Psychiatric issues in aging and dementia


While the prevalence rates of physical health conditions, and in particular Alzheimer’s disease (AD), in people with Down syndrome (DS) have been extensively researched [1, 2] (also see Chapters 11 and 13) much less is known about the prevalence of mental health disorders among people with DS. Where data does exist there is often substantial variation in reported prevalence rates and this is likely due to the diverse study designs used and the nature of the populations surveyed.

Several studies have shown that mental health disorders are more common in individuals with DS as compared to the general population; 10.8%–38% of people with DS are estimated to have a mental health disorder compared to 10.7% of the general population [3]. On the other hand, when compared to other adults with intellectual disability, people with DS appear to have lower rates of mental health disorders, with the prevalence among people with intellectual disability (ID) estimated to be 37.7%–47.6% (see Table 1).

Table 1

Summary of studies investigating mental health comorbidities in individuals with Down syndrome.
Authors Population Age (years) Sample size (n) Findings
Myers and Pueschela (1991) Outpatients at a hospital-based Child Development Centre and residents of an educational facility for people with intellectual disability, USA 1–72 497 22.1% had a mental health disorder

 4.2% attention deficit hyperactivity disorder

 3.6% conduct/oppositional defiant disorder

 2% depression

 1% autism

 1% phobias

 0.8% obsessive-compulsive disorder

 0.2% psychosis


Collacott, Cooper and McGrotherb (1992)All adults with Down syndrome in specified region in UK (matched with individuals with intellectual disability due to other etiologies)16–7837125.9% had a mental health disorder (compared to 37.7% of matched controls)

 11.3% depression

 6.2% conduct disorder

 2.2% autism

 1.6% schizophrenia

 0.5% manic depressive psychosis

 0.3% neurotic disorder

 Depression and dementia more common in those with Down syndrome

 Schizophrenia and personality disorders less common in those with Down syndrome


Maatta et alc (2006)All individuals with Down syndrome within a region in Finland0–6610839% had “problems related to mood or anxiety”

 17% mild depression/withdrawal

 11% moderate depression, anxiety, or fears

 8% severe depression, anxiety, and somatic symptoms

 – 3% severe depression, psychotic symptoms, or severe self-injury


Mantry et ald (2008)All individuals aged over 16 with Down syndrome in Glasgow, Scotland17–74186Point prevalence of conditions judged using four different criteria (clinical, DC-LDe, DCR-ICD-10f, and DSM-IV-TRg), resulting in a range of prevalence figures:

 10.8%–15.6% mental ill health of any type (including dementia but excluding problem behaviors)

 0.5%–2.7% affective disorder

 2.2%–2.7% anxiety disorder

 0%–0.5% obsessive–compulsive disorder

 0%–1.1% autism spectrum disorder

 0.5% alcohol/substance disorder

 0% eating disorder

 0% psychotic disorder


Tasse et alh (2016)Adults with Down syndrome living in Ohio, USA (compared to individuals with intellectual disability due to other etiologies)18–7929122.3% mental health disorder (compared to 47.6% in adults with other intellectual disability)

 12.4% mood disorder

 8.6% anxiety

 7.6% autism spectrum disorder

 6.5% problem behaviors

 2.7% psychosis/schizophrenia

 1.4% eating disorders

 1% personality disorders


Startin et ali (2020)Individuals with Down syndrome recruited via support groups, participant databases, care homes, and National Health Service sites across England and Wales0–73602Standardized morbidity ratios for adults with Down syndrome compared to general population:
Autism: 6.83 in males, 17.6 in females
Attention deficit hyperactivity disorder: 5.04 in males, 5.56 in females
Schizophrenia: 3.67 in males, 0.49 in females
Bipolar disorder: 1.22 in males, 0.79 in females
Depression: 4.97 in males, 3.97 in females
Anxiety: 1.75 in males, 0.57 in females

a Myers BA, Pueschel SM. Psychiatric disorders in persons with Down syndrome. J Nerv Ment Dis 1991;179:609–13.,110,000-00004.

b Collacott RA, Cooper SA, McGrother C. Differential rates of psychiatric disorders in adults with Down’s syndrome compared with other mentally handicapped adults. Br J Psychiatry J Ment Sci 1992;161:671–674.

c Määttä T, Tervo-Määttä T, Taanila A, Kaski M, Iivanainen M. Mental health, behaviour and intellectual abilities of people with Down syndrome. Downs Syndr Res Pract. 2006;11(1):37–43.

d Mantry D, Cooper S-A, Smiley E, Morrison J, Allan L, Williamson A, et al. The prevalence and incidence of mental ill-health in adults with Down syndrome. J Intellect Disabil Res 2008;52:141–155.

e Diagnostic criteria for psychiatric disorders for use with adults with learning disabilities.

f International classification of diseases 10 classification of mental and behavioral disorders: Diagnostic criteria for research.

g Diagnostic and statistical manual of mental disorders, fourth edition revised criteria.

h Tassé MJ, Macho PN, Havercamp SM, Benson BA, Allain DC, Manickam K, et al. Psychiatric conditions prevalent among adults with down syndrome. J Policy Pract Intellect Disabil 2016;13:173–80.

i Startin CM, D’Souza H, Ball G, Hamburg S, Hithersay R, Hughes KMO, et al. Health comorbidities and cognitive abilities across the lifespan in Down syndrome. J Neurodev Disord 2020;12:4.

