International Review of Psychiatry, December 2013; 25(6): 755–763

Dementia in people with intellectual disability: Insights and challenges in epidemiological research with an at-risk population

ELIZABETH EVANS1, ANJALI BHARDWAJ1, HENRY BRODATY2,4,5, PERMINDER SACHDEV2,3, BRIAN DRAPER2,5 & JULIAN N. TROLLOR1,2 1Department

of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW, 2Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 3Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW, 4Dementia Collaborative Research Centre, School of Psychiatry, University of New South Wales, Sydney, NSW, 5Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Avoca Street, Randwick, New South Wales, Australia

Abstract The population with intellectual disability (ID) is ageing, but age-related health concerns such as dementia have received little research attention thus far. We review evidence regarding the prevalence and incidence of dementia in people with ID, and discuss some possible explanations for an increased risk, such as shared genetic risk factors, co-morbid physical and mental disorders, lifestyle factors, trauma, and lowered brain reserve. We discuss practical and theoretical challenges facing researchers in this field, before highlighting the implications of findings to date for future research and clinical care. Research on dementia in this at-risk population has the potential to help us understand dementia in general and to improve services for this group of vulnerable individuals.

Introduction The world’s population is ageing, and dementia has been identified as a public health priority by the World Health Organization (WHO, 2012). Research into ageing and dementia has burgeoned in recent years. However, special populations for whom ageing has specific relevance, such as those with intellectual disability (ID), have received little attention. This is a notable deficiency, as the population with ID has witnessed a dramatic increase in life expectancy, faster than that for the general population (Bigby, 2004), and this is set to continue in the near future (McCarron & Lawlor, 2003). The life expectancy for people with mild ID is now on par with that of the general population (Patja et al., 2000), whereas that for ID of any severity is approximately 60 years (Torr & Davis, 2007). While such increases showcase the improvements in medical and social care for people with ID (Janicki et al., 1999; Sison & Cotten, 1989), some data suggest that those with ID are at an increased risk of age-related brain disorders, such as dementia, the onset for which typically occurs at a younger age (Cooper, 1997b; Strydom et al., 2009a).

In this paper we review literature regarding the prevalence and incidence of dementia in people with ID, and discuss possible reasons for overrepresentation of dementia in this group. We then outline practical and theoretical challenges to research in this area, and highlight the potential value of such work for people both with and without ID. Our review is focused on neurocognitive decline which is not an inherent consequence of the cause of ID. Disorders associated with ID which cause a progressive impairment from an early age, such as Rett syndrome, childhood disintegrative disorder, or the mucopolysaccaroidoses, are not included. The main focus of this review is cohort studies with over 100 participants that include direct assessments and/or clinical interviews, since several authors (e.g. Burt & Aylward, 2000; Strydom & Hassiotis, 2003) recommend the use of both informant measures and direct assessment when investigating dementia in people with ID. Strydom et al. (2009b) already provide an excellent review of recent research into dementia in ID, which encompasses studies using questionnaire and file-review methodologies.

Correspondence: Associate Professor Julian Trollor, Department of Developmental Disability Neuropsychiatry, 34 Botany Street, University of New South Wales, NSW 2052, Australia. Tel: ⫹ 612 9931 9160. Fax: ⫹ 612 9931 9154. E-mail: [email protected] (Received 11 November 2013; accepted 14 November 2013) ISSN 0954–0261 print/ISSN 1369–1627 online © 2013 Institute of Psychiatry DOI: 10.3109/09540261.2013.866938

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Prevalence and incidence of dementia in people with ID In examining the prevalence and incidence of dementia in people with ID, it is useful to consider Down’s syndrome (DS) and intellectual ability other than DS separately.

