Psychosocial Risk Factors for Alzheimer’s Disease in Patients with Down Syndrome and Their Association with Brain Changes: A Narrative Review

Although research data identified various neurophysiological risk factors for AD and dementia, little knowledge is available regarding psychosocial determinants [25]. Previous studies identified many psychosocial risk factors for AD (Table 2). Still, we will present a few of these studies discussing psychosocial risk factors for AD as an introductory background as our focus is mainly on psychosocial risk factors for AD in DS. Also, our review of psychosocial risk factors for AD in the general population can help determine common and distinct pathways and mechanisms underlying the increased risk of dementia compared to people with DS. Zhang et al. [26] performed a 5- and 10-year follow-up study in Shanghai, China. The essential psychosocial risk factors for AD onset and development suggested by this study were not working (jobless or retired), no participation in community activities, analphabetism, and blue-collar status. Burke et al. [27] established a connection between depression, sleep disturbance, and anxiety (as individual factors and comorbid conditions) and the risk of AD development. This study, however, did not use neuroimaging to confirm the diagnosis of AD pathology [27]. A survey by Burnes and Burnette [25] indicated that previous life trauma and posttraumatic stress disorder (PTSD) are good candidates as psychosocial risk factors for AD, according to the evidence presented in this research, by creating a conceptual model relating these factors to AD. Kropiunigg et al. [28] discussed psychosocial stress resulting from adapting to an active but ineffective work style and living with a domineering spouse as a link to an increased risk of AD. Persson and Skoog [29] studied different psychosocial risk factors before the age of 70 in various age groups, such as the death of a parent, divorce of parents, growing up with one parent, different guardians, extreme poverty, death of a spouse, death of a child, serious illness in a child, shift or piece work, arduous manual labor, physical disease in a spouse, mental illness in a spouse, death of siblings or friends, change of residence, and financial status deterioration. Their findings suggest that psychosocial risk factors early in life contribute to the development of dementia later in life [29].

Marital status, stress, depression, inadequate sleep, smoking, cognitive reserve, and physical activity are among the psychosocial risk factors discussed by Silva et al. [16] as risk and protective factors for AD development. The aforementioned studies did not perform any tests to distinguish between familial/early-onset AD and sporadic/late-onset AD in the studied populations. Silva et al. [16] discussed the genetic risk factors associated with the occurrence of both AD types in their review. According to that study and other related studies, familial/early-onset AD compared to sporadic/late-onset AD has significant genetic risk factors influencing AD development, like DS [16, 30].

Wang et al. [31] investigated the association between psychosocial stress at work and an increased risk of dementia at a late age and found that stress conditions associated with the job contributed to a high risk of dementia and AD at a late age. Additionally, a similar study by Seidler et al. [32] explored the role of psychosocial work factors in the onset of dementia. He et al. [33] found that low educational level, low cognitive function, low occupational status, lack of social interaction and leisure activities, and poor well-being affect the onset and development of AD. Bernhardt et al. [34] provided a thorough systemic review of all reported psychosocial risk factor outcomes from controlled trials between 1994 and 2001. That review concluded that factors studied in the articles, such as living alone, having no intimate social links, not participating in social and recreational activities, and never having married, are all linked to dementia. That also review suggests that AD is adversely associated with intellectual diversity and intensity and favorably associated with psychosocial inactivity, unproductive working style, living with a domineering spouse, and physical inactivity in recent studies [34].