The mental health disorder most commonly reported in people with DS is depression [4, 5]. As presented in Table 1, rates of anxiety disorders among people with DS are estimated to be between 0.3% and 8.6%, which is similar to the estimated 2.5%–7% prevalence seen in the general population [3]. Compared to the general population, DS is associated with an increased risk of other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) [6].

Rates of psychotic conditions such as bipolar affective disorder, psychosis, and schizophrenia among people with DS are largely found to be lower than in both the general population [79] and adults with other ID [10]. Challenging or aggressive behavior is also less commonly seen in people with DS when compared to other adults with ID [11, 12].

In a recent study, Startin et al identified sex differences in patterns of mental health comorbidity in DS [6]. The relative rates of schizophrenia, bipolar disorder, and anxiety were increased in males and decreased in females with DS when compared to the general population. Prevalence rates were higher in both males and females with DS for autism, ADHD, and depression, but the higher rate was more pronounced for autism in females (a standardized morbidity ratio for males of 6.83 compared to 17.6 for females).

As well as sex differences, there is variability in the prevalence of mental health disorders across the lifespan of people with DS. Two disorders that show particular patterns in relation to age are depression and regression syndrome, and these are discussed in more detail later.

DS and depression

Depression is a common psychiatric illness occurring in people with DS. It presents a particular challenge in the aging population because of the symptom overlap and diagnostic overshadowing that can occur with Alzheimer’s dementia.

Depression is more common in people with DS when compared with the general population, occurring at 4.97 (95% CI 4.66–5.29) times the rate in males with DS and 3.97 (95% CI 3.72–4.23) times the rate in females with DS [6]. Depression is also more common in DS when compared to the population of people with intellectual disability, despite lower rates of mental illness overall [13].

Startin et al demonstrated an increased prevalence of depression in the middle to older aged population of people with DS [6]. In a sample of 602 people with DS, 18.4% of individuals aged over 36 were diagnosed with depression, compared to 12% of those 16–35 years old.

The increased rate of depression in individuals with DS is likely to be caused by the interplay of multiple risk factors. Neuroanatomical risk factors include smaller total brain and hippocampal volumes, both of which have been associated with depression in the general population [14]. Neurochemical vulnerability is also potentially conferred by lower serotonin levels (demonstrated in fetal DS by Whittle et al [15]) and altered inflammatory profiles. Certain physical illnesses increase the risk of depression and occur more commonly in DS; these include endocrine disorders such as hypothyroidism and diabetes. Furthermore, higher rates of psychosocial stress (such as social rejection and loss [16]) and attachment difficulties can increase the risk of depression further. At present there is insufficient data as to whether other risk factors for depression seen in the general population are present in DS. It has been suggested that depression can also occur in some families of depressed individuals with DS; however, there is inadequate information to draw conclusions about familial risk in DS at this time [14].

In the context of lifelong intellectual impairment affecting communication abilities, it can be difficult to differentiate depression from the initial presentation of other conditions such as hypothyroidism or AD. In DS, as in the general population, depression most commonly presents with reduced interest or pleasure, and this is accompanied by depressed affect (sadness that is visible to others) and tearfulness. These symptoms may occur alongside more generalized slowing and appetite disturbance, with cognitive symptoms such as depressive thoughts (feelings of guilt or worthlessness) being less prominent than in the general population [17].

The prodromal phase of AD can also present with behavioral and psychiatric symptoms in individuals with DS. The most prominent psychiatric symptoms of AD include apathy (loss of motivation and interest), social withdrawal, sleep disturbance, and emotional lability [18]. These symptoms are therefore potentially overlapping with mood disorders, making diagnosing depression particularly challenging in older patients with DS.