Down’s syndrome The increased prevalence of Alzheimer’s disease (AD) in DS relative to the general population has been well-documented through cross-sectional studies, finding a much higher rate of AD compared with known rates for the general population (e.g. Sekijima et al., 1998; Tyrrell et al., 2001). In addition, several large longitudinal studies have examined dementia prevalence and incidence at different ages. For example, a marked age-related increase in the prevalence of dementia was found by Prasher (1995), with only 2% of participants aged 30–39 diagnosed with AD, increasing to 9.4% in those aged 40–49, 36.1% in those aged 50–59, and 54% in those aged 60–69 years. At follow-up, new cases were reported at a rate of 44 out of 119 remaining participants across a 5-year interval, suggesting a relatively high incidence across the entire study group (Prasher et al., 2004). A slightly smaller but important study found a very high prevalence of dementia in a representative sample of adults with DS aged over 30 years. The prevalence of all forms of dementia was 20.7% in those aged 30–39 years and 40–49 years, and 40% in those aged 50–59 years (Holland et al., 1998). Only two participants were aged over 60 years, neither of whom had dementia. At follow-up, the age-specific incidence rates, reported as new cases of dementia over an 18-month period, were 26.1% for those aged 30–39 years, 26.3% for 40–49 years and 22.2% for 50–59 years (Holland et al., 2000). One of the largest studies involving direct assessments of people with DS followed 506 adults with DS aged 45 and above, for 5 years or until their death (Coppus et al., 2006). The prevalence of dementia was high, at 16.8% overall, and increased until age 60, after which it decreased slightly. However, the incidence of dementia continued to increase beyond 60 years. Mortality was significantly associated with dementia status up to 60 years, but not beyond this age, suggesting that the different patterns of incidence and prevalence as people aged was partly related to the high mortality of those with dementia with onset prior to 60 years. As those authors highlight, even in those aged over 60 years, three quarters of their sample did not have dementia. Most adults with DS maintain their cognitive functions at least through their 40s (Zigman & Lott, 2007). For those that develop AD, the average age of

onset is between 50 and 55 years (see Coppus et al., 2006, for a review), which stands in contrast to data from post-mortem studies showing that amyloid plaques and tangles can appear in the brains of people with DS as early as their 30s (Mann & Esiri, 1989) and are almost always present by age 40 (Whalley, 1982). The discrepancy between the onset of AD brain pathology and onset of cognitive and behavioural symptoms of dementia in DS indicates that pathological changes are necessary but not sufficient for the manifestation of dementia due to AD. Other factors which buffer or facilitate the manifestation of dementia in the presence of high pathological burden await clarification in this group. Non-DS ID Dementia in non-DS ID has received less research attention than DS, and reported prevalence rates are more variable. In an epidemiological sample of 134 adults with non-DS ID aged over 65 years, the prevalence of dementia was 21.6%, with a further 4.5% classified as having ‘possible dementia’ (Cooper, 1997a). As expected, these rates were much higher than in a younger group with ID aged 20–65 years, but they were also significantly higher than rates from the non-ID population (Cooper, 1997b). A similar result was found by Strydom et al. (2009a), who diagnosed dementia in 13.1% of their sample of 222 people with non-DS ID aged 60 or above, and in 18.3% of those aged over 65 years. These data suggest that dementia is two to three times more common in people with ID than those without ID, while at follow-up, the incidence of dementia in their sample was up to five times that for the general population. This study also revealed a downward shift in age-associated risk for this group, suggesting that dementia in people with ID occurs at a younger age, and that dementia in these individuals was associated with a shorter survival time (Strydom et al., 2013). By contrast, a longitudinal study in the USA (Zigman et al., 2004) found age-specific prevalence and cumulative incidence rates of ‘possible’ and ‘definite’ dementia in non-DS ID which were not dissimilar to those for the general population. When figures were recalculated to include those participants deemed to meet criteria for dementia but for whom the diagnosis was complicated by another possible medical condition, the prevalence and incidence rose but remained within the range of those for the non-ID population. However, additionally, a substantial proportion (12%) of participants were considered to have ‘questionable’ dementia status, in that they showed some indications of mild functional and cognitive decline, while for a further 9% of participants the severity of pre-existing disability precluded the detection of declines. Similar findings

