Alzheimer’s disease in Down syndrome

For the past thirty years (and perhaps longer) physicians, researchers, and family members of people with Down syndrome recognized that patients with Down syndrome very often seemed to develop symptoms of Alzheimer’s disease. Not only that, but the Alzheimer’s disease symptoms occurred earlier in life than they would in people without Down syndrome. This link has been as intriguing for neuroscience researchers as it has been troubling for caregivers and loved ones of those with Down syndrome. Despite this strong link between the two conditions, there are still as many questions as there are answers; however, the similarities between Alzheimer’s disease and Down syndrome and their simultaneous occurrence in people are helping to unlock the mysteries of both diseases.

Alzheimer’s disease is the most commonly occurring form of dementia in the general population, but it is only one form of dementia. Dementia is defined as a loss of intellectual and cognitive functions while things like perception and consciousness remain intact. In other words, people with dementia are not in a stupor or delirious but are frequently confused and have difficulty performing more complex thought processes. Dementia is associated with memory loss and impaired judgment among other related symptoms. Mood is often affected by the disease as well. People with Alzheimer’s disease may be agitated, depressed, or even experience hallucinations or delusions as part of the disease process.

Down syndrome, without coexisting Alzheimer’s disease, causes a number of cognitive disabilities. Children with Down syndrome are delayed in their motor development and delayed in reaching several cognitive milestones. There are also problems in expressive language development. The delay in social competence is highly variable but is present to some degree in most patients. This latter symptom is tempered by natural gentle warmth, patience, and cheery disposition, though occasional behavioral outbursts are not uncommon. If using the Intelligence Quotient (IQ) scale, patients with Down syndrome generally fall between 25 and 75 (the average score in the population is set at 100). In other words, intellectual capacity is less than average.

Another feature of Down syndrome that is relevant to a discussion of Alzheimer’s disease symptoms is the finding that people with Down syndrome age faster than people without the syndrome. This accelerated aging is most often noticed in the musculoskeletal system but may extend to other organ systems, including the brain and nervous system. It has been said that everyone, if they live long enough, will eventually develop Alzheimer’s disease. Therefore accelerated aging alone may play some role in the increased incidence of Alzheimer’s disease in people with Down syndrome.

However, the cause(s) of this comorbidity (coexistence of two disorders at the same time) likely goes deeper than simply accelerated aging. Quite shockingly, virtually every adult with Down syndrome has changes in their brains that are the same as the changes seen in Alzheimer’s disease.1;2 This means that when a pathologist looks at the brain under a microscope, the characteristic findings seen in Alzheimer’s disease show up in basically all adults with Down syndrome (for those that are interested the changes are amyloid plaques, neurofibrillary tangles, and a loss of cholinergic neurons in the basal forebrain).

In terms of cognitive symptoms (not brain pathology), the prevalence of Alzheimer’s disease in patients with Down syndrome is quite high. Up to 10% of Down syndrome patients ages 30-39 also have diagnosable Alzheimer’s disease. Between ages 40 to 49 the rate is as high as 25% and in ages 50 to 59 the prevalence is 55%. Alzheimer’s disease rates as high as 75% may occur in patients between the ages of 60 and 69.3 For comparison, Alzheimer’s disease occurs in about 14% of people older than 65 in the general population. Thus the rates of Alzheimer’s disease in Down syndrome are clearly higher.

The prevalence and incidence of Alzheimer’s disease in people with Down syndrome varies widely. This is mostly due to the fact that it is challenging for physicians to diagnose Alzheimer’s disease in patients that have the cognitive difficulties. Dementia can be overdiagnosed or underdiagnosed depending on the circumstances. Even the diagnosis of Alzheimer’s disease in patients with “normal” cognitive ability can be tricky. Ideally the physician should know the patient’s level of functioning before and after the suspected onset of cognitive decline. In other words, the neurologist’s job is made easier and the diagnosis is more accurate if there is a baseline level of functioning to which to compare the worsened state.