Moreover, the high prevalence of AD in older people with DS means that clinicians may be more likely to attribute psychiatric and behavioral symptoms to dementia, a form of diagnostic overshadowing. This means that a depressive episode may go untreated, increasing the severity and duration of a potentially curable illness. A significant proportion of adults with DS and dementia also have features of depression (estimated between 48% and 60%) [5, 19]. It is therefore debated as to whether depression in these individuals should be interpreted as an early sign of AD, or as a comorbid but separate condition [20, 21]. Given the frequent co-occurrence of depression during the early stages of dementia in both individuals with DS and the wider population, some experts have viewed depression as a risk factor for AD. There have been several proposed mechanisms for this interaction, including disturbance of the hypo-thalamic axis (HPA), chronic inflammation, and impairments in neurotrophin signaling [22]. Abnormalities of the HPA resulting in increased levels of glucocorticoids have been observed in both AD and depression in the neurotypical population. Higher levels of glucocorticoids are associated with decreased neurogenesis and increased neuronal death in the hippocampus. It can also cause increased vulnerability of neurons to the effects of toxins, including reactive oxygen species (ROS) and β-amyloid. The presence of increased levels of pro-inflammatory cytokines including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNFα) have been described in AD and depression, which may contribute to a neurodegenerative process in both conditions [23]. Alongside this, lower levels of neurotrophins involved in synaptic plasticity modulation and neuronal homeostasis have been found. In particular lower levels of brain-derived neurotrophic factor (BDNF) are observed in the hippocampi of people with depression [24] and those with AD [25] in the general population, and have been linked to synaptic dysfunction, neurodegeneration, and cognitive deficits.

Changes in these systems are also observed in DS and may explain in part the increased co-occurrence of AD and depression. For example, it has been proposed that depression pathways promote β-amyloid deposition and neurodegeneration, accelerating AD progression [26]. This may be through glucocorticoid disruption associated with depression [27] promoting β-amyloid deposition. The elevation of glucocorticoids has also been found in some studies in DS [28], which may further potentiate this interaction.

Individuals with DS have altered immune profiles [29] and show increased interferon and cytokine responses. Elevated levels of these proteins, including TNFα and IL-6, are reported compared to controls without DS, and this occurs even in the absence of infection or autoimmune disease. An association between levels of pro-inflammatory cytokines and dementia is noted in DS, with higher levels of pro-inflammatory mediators found in people with both DS and AD compared to those with DS alone (for a review of this topic, see Chapter 3; Illouz et al., in submission [30]). Low brain BDNF levels have been found in transgenic mouse models of DS and in Ts65DN mouse models a positive correlation between increased BDNF expression and memory enhancement has been observed [31, 32].

DS disintegrative disorder

Adolescents and young adults with DS can present with symptoms of unexplained deterioration in functional and cognitive abilities often referred to as “regression,” and this can mimic early onset dementia. It is increasingly recognized that regression in DS may be a distinct disorder, although its etiology has not been established. The literature refers to cases of “regression,” “autistic regression,” “catatonia,” and “DS disintegrative disorder” which appear to represent the same condition. It will be referred to here as DS Disintegrative disorder (DSDD).

A recent study using international data [33] suggests that the core features of DSDD are related to declines in adaptive functioning, cognitive-executive functioning, and motor control. The four most common clinical features present in 90% of this cohort were changes in social skills, decline in functional skills and increased dependence, attention deficits, and internalizing behaviors. There does not appear to be a clear association with sex or ethnicity.

Physical health investigations are generally unremarkable or give results of uncertain significance. For instance, inflammatory/autoimmune markers may be elevated in some individuals with regression and may respond to immunotherapy [34], but this is not consistent in all people affected by this presentation. Other medical investigations that may be abnormal included coeliac screens, vitamin D levels, polysomnography, and TFTs, but the prevalence of these do not appear to be different to controls. Often individuals with regression have completely normal health investigations.

There are proposed links between symptom onset and psychosocial stressors, and a number of studies have observed a higher number of life stressors experienced by individuals who develop regression, and these are usually in the months preceding onset including life transitions [33, 3537].

The presentation can vary between individuals and has crossover with other common comorbidities including depression, psychosis, thyroid dysfunction, ASD, AD, and obstructive sleep apnea which need to be ruled out before a diagnosis can be made. There are some distinctive features which can help to differentiate DSDD from AD in DS, although there may be common genetic and biological pathways that account for the increased risk of developing each condition. DSDD commonly starts at a younger age with a mean age of onset 17.5 years [33], but new symptom onset has been reported up to the age of 34 years. Similar to AD, regression symptoms usually have an insidious onset, albeit over a relatively shorter period of time; however, they then reach a plateau rather than a continued decline being observed. There are also case reports of spontaneous improvement or a slow regaining of skills in people with DSDD. In contrast, those with AD do not regain lost function [38].

Suggested treatments for regression have included antiinflammatory regimes, electroconvulsive therapy (ECT), psychotropic medications (including antidepressants, benzodiazepines, and antipsychotics), and dementia drugs (acetylcholinesterase inhibitors or memantine) [34, 35, 37, 39]. No treatment has been universally effective, and no RCTs have yet been performed.