Determining the risk factors is essential to assessing the risk of AD in individuals with DS. While identifying risk factors helps evaluate individual and community risk for developing AD, they do not guarantee that all persons with known risk factors will get the disease, nor that individuals without such risk factors would not contract the disease [35]. Neuropathological changes related to triplication of amyloid precursor protein (APP) contribute mainly to the first clinical signs of AD in DS [36]. In autopsy, Alzheimer-type neuritic plaques and neurofibrillary tangles have been found and reported in the brains of 7.5% of people with DS in the early second decade of life, reaching 80% by the fourth decade and 100% in people over 60 years old [37]. Other risk factors that can add more explanations and understanding of the mechanism of the occurrence of the predementia stage in people with DS should be studied and identified [38]. The study of risk factors for dementia in people with DS faces challenges due to the lack of specific and compelling cognitive and neuropsychological status measurements in this population [38]. The most available assessment methods and instruments to assess dementia in persons with intellectual disabilities, including DS, are informants-based tests and do not directly assess cognitive function in those groups [39]. We focused on psychosocial risk factors such as cognitive status, education, years of living in a care institution, physical activity, smoking, sleep, and other risk factors such as age, sex, and some genetic factors (APOE) which contribute additively to the development of dementia (Table 3). Age is considered a strong common risk factor for dementia in DS, and the association between increasing age and the increased risk for dementia in DS is widely indicated [35, 38, 40]. Few studies have assessed sex as a risk factor, with controversial results [38]. Some evidence reports that women are at greater risk due to the low level of postmenopausal estrogen and that women have a higher life expectancy than men [35]. A recent study by Lai, Mhatre et al. [41] evaluated sex differences in AD risk in adults with DS. It showed no significant sex difference in the risk for AD development in adults with DS. However, they found that women with DS had a nearly 2-year duration of dementia more than male individuals with DS from AD onset until death, although having equal mean ages at the beginning of AD. These findings [41] contrast with earlier DS research conducted on a smaller scale [42, 43]. In men with DS, Schupf, Kapell et al. [42] found a greater risk of AD, but Lai, Kammann et al. [43] found the opposite.

In the general population, there is an evidence-based suggestion that a higher level of cognitive functioning, which is linked to a higher level of education, a higher IQ, years of living in a care institution, and employment, is associated with a low incidence of dementia [44]. This study investigated the correlation between education and other environmental factors, such as years of living in a care institution and occupation, and the occurrence of dementia in people with DS. It resulted in the theory that environmental changes can improve cognitive function, leading to the delay of the onset of dementia [44]. These data led to the cognitive reserve hypothesis, suggesting that patients compensate for neuronal loss when the brain works actively to deal with neuronal damage [45]. People with better baseline cognitive abilities can tolerate more AD pathology and neuronal loss than patients with worse baseline cognitive skills [46]. Also, Zigman and Lott [35] assumed that IQ level and cognitive reserve could be possible risk factors for dementia in DS. They suggested that people with DS who function at higher levels (e.g., more excellent premorbid IQ, education, occupation, and language ability) have a reduced risk of AD dementia than their counterparts who perform at lower levels. Another decisive risk factor is a family history caused by genetic or environmental factors. The apolipoprotein E gene (APOE), encoded by three alleles, ε2, ε3, and ε4, is associated with a risk for AD in DS [47]. The apolipoprotein ε4 allele is the most well-known genetic risk factor for sporadic AD, and it is linked to early symptoms and pathology in the general population [48]. The APOE ε4 allele is also a significant risk factor for AD in DS compared to the APOE ε2 allele, which is associated with low risk and a protective role [35, 38, 47]. Although an early meta-analysis of association studies revealed that dementia was higher in individuals with DS carrying APOE ε4 [49], one case–control study in a Dutch community found no effect of APOE genotype on the incidence or onset of dementia in DS [50]. The minimal number of patients studied was a critical limitation of these investigations [47].

