Alzheimer's Disease In Down Syndrome Research Articles

86 - Oxidative Stress and mTOR Activation in Down Syndrome Brain: Roles in Aβ42 and Tau Neuropathology and Transition to Alzheimer Disease-Like Dementia

Down syndrome (DS), the most frequent chromosomal abnormality in humans, results from complete or partial trisomy of chromosome 21 (Chr21). Though there is intellectual disability in DS people from birth, at about 40-50 years of age conversion to Alzheimer disease (AD)-like neuropathology and dementia often occurs. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation and insulin signaling, among other functions, is implicated in several diseases, including AD. Numerous studies, many from our laboratory, linked activation of the mTOR pathway by, among other means, oxidative stress-associated Aβ42 to age-dependent pathology of AD and AD-like dementia in DS. Several Chr21 gene products are associated with oxidative stress, among which is amyloid precursor protein, the source of Aβ42. Specific genes involved in the formation of AD-related senile plaques (composed mostly of fibrillar Aβ), and neurofibrillary tangles (NFT, composed mostly of hyperphosphorylated tau protein), two main pathological hallmarks of AD, are mapped on Chr21. This presentation highlights our recent research on DS brain using oxidative stress and redox proteomics methods showing activation of mTOR signaling contributes to generation of neurotoxic and oxidative stress-associated Aβ-oligomers (and senile plaques) and the formation of NFT. Thus, a vicious cycle between oxidative stress-related, Aβ-associated mTOR activation and mTOR activation-mediated AD-like pathology and dementia in conversion of DS to DS with AD is present. Identification of potential new therapeutic targets associated with the mTOR pathway to modulate this conversion in DS to DS with AD and new insights into AD itself resulted from our studies and will be shown.

Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome.

Neurotrophic factors, including the members of the neurotrophin family, play important roles in the development and maintenance of the nervous system. Trophic factor signals must be transmitted over long distances from axons and dendrites to the cell bodies of neurons. A mode of signaling well suited to the challenge of robust long distance signaling is the signaling endosome. We review the biology of signaling endosomes and the "signaling endosome hypothesis". Evidence for disruption of signaling endosome function in disorders of the nervous system is also reviewed. Changes in endosome structure in Alzheimer disease (AD) and Down syndrome (DS) are present early in these disorders. Data for the APP products responsible are reviewed and the consequent changes in signaling from endosomes discussed. We conclude by pointing to the need for additional studies to explore the biology of signaling endosomes in normal neurons and to elucidate their role in the pathogenesis of neurodegeneration.

MTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia.

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aβ generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aβ and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS.

STRUCTURAL CORRELATES OF ALZHEIMER’S DISEASE AND AGING IN DOWN SYNDROME: AN MRI STUDY

Down syndrome (DS) has been proposed as a genetic form of Alzheimer's Disease (AD). However, few studies had assessed the structural correlates of AD and aging in DS. Our objective was to evaluate the brain regions vulnerable to AD and aging in DS and the possible modulating effects of amyloid deposition. Subjects were recruited from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI), a longitudinal cohort to study AD in DS. 68 subjects underwent a 3 Tesla structural MRI and a lumbar puncture (mean age: 41.32, 34.1% female). DS subjects were classified into a cognitive stable group (cs-DS, N=52) and an AD group (n=16). The AD group was subdivided into prodomal Alzheimer (p-DS, N=10) and AD dementia (d-DS, N=6) subgroups. CSF Aß1–42 levels were measured by ELISA. Subjects were classified as Aß+ or Aß- (cutoff <550pg/ml). Cortical thickness (CTh) and normalized hippocampal volume (HV) were obtained using Freesurfer v5.1. We computed the mean CTh in a well-known AD signature map (Dickerson 2009). We performed group comparissons and correlation analyses. We also performed an interaction analysis between age and CSF Aß1–42 to show the regions with an amyloid by age interaction on CTh. The AD group had extensive regions of cortical atrophy in posterior temporoparietal areas with a relative preservation of frontal areas when compared with s-DS. There was a significant gradient of atrophy in the AD signature and HV across groups (d-DS>p-DS>cs-DS). Aging negatively correlated CTh in cs-DS in regions of the frontal cortex. This correlation was also significant for HV but not for the AD signature. CSF Aß1–42 did not correlate with CTh and there were no differences in the Aß+ vs Aß- comparison in cs-DS. However, we found a significant interaction between CSF Aß1–42 levels and age on brain structure in posterior regions.