“Diagnostic overshadowing” [40] is a phenomenon clinicians should be mindful of when working with people with DS. It occurs when it is incorrectly assumed that symptoms of a mental health disorder, such as tearfulness or irritability, are simply due to an individual having an intellectual disability. Similarly, symptoms of physical ill health such as fatigue and weight loss can be erroneously attributed to an individual’s intellectual disability or a mental health disorder [41].

Physical health conditions that are more common in people with DS should therefore always be considered as part of a psychiatric evaluation. They include obstructive sleep apnea, endocrine disorders (notably hypothyroidism), vision and hearing disorders, coeliac disease, constipation, and gastroesophageal reflux [4245].

These diagnostic challenges can be particularly pertinent when making a diagnosis of AD. As adults with DS get older it can be difficult to determine if features such as apathy and withdrawal are due to depression or early AD. Similarly, the development of symptoms such as hallucinations and delusions could also indicate either AD or a mental health disorder, such as late-onset schizophrenia or psychotic depression. Urv et al. found that visual hallucinations and delusions (most frequently about people stealing possessions) were twice as common in adults with DS and dementia as compared to adults with DS without dementia [21].

Ball et al. found changes in personality and behavior such as social withdrawal, apathy, and emotional lability to be more prominent in the early stages of dementia in people with DS [46]. This is in contrast to the memory changes more commonly seen in the general population. However, new evidence is emerging that memory changes may be some of the first changes observed in dementia in DS when assessed using direct cognitive assessment, but can be missed by carers (see Chapter 15). In this case it may be that personality and behavior changes are in fact a later manifestation in DS dementia than previously thought [47]. Baseline cognitive testing that can be used to monitor future decline is therefore recommended for people with DS (see British Psychological Society and Royal College of Psychiatrists guidelines: Dementia and People with Learning Disabilities).

To help differentiate between mental health disorders, physical health conditions, and AD, clinicians should undertake comprehensive assessments including vision and hearing checks, blood tests to exclude conditions such as hypothyroidism and anemia, a urine screen for infection, and consider brain imaging. Vision and hearing issues are particularly important to consider in the differential diagnosis of mental health issues in older adults with DS, since conditions such as glaucoma and cataracts are common and increase with age [6], while hearing loss has been demonstrated in virtually all individuals over the age of 60 in some studies [48].

Brain imaging is useful in ruling out certain neurological conditions, but findings are often nonspecific in people with mental health disorders or early stage AD. In the later stages of AD, magnetic resonance imaging (MRI) may show reductions in the volume of the whole brain, hippocampus, and temporal lobes, but a grossly “normal” MRI would not rule out AD [49] (see Chapter 8).

It is recognized that standard diagnostic criteria are often difficult to apply in people with DS. It is often recommended that specific diagnostic criteria are adapted, or at least that the interpretation of criteria concerning areas such as functional ability is standardized for people with DS. This is to take into account common comorbidities, variations in presentation and communication difficulties including impairments in expressive language. This is the approach that was taken with the development of the DM-ID-2 to adapt and apply DSM-5 criteria to individuals with ID [50].

Following we have outlined some potential differences that may guide a clinician to consider whether a person with DS may be presenting with depression or AD. These lists are neither diagnostic nor definitive as all symptoms may be indicative of depression or dementia and can also represent a comorbid presentation.

Symptoms that may be more suggestive of depression Symptoms that may be more suggestive of Alzheimer’s dementia
Younger age (first episode typically in 20s and 30s) although older adults can also be affected
Older age (after age 40; typically starting in their 50s)
Affective symptoms may be associated with a known trigger or be linked to specific thoughts
A so-called sadness for no reason has been described
Symptoms may be associated with recent stressful life events including bereavement and transitions
May observe nonspecific cognitive changes particularly related to motivational and mood aspects such as fatigue, anhedonia, poor concentration, tearfulness, hypochondriasis, and reduced confidence
Early cognitive deterioration may show more specific changes in memory, speech, learning, skills, and disorientation; AD progressively affects cognition with global impairment
Sleep disturbance may have pattern of early morning waking rather than difficulties related to initiation and maintenance of sleep
Sleep disturbance may be particularly observed at night and can be linked to signs of delirium and “sundowning”
Cognitive and mood symptoms may improve with pharmacological and psychological treatments for depression
May occur more acutely over a shorter time period
May show more insidious symptom development
Plateauing after initial symptom development. Improvement in mood and motivation with regain of function following successful treatment
Progressive decline often associated with development of neurological symptoms including seizures. Recovery of function does not occur
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Sep 12, 2021 | Posted by in NEUROLOGY | Comments Off on Psychiatric issues in aging and dementia
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