This is particularly true when diagnosing Alzheimer’s disease in patients with Down syndrome—comparison to a baseline is extremely important. Often the neurologist meets with a patient that has suffered a decline in one area. Perhaps that patient with Down syndrome is no longer able to reliably perform tasks that they once could with little or no help. Perhaps there are new symptoms of depression or problems with sleep or perhaps there has been a loss of control over bowel or bladder leading to wetting or messing. Because the association of Alzheimer’s disease and Down syndrome is so common, many doctors seem to attribute this change in function to the onset of dementia. As a result, it is quite common that Alzheimer’s disease is overdiagnosed.4

Therefore it is very important to rule out other causes of a change in function before a physician makes a diagnosis of dementia. This is important for at least two reasons. One reason is that the other causes of cognitive decline and functioning are more easily and rapidly treated than Alzheimer’s disease. If the change in the ability to control urine is due to a bladder infection, for example, a simple antibiotic can cure the problem. The second reason is that the correct diagnosis can avoid expensive and unnecessary treatments for Alzheimer’s disease, like cholinesterase inhibitors (e.g. donepezil).

A situation that would make diagnosis of Alzheimer’s disease in Down syndrome easier and more definitive is if the decline occurs in a number of areas at once. For instance problems are occurring with memory have lead to functional deficits and are associated with behavioral changes. If the patient has a steady job or participates in a daily set of tasks, a decline in the ability to do these duties is a good first indicator that dementia may be a problem. While other diseases still need to be ruled out, a global decline at least raises the possibility of Alzheimer’s disease.

However the diagnosis is slowed because the onset is usually more subtle. The earliest signs of dementia in Down syndrome are usually confusion, disorientation, and wandering which may be hard to detect, even for close caregivers. Often the first symptoms Alzheimer’s disease in Down syndrome are simply a worsening of symptoms that were present for a very long time. This can make proper diagnosis nearly impossible. Diagnosis at this stage usually only occurs when a caregiver notices a change in normal daily functioning and can convey that to a neurologist that has experience in dementia and developmental disorders. Even so, an average of two years elapses between first symptoms and a correct diagnosis of Alzheimer’s disease in most cases.

Trouble learning new information or learning new skills is also an early symptom, but again, it is very difficult 1) to notice a deficit 2) to link that deficit to the onset of Alzheimer’s disease specifically. It may be easier to recognize early Alzheimer’s disease by changes in the ability to communicate effectively, a loss of manners (behavior at the table or bathroom habits), or worsening personal care and hygiene.

Once Alzheimer’s disease fully takes hold of a person with Down syndrome the disease is easily recognizable. Sadly, the disease leads to a rapid decline in function—more quickly than the disease would affect a person with higher cognitive ability. Activities of daily living (ADLs) drop off quickly. In advanced disease, the patient is essentially totally dependent on others for care.

There is not a single test or set of tests that definitively diagnoses Alzheimer’s disease and any tests that may be used in persons of average or higher intelligence are notoriously unreliable in persons with Down syndrome. For example, gene marker tests for Alzheimer’s disease are of little use in Down syndrome patients. Many tests may be done, however, to rule out other causes of delirium or reversible cognitive problems. Routine blood work may be done including serum electrolytes and blood cells counts. Liver and kidney function may be tested. Levels of certain vitamins like folic acid and B12 may be determined to check for deficiencies. A lumber puncture (spinal tap) may be done if the change in mental status is possibly due to an infection of the brain, like meningitis.

Imaging studies, like CT or MRI, might be useful in ruling out causes of cognitive decline other than Alzheimer’s disease. Unfortunately there are currently no reproducible or consistent differences in the way the Down syndrome brain appears with or without Alzheimer’s disease. This means that no radiological study can be done to make the Alzheimer’s disease diagnosis. In the future, PET (positron emission tomography) may provide some help in this regard but it is not used for routine diagnosis of Alzheimer’s disease in Down syndrome.

