and AD. Results have been negative or of modest benefit that were not sustained for more than a few months.^{[64, 65, 66, 67, 68, 60, 61]}

A Cochrane review of the use of donepezil in persons with DS found only 1 small randomized controlled study on the effects of donepezil. This study showed a modest, nonstatistically significant, benefit in persons with DS and AD who were able to tolerate the side effects of the medication.^[62]

One study with rivastigmine showed mild, nonstatistically significant improvement.^[63] A Cochrane review of the use of rivastigmine in people with DS found 4 studies addressing this issue, but 3 were excluded because they did not meet the standards requested and one was awaiting assessment. The conclusion was that there was no evidence that rivastigmine is useful in this population.^[69]

A Cochrane review of the use of galantamine failed to find any study in this population.^[70]

Antagonist of NMDA

Memantine is the only drug of this group approved for use in AD. A Cochrane review mentioned the existence of 1 randomized controlled trial in persons with DS and AD, but the results are not yet available.^[71]

Other drug therapies

Several other classes of drugs have been tested in persons with AD without DS. Neuroinflammation may have a role in the pathogenesis of AD,^[72] but clinical trials with anti-inflammatory drugs have failed to show consistent efficacy.

Drugs that decrease the accumulation of beta amyloid in the brain have been tried in persons with mild AD without DS, but even though the tolerance was good and there was a reduction in the amount of Abeta 42 in the CSF of the individuals involved in the research, there was no significant clinical impact.^[73] Trials with active immunization of patients with Abeta were halted because 7% of patients developed encephalitis. How effective immunization was in slowing progression in this trial is controversial.

Estrogen epidemiologic data suggested that postmenopausal women taking estrogen were at a decreased risk of developing AD. However, a clinical trial testing this hypothesis among women older than 65 years and with a family history of AD was halted because the women treated with estrogen appeared to have increased risk for dementia. Data suggest that estrogen may have a protective role if started in younger women at the onset of menopause. Present evidence does not support the use of estrogen for the treatment or prevention of AD.

Antioxidants

Data suggest that free radicals may contribute to neurodegeneration in AD, but clinical trials have not consistently shown efficacy of antioxidants. Several studies have addressed this issue, few of them in persons with DS.

A study of the use of lipoic acid in persons with DS failed to show any clinical impact.^[74] A Cochrane report also indicates that there is no evidence of benefit, and lipoic acid should not be recommended for the treatment of dementia.^[75]

Acetyl-L-carnitine for the improvement of visual memory and attention was reported in the only study done in persons with DS. This effect was not seen in a control group of persons with mental deficiency but no DS, suggesting some specificity.^[76] Other studies in persons with mild cognitive impairment and AD also showed some improvement. Acetyl-L-carnitine was given to 40 individuals with DS in a double-blind protocol for 6 months, but it did not result in any benefit in persons with DS.^[77] At present, the routine use of this medication it is not recommended.

A 2-year randomized, double-blind, placebo-controlled trial assessed daily oral antioxidant supplementation (900 IU of alpha-tocopherol, 200 mg of ascorbic acid, and 600 mg of alpha-lipoic acid) in 53 persons with DS and dementia.^[78] Although supplementation was safe, there was no improvement found in cognitive function or stabilization of cognitive decline.

Increased antioxidant effects in cells in patients with AD may improve some symptoms; however, a Cochrane meta-analysis found no evidence to support the use of melatonin in persons with dementia.^[79]

Some studies suggested that diets containing high amounts of vitamin E could prevent dementia^[80] ; however, other studies disagree.^[81] A Cochrane review also found no solid evidence for the use of vitamin E in AD but identified enough benefit to justify further studies.^[82]

Vitamins B-6, B-12, and folic acid are cofactors in the metabolism of homocysteine that might accumulate if there is a deficiency of these vitamins. A high level of homocysteine is a risk factor for the development of AD. The administration of 5 mg/d of folic acid alone or in combination with 5 mg/d of vitamin B-6 or 100 micrograms of B-12, or both, decreased the blood levels of homocysteine in persons with DS.^[83] No other studies have evaluated the use of these vitamins in persons with DS. In general, the evidence available does not demonstrate a beneficial effect of these vitamins in the prevention or treatment of AD.

The herbal product ginkgo biloba is probably the most commonly used alternative treatment for the prevention of age-related cognitive decline.^[84] The information available is still controversial, with studies showing some mild benefit, while others have failed to show any positive change.^[85] The only study of gingko involving 2 teenagers with DS showed some benefits in social and academic skills.^[86]

Curcumin is an herb that is used to preserved food; it is widely consumed in India and might be related to the lower incidence of AD in India. Curcumin is a potent antioxidant and anti-inflammatory. There is no investigation of the effect of curcumin in persons with DS.

