News & Views Archives

Issue No. 4, Summer 2005

Our daughter is reading and learning at a remarkable rate, and I fear the day that she begins to lose all that she has worked so hard for.

This is a quote from a parent via email. As if parents of children with Down syndrome didn’t have enough on their plates, many worry that their loved one with Down syndrome may get Alzheimer’s disease (AD) when they get older. A lot of progress has been made in recent years regarding AD in the general population, and the association between elderly people with Down syndrome and AD is now well established. Below, we review some of the current literature on Down syndrome and AD.

It may seem far away, but October is National Down Syndrome Awareness Month. Many Buddy Walks are planned all over the country during this month. To locate a walk near you, check out the NDSS Buddy Walk webpage.

If you live in the Bay Area, you may find the Down Syndrome Connection a useful resource. The Down Syndrome Connection consists of parents, educators, therapists and concerned persons that seek to optimize the quality of life for individuals with Down syndrome by offering direct services to them and their caregivers, and by educating the general public about the special concerns and unique needs of the Down syndrome community. Services include one on one therapy, parent advocacy, counseling, parent and sibling support groups, and a unique STEP program of therapeutic and interactive classes that focus on building physical skills and interpersonal relationships. The Down Syndrome Connection partners with community businesses and organizations to raise funds and to create greater community awareness.

We are always looking for images of people with Down syndrome of all ages to feature on our website. If you would like to share a picture, please send it via attachment to dsresearc@med.stanford.

In the spotlight

Down Syndrome and Alzheimer's Disease
By Sietske Heyn, Ph.D.

Thanks to medical progress and increased inclusion in families and communities, individuals with Down syndrome enjoy a much healthier and longer life than just a few decades ago (Prasher and Krishnan, 1993). Consistent with findings in the general population, the rate of dementia in individuals with Down syndrome increases with increasing age (Tyrrell et al., 2001). However, the likelihood that individuals with Down syndrome will develop Alzheimer's disease (AD) is much higher, and clinical signs appear much earlier than in the general population. After the fourth decade, adults with Down syndrome often experience a decline in cognitive function and many develop dementia. In fact, virtually all individuals with Down syndrome older than 40 years show brain changes indistinguishable from AD (Wisniewski, 1985; Mann, 1988).

What exactly is AD? AD is a nervous system disorder that slowly but progressively robs a person of his or her memory and other cognitive functions. At first, the person may be agitated and confused, but over time, their personality and behavior change. They become more and more forgetful and incapable of taking care of themselves. Loss of short-term memory is generally an early sign. AD is characterized by the development of neuritic plaques (Fig. 1, left panel), neurofibrillary tangles (Fig. 1, right panel), shrinkage of neurons and synaptic loss in certain areas of the brain (for a review see Selkoe, 2001). A part of the brain called the hippocampus, which plays a major role in learning and memory, is especially affected. Even though many healthy older individuals without Down syndrome may also exhibit neuritic plaques and neurofibrillary tangles, it is the increased accumulation of these hallmarks, along with other metabolic changes in the brain that are thought to be the underlying cause of AD.

Figure 1. Left panel: Example of a neuritic plaque from the hippocampus of a 56 year-old person with Down syndrome. Right panel: Example of a normal-appearing neuron (a) and a neurofibrillary tangle-bearing neuron (b) from the same person as in the left panel

Although it is difficult to measure true rates, people with Down syndrome have a higher predisposition to AD than the general population. In one study of institutionalized individuals with Down syndrome, the prevalence rate of dementia was 8% between the ages of 35 and 49 years, 55% between the ages of 50 and 59, and 75% in those older than 60 years (Lai and Williams, 1989). Another study of non-institutionalized individuals reported 0% in the age range 20-29 years, 33% in the age range 30-39 years, and 55% in the age range 40-52 years (Franceschi et al., 1990). In a recent study of the general population, Desai and Grossberg (2005) found that the prevalence of AD rises exponentially from 5% in people aged 65 to 74 to almost 50% in people older than 85.

In addition to having a higher predisposition to AD, individuals with Down syndrome on average show clinical symptoms at a much younger age than people without Down syndrome (Wisniewski, 1985). For example, in a study by Prasher and Krishnan (1993), the mean age of onset of dementia in people with Down syndrome was 51.7 years, but could start as early as 31 years. In the general population, approximately one in 10 individuals over 65, and nearly half of individuals over 85 years is affected (Evans et al., 1989).

Why are people with Down syndrome more susceptible to developing AD? Though the exact causes of AD are not entirely understood, at least one gene that is widely believed to be involved is located on chromosome 21. This gene encodes a protein called amyloid precursor protein (APP) which when processed in a certain way leads to the formation and accumulation of neuritic plaques (reviewed by Selkoe, 2001). Since people with Down syndrome have an extra chromosome 21, they also have an extra copy of the gene that encodes APP. It is hypothesized that the presence of this extra gene may lead to increased accumulation of neuritic plaques and hence may be partially responsible for the high rate of AD observed in the Down syndrome population (reviewed by Mrak and Griffin, 2004).

Recognizing early signs of mental decline and making a diagnosis of dementia in adults with Down syndrome is challenging. Because people with Down syndrome have a lower level of intellectual functioning, standardized tests for detecting dementia in the non-learning impaired population often do not work for people with Down syndrome (Prasher et al., 2004). In addition, no accepted standard instrument is available for evaluating and assessing signs and symptoms of dementia in people with Down syndrome. False positives may arise due to other conditions common to people with Down syndrome presenting as dementia, such as depression, hypothyroidism, or due to test failure resulting from sensory impairment or poor communication and attention during testing (Prasher and Krishnan, 1993).