Dementia in people with intellectual disability come from an 11-year study in which the incidence of dementia in 144 people with non-DS ID aged 60 and over was comparable to that of the general population, when based on strict DSM-III-R criteria (Evenhuis, 1997). However, the number of participants showing significant progressive decline was nearly twice that of those who received DSM-III-R diagnoses, but almost half of these did not fulfil strict DSM-III-R criteria. These studies highlight the potential for reported rates to be confounded by factors relating to the difficulty of accurately diagnosing dementia in this group. Given that studies have yielded conflicting results, it is not yet possible to draw conclusions regarding an increased risk of dementia in people with ID. However, there are number of hypothetical reasons why rates of dementia may be higher in this population, which are explored below in a review of risk factors for dementia in people with ID.

Putative risk factors for dementia in people with ID Genetic factors Certain genetic or epigenetic factors may contribute shared risk for both dementia and ID, particularly DS. A striking example is the triplicate chromosome 21 in DS which includes the amyloid beta precursor protein (APP) gene. Resultant over-expression of APP is one mechanism which appears to contribute to the formation of excess amyloid plaques, a central feature of AD pathology in the brain (see Hardy & Selkoe, 2002, for a review). In keeping with this is the observation that serum levels of the protein product found in amyloid plaques and tangles (Aβ 42) are higher in people with DS than in typically developing people or in those with non-DS ID (Mehta et al., 1998). Potential for modification of risk trajectories in people with DS is raised by the improvements in learning and memory in a mouse model of DS following the use of a ϒ-secretase inhibitor to lower β-amyloid levels (Netzer et al., 2010). Evaluating other genetic links between risk factors for DS and dementia could ultimately lead to new treatments for both conditions. Other genes on chromosome 21 may also be implicated in AD, including S100 calcium binding protein beta and superoxide dismutase 1 (SOD1) (Roizen & Patterson, 2003). Among others, the SOD1 gene plays a role in reactive oxygen species metabolism, and therefore may mediate dementia risk via the oxidative stress pathway.The DYRK1A gene, also located in the DS critical region, has been found to influence tau protein phosphorylation (Kimura et al., 2007). DYRK1A contributes to the DS phenotype in mouse models (Altafaj et al., 2001), and is overexpressed in

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the brains of people with DS above the age of three (Dowjat et al., 2007). Further evidence of a shared genetic susceptibility to DS and AD comes from findings of an increased rate of DS within maternal line relatives of probands with early onset AD (Heston, 1982). This association has also been found in the other direction: mothers who bore children with DS prior to age 35 were at increased risk of AD, compared with mothers whose children had other forms of ID (Schupf et al., 1994). Mothers whose children with DS were born after age 35 had no increased risk, nor did fathers, regardless of their age at the birth of the child. Brain reserve Reserve theories postulate that the appearance of dementia symptoms is mediated by the extent to which the individual can maintain cognitive function in the face of brain changes such as those arising through insult, inflammation, or from the accumulation of plaques and tangles (Stern, 2002). In line with this are findings from the general population that those with higher IQ tend to show decreased rates of dementia overall (Valenzuela & Sachdev, 2006). Therefore, a significant question that arises is whether level of intellectual function is related to dementia risk within the ID population. Studies regarding the relationship between IQ and dementia risk in people with ID have yielded discrepant results, with some (e.g. Strydom et al., 2009a; Zigman & Lott, 2007) finding no association between level of ID and dementia risk, while others (e.g. Oliver et al., 1998) have found increased severity of ID to be associated with faster cognitive decline in DS. It is possible that null findings relate to the difficulty of diagnosing dementia in people with more severe levels of ID (Moss & Patel, 1995), since a condition which affects functional status might be more recognizable in those with milder ID who have relatively more functional abilities. Alternatively, the increased mortality of people with severe ID may mean that a healthy survivor effect contributes to a reduced prevalence of dementia in those with severe ID who live into older ages (Strydom et al., 2009a). Beyond IQ, lifestyle factors which may contribute to, or be a measure of cognitive reserve may hold particular relevance to dementia risk in the population with ID. In the general population, levels of education, occupational status, and engagement in mentally stimulating leisure activities and social activities have been found to mediate dementia risk (Valenzuela & Sachdev, 2006). Compared with those without ID, people with ID tend to have poor social networks and low rates of employment (Emerson & Hatton, 2007), along with reduced adult educational opportunities (Hall et al., 2005).