Nonsteroidal anti-inflammatory agents

Some studies have suggested that NSAIDs might be beneficial; however, no studies have been done in persons with DS.

Psychotropic medications

Typical and atypical neuroleptics are often used to treat agitation, aggression, and hallucinations in patients with AD without DS. A black box warning from the FDA warns about the use of atypical neuroleptics in patients with dementia. Nonetheless, most experts still occasionally use atypical neuroleptics, such as quetiapine, with the least extrapyramidal side effects in treating AD patients with agitation. Physicians need to inform patients’ families that they are prescribing such medications despite the black box warning.

The use of atypical antipsychotic medications in persons with AD but no DS for the treatment of aggression, psychosis, or agitation showed that the adverse effects offset the benefits.^[87]

Other medications

Small trials have examined using antiseizure medications such as valproate, carbamazepine, and lamotrigine for treatment of agitation in AD. Results have been inconsistent.

Selegiline is a neuroprotective medication that might be of benefit in persons with DS.^[88] A Cochrane meta-analysis of selegiline failed to show any positive effect. This medication has not been evaluated in persons with DS.^[89]

In many instances, medications might be needed to treat the frequent comorbid conditions observed in persons with DS.^[90]

Surgical care

Some patients may require placement of a feeding tube, and some patients may need a tracheostomy.

Consultations

Consult a neurologist and/or a gerontologist for diagnosis, advice, and follow-up care. Also consult rehabilitation specialists. In advanced stages, consult an ethics specialist regarding decisions for resuscitation and/or hospice care.

Diet

No particular diet is required. As the disease progresses, dysphagia may become a prominent feature, and changes in food texture usually are recommended. A dietitian's help may be needed at this stage.

In advanced stages, limited intake may be associated with severe weight loss. At this point, consider a feeding tube.

Activity

Animal studies have shown that physical exercise and/or environmental enrichment increased growth in some areas of the brain. Based on this, Head et al suggested that the application of these ideas might have a significant positive impact in aging persons with DS.^[31] These ideas have not been scientifically proven in persons with DS; however, a good comprehensive plan for individuals with AD should include a variety of physical and social activities.

Further inpatient care

Inpatient care is not necessary except when the patient presents with acute medical complications. In the advanced stage of the disease, institutionalization may be required. In these individuals, hospice care might be an option to consider.^[91]

Further outpatient care

Most services are provided in the outpatient setting. Consult a team that is experienced in managing AD patients with DS.

Transfer

When the severity of the dementia creates dangerous situations, individuals with AD need to be transferred from their usual living conditions. The ideal situation is to obtain support from the family or to arrange for caretakers at home so that the patient is maintained in a familiar and friendly environment as long as possible.

Deterrence/Prevention

At present, there is no known method or treatment for the prevention of AD. However, some epidemiologic studies have evaluated the importance of lifestyle, diet, and other risk factors.^{[92, 93]} Trials have been performed with gingko biloba, NSAIDs, estrogens, vitamins E and C, and beta-carotenes, but there is no clear evidence of positive results.^{[45, 46, 94, 95]}

Complications

Good nursing care is needed to avoid complications (eg, decubitus ulcers, aspiration pneumonia, deterioration of gastroesophageal reflux, fractures, dysphagia, urinary tract infections, accidents).

As no treatment is available for the primary disease, prognosis is poor. 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 of those have AD.

Discuss issues related to diagnosis and prognosis with the family and caregivers early in the course of the disease. In addition, establishing rapport with a team that specializes in the management of AD is useful.

Caregivers are an important component in the care of persons with AD. In most instances, caregivers are family members. Caregivers endure a significant burden that might result in physical and emotional disorders.^[96] A good program for the treatment of persons with AD, with or without DS, should include education for and protection of the caregivers. A program consisting of 2 sessions of individual therapy for the caregiver of a person with AD (usually the spouse), 4 sessions of family counseling, support group participation, and continuous availability of phone counseling for the caregiver resulted in a 28.3% reduction in nursing home placement and a delay of almost a year and a half in the admission to a nursing home when that was needed. These positive results were achieved without a negative impact on caregiver well-being.

For patient education information, see the Dementia Center.

Individuals with DS are considered independent adults when older than 18 years. Instruct parents to obtain legal guardianship through the courts; otherwise, any authorization provided by the parents has no legal value. Discuss issues such as surgical procedures, placement of feeding tubes, and hospice care with the legal guardians.