In contrast to noncarriers, APOE ε4 carriers are at increased risk for dementia in DS, with an earlier start and rapid progression, according to a recent longitudinal, large cohort study of people with DS [51]. According to the available data, the evidence for a link between APOE ε4 and dementia in DS is very suggestive [48]. Few studies reported the effect of physical activity on cognitive function and dementia risk in DS [52]. Some of these studies used the mouse model of DS (Ts65Dn mice) and found essential evidence that physical activity may help with cognition. Voluntary wheel running in mice, for example, was linked to improved performance in cognitive tasks when compared to sedentary controls, especially when considering hippocampal-mediated processes, which are essential during AD [53‐55]. Previous mouse model reports found that physical activity impacts gene and protein expression, neurogenesis, and brain morphology [53, 54, 56]. The Ts65Dn mouse is the most well-studied and extensively utilized DS animal model. It has a freely segregating additional chromosome with the triplication of mouse chromosome 16’s distal region, which is syntenic to a portion of human chromosome 21’s long arm [57]. The Ts65Dn mice mimicked many characteristics of DS, including cognitive impairment and hippocampus-dependent memory function [57‐59]. Despite some genetic limitations caused by partial triplication of human chromosome 21 (HSA21) orthologous genes and concurrent triplication of some non-HSA21 genes [60], the Ts65Dn model reproduces many of the phenotypic aspects of the human disease, including brain changes and impaired learning and memory and is presently the sole mouse model utilized for preclinical discovery of pharmaceutical treatments targeting cognitive deficits in DS [61]. A 12-week exercise program improved episodic memory in human studies, including people with DS [62]. These studies documented improvements in executive function assessments such as inhibition [63, 64], attention shifting [65], response time [66, 67], and semantic fluency [68, 69]. However, there are differences in effect sizes and findings between these studies [52]. A recent survey by Pape et al. [52] examined the association between physical activity, regular exercise, and cognitive function in DS. The findings of their investigation indicated that frequent moderate and high-intensity exercise might reduce the possibility of clinically detectable mental deterioration in the DS group, with possible long-term benefits [52]. In 61 adults without dementia living with DS, Fleming et al. [70] investigated the relationship between everyday physical activity measured with an actigraph accelerometer and cognitive functioning and early AD pathology measured with PET amyloid-β and tau and diffusion tension imaging measures of white matter integrity. The amount of time spent on sedentary and moderate-to-vigorous activity was related to cognitive performance (negatively and positively, respectively; correlation coefficient (r) = − 0.472–0.572, significance (p) < 0.05). Both sedentary behavior and moderate-to-vigorous exercise are linked to white matter integrity in the superior and inferior longitudinal fasciculi (fractional anisotropy: r = − 0.397 to − 0.419, p < 0.05; mean diffusivity: r = 0.400, p = 0.05) [70].

No specific study from our reviewed literature correlated ethnicity as a risk factor for AD in DS, so future studies should consider this data. Also, no published research directly discussed the role of sleep as a risk factor for AD in DS. Chen et al. [71] examined the impact of sleep disturbance on executive function in individuals with DS. The results indicated an association between obstructive sleep apnea, common in people with DS with high body mass index, and more significant impairments in executive functions, including verbal fluency and inhibitory control. According to these findings, understanding the relationships between poor sleep, cognitive impairment, and deterioration in individuals with DS requires further research. These findings reveal a link between poor sleep and cognition in young individuals with DS and how their sleep issues affect AD development [71].

Considering smoking as a risk factor for dementia in the general population is unclear [72]. Research supported by the tobacco industry (conflict of interest) indicated a low risk of dementia associated with smoking [73]. Nonetheless, research data with no tobacco industry affiliation (e.g., tobacco companies providing study funding, study author(s) currently or previously employed by a tobacco company) reported a significantly increased risk of AD [73]. We did not find a study investigating the relationship between smoking in DS directly or passively (e.g., family members) and the risk of AD development. Many researchers who looked at potential psychosocial risk factors struggled with assessment and diagnostic challenges, making it difficult to compare results from different studies [38]. Future researchers looking into the prevalence rates and psychosocial risk factors for AD in people with DS should consider these observations.

No specific study investigated DS brain areas changes related to AD, specifically the hippocampus or corpus callosum, and correlated such changes with psychosocial risk factors. Here, we correlate the results of previously published studies regarding the neuroanatomical changes related to dementia in DS with the results discussing the effect of psychosocial factors on cognitive function. All people with DS develop neuropathological features of AD by 40 years of age [13, 37, 74, 75]. The aging processes in DS are associated with the deposition of senile plaques and neurofibrillary bundles [76]. The buildup of these deposits, their distribution pattern in the brain, and the involvement of specific neurons are remarkably similar to the pathological changes that characterize AD [37]. A better understanding of how the DS brain develops with the help of a development-oriented approach will shed light on critical neurological principles of DS in children and illuminate the basics of the phenotype in adults, particularly the increased risk of early AD [35]. Therefore, DS provides a framework for studying the morphological brain changes in the early stages of AD [77].