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Specific findings regarding the presentation of dementia in people with DS may also contribute to our understanding of brain reserve. In people with DS, frontal lobe type symptoms, including behavioural and personality changes and declines in executive function, may appear before memory deficits can be diagnosed (Adams & Oliver, 2010; Ball et al., 2006, 2008; Deb et al., 2007a; Holland et al., 2000). People with DS who showed such frontal symptoms were 1.5 times as likely to receive an AD diagnosis 5 years later compared with participants with DS without any diagnosis at baseline (Ball et al., 2006). Detailed measurement of brain structure and structural and functional connectivity in the brains of adults with DS may assist in determining the extent to which the proposed underdevelopment of the frontal lobes contribute to a specific vulnerability to early loss of frontal lobe function (Ball et al., 2008; Holland et al., 1998). Brain trauma Head trauma may be a risk factor for later dementia in the general population, at least for males (Fleminger et al., 2003; Mortimer et al., 1991). The extent to which brain trauma confers risk of dementia in people with ID is unknown, but brain trauma in the perinatal period is a risk factor for ID. Theoretically, such trauma in early life could also confer vulnerability to later dementia. Additionally, the observed high rate of head injuries in people with ID (Janicki et al., 2002) may also confer dementia risk in the same manner as it does in the general population. Emotional trauma Emotional trauma and associated post-traumatic stress disorder have been found to increase risk of dementia in the general population (Dunt et al., 2012; Yaffe et al., 2010). Whether such a relationship exists in people with ID is not yet known, but compared with those without ID, people with ID experience higher rates of maltreatment such as physical, sexual, verbal and psychological abuse, neglect, and financial exploitation (Horner-Johnson & Drum, 2006). Poor diet and exercise In the general population, a higher intake of vegetables and fruits, fish, poultry, nuts and salad dressing, along with lower intake of red meat and high-fat dairy foods, has been associated with a reduced risk of AD (e.g. Gu et al., 2010). While studies of dementia risk and nutrition in people with ID are currently lacking, studies in the ID population without dementia have highlighted the extremely poor dietary intake of this group: up to 6% of American adults with ID

living in community residential settings were found to eat enough fruit and vegetables while over 70% consumed too much fat (Draheim et al., 2007), and similarly, only 8% of adults with ID in a UK study consumed a balanced diet (Robertson et al., 2000). Obesity is common in people with ID compared with those without, and especially amongst those with mild and moderate ID, and a large portion of those with severe ID have feeding difficulties and are at risk of being underweight (Melville et al., 2007). Extremely low levels of physical activity have also been reported in adults with ID, even amongst those who are able to engage in exercise (Adolfsson et al., 2008; Hilgenkamp et al., 2012). Medical risk factors In people with ID, dementia has been found to be associated with poorer overall physical health (e.g. Cooper, 1997b; Moss & Patel, 1997), and with specific conditions such as depression (Evenhuis, 1997). Compared with their non-ID peers, people with ID are at higher risk for a range of health conditions, including sensory impairments, epilepsy, gastro-intestinal problems, infectious diseases, congenital heart disease, respiratory disease, musculoskeletal disorders, and diabetes (O’Hara, 2008; Scheepers et al., 2005; Wallace & Beange, 2008), as well as poorer mental health (e.g. Cooper et al., 2007; Einfeld & Tonge, 1996). The increased rates of epilepsy in people with ID warrants special attention, since pre-existing epilepsy has been found to increase the risk of dementia in the non-ID population (Breteler et al., 1995), and those with dementia are at increased risk of seizures, both in the general population (Hesdorffer et al., 1996), in DS (Tyrrell et al., 2001) and in non-DS ID (Cooper, 1997b). The associations between poor health and dementia, coupled with the overall poorer health profile of people with ID, including the high rates of epilepsy in this group, may partly explain the increased dementia risk in this population.