Where does all of this information lead us? Since individuals with Down syndrome are getting older than ever before, there is an increasing need for accurate diagnostic procedures to make progress in understanding and treating dementia in adults with Down syndrome. There is also a growing need for accurate methods of differentiating individuals who have progressive, irreversible AD from those who have cognitive decline caused by treatable conditions (Aylward et al., 1997).

Despite the lack of standardized diagnostic methods for AD in Down syndrome, there are several tests that have some reliability and validity in the diagnosis. One such tool that has been widely used is the Adaptive Behavior Scale (ABS) (Nihira, 1974). Recently Prasher et al. (2004) have designed an informant-based questionnaire adapted from the ABS. This Adaptive Behavior Dementia Questionnaire can be given by caregivers annually and is used to detect changes in adaptive behavior over time. Other tests include the Dementia Questionnaire for Persons with Mental Retardation (Evenhuis et al., 1990) and the Dementia Scale for Down Syndrome (Gedye, 1995).

Aylward et al. (1997) recommend that all adults with intellectual disabilities (including people with Down syndrome) should be evaluated at least once in early adulthood using standardized procedures to establish a baseline of functioning. Baseline evaluations and periodic screens are recommended to document changes in behavior and mental status over time. This can greatly facilitate the potential diagnosis of AD and other mental health issues as the person serves as his or her own point of reference.

Once the diagnosis of AD had been made in an individual with Down syndrome, one may consider therapy to slow down progression of the disease. Drugs that have been approved for the use in AD in the general population may also show benefits in individuals with Down syndrome. Cholinersterase inhibitors such as donepezil, for example, may have a positive effect for some people with Down syndrome (reviewed by Prasher, 2004). For a current review of donepezil in Down syndrome, you may also refer to News & Views issue No 3. Given the tight relationship between the APP gene and the incidence of AD, one might also envision targeting this gene for therapy (reviewed by Selkoe, 2001).

In summary, progress has been made towards understanding AD in general, which has also helped in trying to understand the early onset of AD in Down syndrome. However, since people with Down syndrome are becoming older, the prevalence of AD in the Down syndrome population is increasing. With this increase, there comes a rising need to find better diagnostic tools so that families and caregivers can be better prepared to find proper programs and the best available treatment.


References

Aylward, EH, Burt, DB, Thorpe, LU, Lai, F, and Dalton, A (1997) Diagnosis of dementia in individuals with intellectual disability. J Int Disab Res. 41:152-164

Desai, AK, and Grossberg, GT (2005) Diagnosis and treatment of Alzheimer’s disease. Neurology. 64 (Suppl. 3):S34-S39

Evans, DA, Funkenstein, HH, Albert, MS, Scherr, PA, Cook, NR, Chown, ML, Hebert, LE, Hennekens, CH, and Taylor, JO (1989) Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA. 262(18):2551-2556

Evenhuis, HM, Kengen, MMF, and Eurling, HAL (1990) Dementia Questionnaire for Mentally Retarded Persons. Hooge Burch, Zwammerdam, the Netherlands

Franceschi, M, Comola, M, Piattoni, F, Gualandri, W, and Canal, N (1990) Prevalence of dementia in adult patients with Trisomy 21. Am J Med Gen Suppl. 7:306-308

Gedye, A (1995) Manual for the Dementia Scale for Down Syndrome. Gedye Research and Consulting. Vancouver, Canada

Lai, F, and Williams, RS (1989) A prospective study of Alzheimer disease in Down syndrome. Arch Neurol. 46:849-853

Mann, DMA (1988) The pathological association between Down syndrome and Alzheimer disease. Mech Ageing Dev. 43:99-136

Mrak, RE, and Griffin, WS (2004) Trisomy 21 and the brain. J Neuropath Exp Neurol. 63(7):679-685

Nihira, K, Foster, R, Shellhas, M, and Leyland, H (1974). AAMD Adaptive Behaviour Scale, 1974 revision. Washington, DC: American Association on Mental Deficiency

Prasher, VP, and Krishnan, VHR (1993) Age of onset and duration of dementia in people with Down syndrome: Integration of 98 reported cases in the literature. Int J Ger Psy. 8:915-922

Prasher, VP (2004) Review of donepezil, rivastigmine, galantamine and memantine for the treatment of dementia in Alzheimer’s disease in adults with Down syndrome: implications for the intellectual disability population. Int J Geriatr Psychiatry. 19:509-515

Prasher, V, Farooq, A, and Holder, R (2004) The Adaptive Behaviour Dementia Questionnaire (ABDQ): Screening questionnaire for dementia in Alzheimer’s disease in adults with Down syndrome. Res Dev Disb. 25:385-397

Selkoe, DJ (2001) Alzheimer’s disease: Genes, proteins, and therapy. Physiol Rev. 81:741-66

Tyrrell, J, Cosgrave, M, McCarron, M, McPherson, J, Clavert, J, Kelly, A, McLaughlin, M, Gill, M, and Lawlor, BA (2001) Dementia in people with Down’s syndrome. Int J ger Psych. 16:1168-1174

Wisniewski, KE, Wisniewski, HM, and Wen, GY (1985) Occurrence of neuropathological changes in dementia of Alzheimer’s disease in Down syndrome. Ann Neurol. 17:278-282