Hippocampal and temporal lobe volume reductions are typical of AD and people with DS living with dementia [15, 78, 79]. These volume reductions are associated with cognitive decline in both AD and people with DS living with dementia groups in a study by Mullins et al. [20]. Th results of that study showed a positive correlation in patients with AD between the Mini-Mental State Examination (MMSE) score and the corrected hippocampus and temporal lobe volumes. Previous research reported a similar finding and revealed that performance on the MMSE correlates directly with hippocampal volume [80]. The decline in the hippocampus and temporal lobe volumes affects their functions, which is observable by the correlation between MMSE scores and the reduced volume in these regions [20]. The hippocampal structures involved in explicit memory deficits, the dentate gyrus, the essential core areas of hippocampal efferences and afferences, and the corpus callosum are crucial areas for studying structural changes related to AD. Memory impairment was one of the first clinical signs identified when evaluating the existing evidence of structural changes in the hippocampus in patients with AD [77]. This symptom worsened slowly over time and manifested as personality changes, loss of language skills, and affection of the extrapyramidal motor system. Histopathological examinations show the hippocampus structure as one of the first and most severely affected areas by AD [77]. A longitudinal assessment study of brain anatomy changes preceding dementia in DS by Pujol et al. [81] found that the brain volume changes and their links to cognitive impairment progression are generally consistent with well-known anatomical abnormalities that signify dementia development in AD. Thus, even though it occurs in a complicated scenario with extensive baseline pathology and a high potential for interactions between developmental and age-related alterations, brain involution in older people with DS appears to reflect the degenerative process of AD. The basal forebrain, hippocampus, and prefrontal lobe, which are impacted early in AD, were specifically impaired in DS before dementia in this study. Neurofibrillary damage and the loss of projection neurons responsible for the afferent and efferent connections of the hippocampal formation result in both disconnections of the intra-hippocampal relationships and the isolation of the hippocampus from other parts of the brain responsible for memory loss in AD [82‐84]. By the age of 40, the proportion of individuals with DS who undergo a process of cognitive impairment, such as that in AD, is observably high [14]. The chronological hierarchy of symptoms begins with slowly progressing memory loss and leads to a general decline in cognitive skills accompanying dementia and emotional changes [85‐88]. Research based on MRI scans indicated that hippocampal atrophy, which is significant in sporadic and DS-associated AD, can serve as a measure of allocortical neuronal degeneration [14, 77, 83, 84, 89].

Previous MRI studies proposed atrophy of the corpus callosum as a possible marker for the loss of intracortical-projecting neocortical association neurons in AD [90‐94]. The projecting neurons from the corpus callosum are a subgroup of the large pyramidal neurons in the association cortex’s lamina III and V [95‐97], which are particularly vulnerable to AD [98‐100]. Therefore, several studies reported atrophy of the corpus callosum in Alzheimer-type dementia [14, 101‐106]. Clinical symptoms of dementia in DS are memory loss, behavioral changes, language difficulties, neurological alterations, and decreased cognitive skills [107, 108].

Teipel et al. [14] investigated the effect of age on volume changes in the hippocampus and corpus callosum and found a correlation between neuropsychological scores and regional volumes in people with DS without dementia. This study demonstrated a decreased volume of hippocampus and corpus callosum regions with increased age and also showed a correlation between the size of corpus callosum areas and the global cognitive score, orientation, language, and visuospatial test scores in people with DS [14]. Kesslak et al. [109] and Raz et al. [110] found that the parahippocampal gyrus (PHG) is significantly larger in people with DS compared with normal aging and AD. Pathological and neuroimaging studies revealed that AD significantly impacts this structure, particularly its anterior portions [111, 112]. Raz et al. [110] indicated a correlation between the enlargement of the PHG and decreased total cognitive function. Mullins et al. [20] investigated the medial temporal lobe and found a reduced volume of this region associated with cognitive decline. A study by Krasuski et al. [113] found that the right and left amygdala, hippocampus, and posterior parahippocampal gyrus in the DS group have a smaller volume than in the control group. These regional brain volumes were significantly associated with greater age; this association was not observable in the anterior part of the parahippocampal gyrus. The hippocampus and amygdala volumes were positively correlated with memory assessment results [113] (Table 4). However, AD has the character of a gradual beginning and inevitable atrophy development in the medial temporal lobe [114]. The entorhinal cortex is usually the first part of the brain to deteriorate, followed by the hippocampus, amygdala, and parahippocampus [115‐118]. The posterior cingulate and other limbic lobe components, including the amygdala, are also affected early. The temporal neocortex is ultimately affected, followed by all neocortical association regions, generally in a balanced way. The loss pattern differs between disorders, indicating preferential neuronal vulnerability and disease manifestation at the regional level [119].