What are the practical and theoretical challenges of conducting research in this area? The discrepant findings from different studies of dementia in people with ID at least partly reflect the different diagnostic criteria, sampling techniques and methodologies used (Strydom et al., 2010). These issues in turn highlight some of the theoretical and practical considerations in undertaking research in this field. Difficulty in defining dementia in people with ID The criteria used to diagnose dementia in the non-ID population present a challenge for this field. The

Dementia in people with intellectual disability diagnosis of ID is based on both an IQ score below approximately 70, and concurrent deficits in adaptive behaviour (Schalock et al., 2007). The diagnosis of dementia is based on cognitive decline that impacts on everyday activities, typically termed ‘activities of daily living’ (ADL) and ‘instrumental activities of daily living’ (IADL). As both adaptive behaviour and ADL are similar constructs, the identification of further dementia-related impairment in people with ID can be difficult, and relies on a clear understanding of optimal baseline functioning. Good baseline assessments of adaptive behaviour and cognition in middle-aged individuals with ID are often unavailable, and their measurement may be influenced by many factors such as stress levels, depression and intercurrent medical illnesses. Further, if longitudinal decline in cognitive function and ADL are demonstrated, the relatively low baseline functioning of many individuals introduces a level of complexity into their interpretation. The application of nosological criteria presents a further challenge. Several studies (e.g. Evenhuis, 1997; Zigman et al., 2004) have reported a substantial number of participants showing some changes in cognition while not meeting stricter diagnostic criteria, resulting in a large number of ‘possible’ or ‘dubious’ diagnoses. A comparison across DSM-IV, ICD-10, and DC-LD criteria, found that although correlations between the criteria were good, the DSM-IV criteria were more inclusive than ICD-10 (Strydom et al., 2007), while another (Holland et al., 1998) found that in DS, Cambridge Mental Disorders of the Elderly Examination (CAMDEX) criteria, which require a decline in memory and either additional cognitive change or personality change, resulted in twice as many participants diagnosed with AD. Greater confidence in diagnosis may be more likely using the newly released DSM-5 criteria, since it allows a diagnosis of neurocognitive disorder (NCD) in individuals with substantial decline in only one domain (APA, 2013). Nonetheless, it is likely that some DSM-5 criteria for major and mild NCD will require modification to suit this population. In particular, the approach to determining whether cognitive deficits interfere with ‘independence in everyday activities’ (Criterion B for major and mild NCD) (APA, 2013, pp. 602, 605) requires modification and contextualization to an individual’s baseline skills, as complex IADL are likely to already be impacted by a person’s pre-existing ID. Moreover, in some cases, a person with ID may have little opportunity to exercise independence in some IADL. As the DSM-5 diagnostic features emphasize, when assessing NCD, reported difficulties must represent changes rather than life-long patterns for the individual in question. A challenge for the field of ageing research in people

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with ID is to determine ways to quantify changes in social and occupational function for this group, including the determination of what constitutes ‘accommodation’ versus ‘interference’ in everyday ADL. We would suggest it may be useful to determine whether deteriorations in cognition necessitate a change in level of support required, with systematic questioning surrounding adaptations in care routines which may have taken place naturalistically. Representative sampling Compared with research on the non-ID population, obtaining adequate sample sizes for epidemiological research is far more difficult in adults with ID (Hilgenkamp et al., 2011). Non-representative sampling can greatly influence results when studying the prevalence and incidence of dementia: those living in nursing homes or institutions are more likely to have dementia, which speaks to the importance of epidemiological sampling for studying dementia in ID. Historical changes to policies regarding institutionalization and the social inclusion, rehabilitation and education of people with ID mean that people with ID of differing ages may have lived through vastly different experiences (Carr, 2005; Oliver, 1999; Prasher, 1999; Sison & Cotten, 1989). Given that lifetime engagement in educational, occupational, social and leisure activities influence dementia risk in the general population, cohort effects in this group warrant investigation. Studies adopting a crosssectional design or focusing on only a small age range risk overlooking such cohort effects, which will likely only be uncovered through cross-sequential studies covering broad age ranges. Determining an appropriate starting age for prospective studies of cognitive decline in ID is a challenge, as the lower life expectancy of people with ID (Bittles et al., 2002) means that applying the same age inclusions as studies in the non-ID population is likely to miss people with ID who have aged – and died – younger. This is especially so for those with more severe ID. Sampling too old an age group risks results being influenced by the ‘healthy survivor effect’. Added complexity in assessing cognitive and functional decline Assessing cognitive decline in people with ID is particularly challenging because this group is likely to score poorly on tests of cognitive function designed for the general population, even in the absence of dementia (Deb & Braganza, 1999; Strydom & Hassiotis, 2003). Due to the variable baseline functioning in people with ID, the ideal approach to assessment of dementia in this population is

