A multi-level developmental approach to exploring individual differences in Down syndrome: genes, brain, behaviour, and environment

IMPORTANCE Risk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Here we investigate associations of APOE ε4 with attention across the life span of individuals with DS. OBJECTIVE To investigate associations between APOE ε4 and attentional abilities in young children and in adults with DS. DESIGN, SETTINGS, AND PARTICIPANTS In this cross-sectional study, data were collected from 80 young children with DS (8-62 months of age) and 240 adults with DS (16-71 years of age) during the period from 2013 to 2018 at a research center to examine the association between APOE status (ε4 carrier vs ε4 noncarrier) and attentional abilities. EXPOSURE APOE status (ε4 carrier vs ε4 noncarrier). MAIN OUTCOMES AND MEASURES For the children, attentional ability was assessed using an eye-tracking paradigm, the gap-overlap task; the size of the gap effect was the primary outcome. For the adults, attentional ability was assessed using the CANTAB simple reaction time task; the standard deviation of response time latencies was the primary outcome. Cross-sectional developmental trajectories were constructed linking attentional ability with age in ε4 carriers and ε4 noncarriers for children and adults separately. RESULTS The child sample comprised 23 ε4 carriers and 57 ε4 noncarriers. The adult sample comprised 61 ε4 carriers and 179 ε4 noncarriers. For the children, a significant difference between trajectory intercepts (η p 2 = 0.14) indicated that ε4 carriers (B = 100.24 [95% CI, 18.52-181.96]) exhibited an attentional advantage over ε4 noncarriers (B = 314.78 [95% CI, 252.17-377.39]). There was an interaction between APOE status and age (η p 2 = 0.10); while the gap effect decreased with age for ε4 noncarriers (B = −4.58 [95% CI, −6.67 to −2.48]), reflecting the development of the attention system, there was no change across age in ε4 carriers (B = 0.77 [95% CI, −1.57 to 3.12]). For the adults, there was no main effect of ε4 carrier status, but there was an interaction between APOE status and age (B = 0.02 [95% CI, 0.004-0.07]), so that ε4 carriers had poorer attentional ability than ε4 noncarriers at older ages. CONCLUSIONS AND RELEVANCE APOE ε4 is associated with an attentional advantage early in development and a disadvantage later in life for individuals with DS, similar to the pattern reported (continued) Key Points Question What are the associations between the Alzheimer disease risk allele apolipoprotein E (APOE) ε4 and attention across the life span of individuals with Down syndrome? Findings In a cross-sectional study including 80 young children and 240 adults with Down syndrome, an advantage was observed in attention for ε4 carriers relative to ε4 noncarriers among young children. Among young adults, no attentional advantage was observed in ε4 carriers, and possession of an ε4 ...

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“…8 This would explain the improved early performance at the expense of a decreased performance during aging. 22…”

Section: Discussionmentioning

confidence: 99%

Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome

et al. 2020

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“…The APOE genotype has also been found to modulate the age of onset and progression of AD in DS. DS carriers of the E4 allele have a greater risk of developing AD and an earlier onset of the disease when compared to carriers of other alleles [25,29].…”

Section: Amyloid Plaquesmentioning

confidence: 98%

“…In AD brains, one of the causes of the accumulation of Aβ aggregates is their defective clearance from the brain, a process normally facilitated by ApoE. Indeed, the major genetic risk factor for sporadic AD is a polymorphism of ApoE [10,24,25]. ApoE contributes to the maintenance of brain homeostasis through numerous pathways, including the regulation of cholesterol, glucose metabolism, synaptic plasticity, neurogenesis, inflammatory responses, and Aβ metabolism [26][27][28].…”

Section: Amyloid Plaquesmentioning

confidence: 99%

Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

Martı́nez-Cué

Rueda

2020

IJMS

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Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.

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“…This profile is characterized by a general cognitive delay, relative strengths in nonverbal abilities, and impairments beyond mental age expectances in language, phonological processing, verbal memory and verbal working memory 2 – 6 . However, it is important to note that the cognitive phenotype described above is variable across individuals with DS 7 .…”

Section: Introductionmentioning

confidence: 99%

Relationship between Apgar scores and long-term cognitive outcomes in individuals with Down syndrome

Soriano

Rosser

Hamilton

et al. 2021

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This study examined the contribution of the Apgar score at 1 and 5 min after birth to later cognitive functioning in 168 individuals with Down syndrome who were between 6 and 25 years of age at time of cognitive testing. Our results showed that a lower Apgar score at 1 min was related to a worse performance in later cognitive measures of receptive vocabulary, verbal comprehension and production, visual memory and working memory. Results also showed that a lower Apgar score at 5 min was only related to worse later outcomes of verbal comprehension and production and auditory working memory. Our findings suggest a need for future studies investigating how specific perinatal events reflected in the Apgar score are linked to later cognitive functioning in individuals with Down syndrome.

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A multi-level developmental approach to exploring individual differences in Down syndrome: genes, brain, behaviour, and environment

Cited by 16 publications

References 81 publications

Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome

Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome

Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

Relationship between Apgar scores and long-term cognitive outcomes in individuals with Down syndrome

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