Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

Zigman, Warren B.; Devenny, Darlynne A.; Krinsky‐McHale, Sharon J.; Jenkins, Edmund C.; Urv, Tiina K.; Węgiel, Jerzy; Schupf, Nicole; Silverman, Wayne

doi:10.1016/s0074-7750(08)00004-9

Cited by 87 publications

(136 citation statements)

References 147 publications

(184 reference statements)

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“…A relevant issue in this regard is the association between the duplication of APP Hsa21 gene, encoding amyloid beta precursor protein involved in Alzheimer disease (AD) and early onset of an AD-like dementia in a progressively larger proportion of subjects with DS with increasing age. While we have pointed out here that the ID evident since the first years is a universal sign of DS, formerly known as mental retardation and diagnosed before the age of 18 years, a form of dementia similar to AD affects only a proportion of subjects with trisomy 21 (79,80), although the risk may be upward of 70% when reaching 70 years of age, and is seen as progressive deterioration of cognitive and functional abilities. No convincing relationship between severity of ID (or Intelligence Quotient—IQ—score) and risk of AD has been found in people with DS (79).…”

Section: Discussionmentioning

confidence: 76%

“…While we have pointed out here that the ID evident since the first years is a universal sign of DS, formerly known as mental retardation and diagnosed before the age of 18 years, a form of dementia similar to AD affects only a proportion of subjects with trisomy 21 (79,80), although the risk may be upward of 70% when reaching 70 years of age, and is seen as progressive deterioration of cognitive and functional abilities. No convincing relationship between severity of ID (or Intelligence Quotient—IQ—score) and risk of AD has been found in people with DS (79). As these facts suggest, the intimate mechanisms at the base of these cognitive alterations must be different.…”

Section: Discussionmentioning

confidence: 76%

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Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

et al. 2016

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A ‘Down Syndrome critical region’ (DSCR) sufficient to induce the most constant phenotypes of Down syndrome (DS) had been identified by studying partial (segmental) trisomy 21 (PT21) as an interval of 0.6–8.3 Mb within human chromosome 21 (Hsa21), although its existence was later questioned. We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we built an integrated, comparative map from 125 cases with or without DS fulfilling stringent cytogenetic and clinical criteria. The map allowed to define or exclude as candidates for DS fine Hsa21 sequence intervals, also integrating duplication copy number variants (CNVs) data. A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects. Also being spared by any duplication CNV in healthy subjects, HR-DSCR is proposed as a candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has relevant homology only to the chimpanzee genome. Searching for HR-DSCR functional loci might become a priority for understanding the fundamental genotype-phenotype relationships in DS.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 76%

Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

et al. 2016

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“…Functionally and structurally damaged mitochondria do not produce sufficient ATP and are more prone in producing proapoptotic factors and ROS [81], which also represent an early stage in neurodegenerative process [82]. An increased risk for AD manifests in most of DS individuals starting from 40 years of age [83,84]. The similarity of neurodegenerative processes between DS and Alzheimer disease (AD) and the high prevalence of AD in DS patients suggest that AD and DS share common brain alterations possibly due to similar molecular pathways involved in the pathogenesis, such as mitochondrial dysfunction and oxidative stress [85].…”

Section: Intellectual Disability and Neurodegenerationmentioning

confidence: 99%

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

Izzo¹,

Mollo²,

Cicatiello³

et al. 2018

Advances in Research on Down Syndrome

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Down syndrome (DS) consists of a complex phenotype with constant features, such as mental retardation and hypotonia, and variable features, including heart defects and susceptibility to Alzheimer's disease, type 2 diabetes, obesity and immune disorders. Overexpression of genes mapping to chromosome 21 (Hsa21) is directly or indirectly responsible for pathogenesis of DS phenotypic features, as overexpressed Hsa21 genes dysregulate several other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function. Recent studies highlight a link between mitochondrial dysfunction, consistently observed in DS subjects, and DS phenotype. In this review, we first provide a basic overview of mitochondrial alterations in DS in terms of mitochondrial bioenergetics, biogenesis and morphology. We then discuss how mitochondrial malfunction may contribute to the pathogenesis of clinical manifestations and how specific Hsa21 genes may cause the disruption of mitochondrial phenotype. Finally, we focus on drugs, which affect mitochondrial function and network to propose possible therapeutic approaches aimed at improving and/or preventing various aspects of the DS phenotype. Our working hypothesis is that correcting the mitochondrial defect might improve the neurological phenotype and prevent DS-associated pathologies, thus providing a better quality of life for DS individuals and their families.

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“…2 Additional risk factors common to both groups include hypercholesterolemia, estrogen deficiency, reduced cerebral reserve, and the presence of multiple medical problems. 3 Patients with AD in both at-risk groups show a history of slowly progressive cognitive decline, typically involving problems in recent memory as well as one or more other cognitive domains, such as orientation, language, attention, visuospatial abilities, and executive functioning.…”

mentioning

confidence: 99%

“…3,4 Some have argued that executive dysfunction, including problems with planning, attention, and articulation, and other frontal lobe symptoms, including apathy, depression, indifference, and uncooperativeness, are the earliest manifestations of DS-AD. 5,6 Others emphasize memory problems over frontal lobe symptoms.…”

mentioning

confidence: 99%

Cognitive Profiles on the Severe Impairment Battery Are Similar in Alzheimer Disease and Down Syndrome With Dementia

Dick

Doran

Phelan

et al. 2016

Alzheimer Disease &Amp; Associated Disorders

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Previous research has revealed similarities in the neuropathology, clinical presentation, and risk factors between persons with Alzheimer’s disease from the general population (GP-AD) and those with Down syndrome (DS-AD). Less is known, however, about the extent of similarities and differences in the cognitive profiles of these two populations. Fifty-one moderate-to-severely demented GP-AD and 59 DS-AD individuals participated in this study which compared the cognitive profiles of these two populations on the Severe Impairment Battery (SIB), controlling for gender as well as level of functional ability using a modified version of the Bristol Activities of Daily Living Scale. Overall, the neuropsychological profiles of the higher-functioning individuals within the DS-AD and advanced GP-AD groups, as represented by mean difference scores on the SIB as a whole and across the nine separate cognitive domains, were very similar to one another after adjusting for gender and functional impairment. To our knowledge, this is the first study to directly compare the cognitive profiles of these two populations on the SIB. Findings suggest that the underlying dementia in GP-AD and DS-AD may have corresponding and parallel effects on cognition.

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Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

Cited by 87 publications

References 147 publications

Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

Cognitive Profiles on the Severe Impairment Battery Are Similar in Alzheimer Disease and Down Syndrome With Dementia

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