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through repeat administration of direct assessments (Strydom & Hassiotis, 2003). At least three longitudinal assessments help differentiate dementia from ‘bounce’ in test scores (Burt et al., 2005), and the same approach could be usefully employed for the clinical assessment of dementia in people with ID. An international Working Group has previously recommended baseline function be established by the age of 50 for non-DS ID, and by 40 for people with DS (Burt & Aylward, 2000), though some clinical guidelines suggest even earlier for people with DS (e.g. Turk et al., 2001). At a population level, cognitive and functional decline could be evaluated in people with ID in a cost-effective manner through carer-report questionnaires such as the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) (Deb et al., 2007b) or Adaptive Behaviour Dementia Questionnaire (Prasher et al., 2004), with those flagged at risk of decline receiving full diagnostic assessments. However, there is no accepted ‘gold standard’ instrument for diagnosing dementia in this group, and most instruments designed to screen for or assess cognitive decline in people with ID have so far been developed on samples restricted to DS. Because DS is associated with a unique cognitive and behavioural phenotype, and with a propensity for AD in particular, it is unclear whether these tests will perform as well in assessing other types of dementia, or in non-DS ID. Furthermore, most cognitive tests are not suitable across all levels of ID, yielding floor or ceiling effects which reduce sensitivity to change. Biological assessments are particularly challenging for people with ID. Ideally, any assessment for dementia should include a blood test to screen for conditions which may mimic symptoms, such as thyroid dysfunction or folate deficiency. Brain imaging can aid in diagnosis and subtyping (NCCMH, 2007), and when obtained contemporaneously with cognitive testing, can aid identification of links between brain pathology and cognitive symptoms. However, obtaining these measures as part of a clinical or research assessment may be difficult in people with ID, who can have trouble cooperating with MRI protocols, even after sedation (Prasher et al., 2003). Implications of research in this field Research into dementia in ID is important to meet the needs of an ageing population with ID. In addition, researching dementia in people with ID may lead to a greater understanding of dementia risk factors such as head trauma, emotional trauma, epilepsy, poor nutrition and physical activity levels, and a reduced engagement in activities which are relevant for people both with and without ID. Associations between DS and AD have already played a vital role

in understanding the role of the APP gene in AD (OMIM, 2013). Since then, the high risk of AD in DS has also prompted researchers to investigate chromosome 21 for other genes contributing to dementia risk, such as DYRK1A (e.g. Kimura et al., 2007). Such research could potentially lead to treatments to prevent, slow, or even reverse the effects of AD, both in those with and without ID. Key areas of future study in this field include investigating the biological and environmental risk factors for dementia in people with ID, refining instruments for assessing dementia in this group, clarifying dementia risk and course in people with genetic ID syndromes other than DS, and research on the needs of carers of older people with ID (Strydom et al., 2009b).

Conclusion The study of dementia in people with ID is an exciting, but still relatively new field. Overall it appears that dementia risk is high in both DS and non-DS ID, particularly in younger age groups. The increasing life expectancy of people with ID highlights the importance of understanding the factors which may mediate dementia in this group and planning appropriate services for older people with ID. However, the study of dementia in ID also holds the potential to contribute to our understanding of dementia overall. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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