Further complicating matters is that the traditional neuropsychological tests that are used to diagnose Alzheimer’s disease are unreliable in Down syndrome patients. Also, if the patient’s baseline mental performance is quite low, patients with Down syndrome may not be able to effectively participate in the testing.

There are several neuropsychological tests that have been developed that may be more appropriate for use in patients with Down syndrome. The major focus of these tests are to identify changes from the patient’s specific baseline rather than comparing performance to some average level of functioning. In other words, if the patient gets worse from a previous level of functioning, the test should be able to detect it. This is approach is much more promising than trying to compare test results to some established norm. These tests also rely heavily on the reports and experiences of the primary caregiver(s).

The Dementia Questionnaire for Mentally Retarded Persons is an Alzheimer’s disease (or dementia) screening tool that is designed to be completed by caregivers. The Dementia Scale for Down syndrome is useful under some circumstances though it is most sensitive for patients that have already reached a middle or moderate stage of dementia. While it is not a tool used to diagnose Alzheimer’s disease in people with Down syndrome per se, the Alzheimer’s Functional Assessment Tool is perhaps the best questionnaire for guiding treatment decisions and program placement. It can be performed every six months as a way of determining if there has been a decline from a previous level of functioning. (A copy of the questionnaire is provided.)

Unfortunately the treatment of Alzheimer’s disease in people with Down syndrome is quite poor. The standard treatments for Alzheimer’s disease patients (which are not really very helpful in that capacity) are virtually ineffective in people with Down syndrome. Four cholinesterase inhibitors and memantine (a glutamate receptor partial antagonist) are the only medicines currently approved by the FDA for the treatment of Alzheimer’s disease. With the exception of donepezil (Aricept) none of these drugs has been tested specifically in Down syndrome patients and none are specifically reviewed by the FDA for use in patients with Down syndrome.

For any real benefit, these drugs need to be started early in the course of Alzheimer’s disease. Sadly in Down syndrome, the Alzheimer’s disease is usually not recognized until its middle or late stages. While these drugs may not help stop the decline of mental capacity, one hope is that they may help treat other symptoms of Alzheimer’s disease, like agitation and behavioral outbursts. This is especially helpful since antipsychotic medications are not to be used in patients with dementia. Antiepileptic (anti-seizure) drugs have been tried but are not terribly useful, either.

The best approach to diagnosis and treatment of Alzheimer’s disease in people with Down syndrome is to find a neurologist that specializes in the treatment of dementia and has experience with patients that also have Down syndrome. This medical professional should be familiar with the patient and have several appointments over time. In that way the doctor will also be able to help detect any functional decline. Caregivers should keep an eye out for changes in behavior and cognitive ability and make a record these changes in a journal with dates and descriptions. This could provide invaluable information to the diagnosing physician.

Early diagnosis is helpful, but challenging. Earlier diagnosis means more treatment options; however, Alzheimer’s disease is progressive and incurable, regardless of who is afflicted with it. In addition to a neurologist, a good social worker may be able to coordinate care and identify services that could help provide short and long term care.

Alzheimer’s disease in Down syndrome Reference List

(1) Shamas-Ud-Din S, Holmes C. Genetics of Down’s syndrome and Alzheimer’s disease * Authors’ reply. The British Journal of Psychiatry 2002;181:167-168.

(2) Mann DM. Alzheimer’s disease and Down’s syndrome. Histopathology 1988;13:125-137.

(3) Smith DS. Health care management of adults with Down syndrome. Am Fam Physician2001;64:1031-1038.

(4) Chicoine B, McGuire D, Hebein S, Gilly D. Development of a clinic for adults with Down syndrome. Ment Retard 1994;32:100-106.

Written by Michael Todd Sapko MD, PhD, with minor editing by Donald Urquhart, Psychologist.