DEFINING COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME

Down syndrome (DS) is associated with a specific mechanism for Alzheimer's disease related to overproduction of amyloid due to APP gene triplication on chromosome 21. DS is therefore an important population in which to consider amyloid targeting treatments to prevent or delay onset of clinical symptoms. Although amyloid pathology suggestive of Alzheimer's disease (AD) are present in the brains of nearly all individuals with Down syndrome (DS) after the age of 30, there is considerable variability in age of onset of clinical symptoms. We need a better understanding of the natural history of AD in DS and clinical progression as well as associated biomarkers in order to conduct such trials. The London Down syndrome consortium has been conducting an in-depth longitudinal cognitive phenotyping study of >400 adults with DS using a variety of cognitive tasks including tests of memory and executive functions (using CANTAB computer tasks and table-top tasks) and symptoms of dementia (using CAMDEX-DS). All participants donated blood or sputum for DNA and genetic analysis. We will present data on the sequence of cognitive decline with aging in DS, clinical predictors of decline, and clinical differences associated with APOE and other genetic markers. Such data may be used to develop reliable cognitive outcome measures and to stratify and plan clinical trials to prevent or delay AD in the DS population. Some of the issues related to conducting clinical trials in this population will be highlighted alongside potential solutions.

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB−, and 6 (11.7%) converted from PiB− at cycle 1 to PiB+ at cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB− evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome

Down syndrome (DS), present in nearly six million people, is associated with an extremely high risk to develop Alzheimer's disease (AD). Amyloid-β and tau pathology are omnipresent from age 40 years onward, but clinical symptoms do not appear in all DS individuals. Dementia diagnostics is complex in this population, illustrating the great need for predictive biomarkers. Although blood biomarkers have not yet proven useful, cerebrospinal fluid (CSF) biomarkers (low amyloid-β42, high t-tau, and high p-tau) effectively contribute to AD diagnoses in the general population and are increasingly used in clinical practice. Surprisingly, CSF biomarkers have been barely evaluated in DS. Breaking the taboo on CSF analyses would finally allow for the elucidation of its utility in (differential) diagnoses and staging of disease severity. A sensitive and specific biomarker profile for AD in DS would be of paramount importance to daily care, adaptive caregiving, and specific therapeutic interventions.

Dissecting Alzheimer disease in Down syndrome using mouse models.

Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.

Generation of Rabbit Monoclonal Antibody to Amyloid-β38 (Aβ38): Increased Plasma Aβ38 Levels in Down Syndrome.

Secreted soluble amyloid-β (Aβ)38 is the second most prominent Aβ form next to Aβ40, and is found in cerebrospinal fluid (CSF) and blood. Recent studies have shown the importance of quantitation of CSF Aβ38 levels in combination with those of Aβ40 and Aβ42 to support the diagnosis of Alzheimer's disease (AD), and other neurodegenerative diseases, and to facilitate drug discovery studies. However, the availability of reliable and specific Aβ38 monoclonal antibody is limited. Our first aim was to generate and partially characterize rabbit monoclonal antibody (RabmAb) to Aβ38. The antibody was specific to Aβ38, since it did not react with Aβ37, Aβ39, Aβ40, or Aβ42 in ELISA or immunoblotting. The antibody was sensitive enough to measure Aβ38 levels in plasma. Our second aim was to quantitate Aβ38 levels in plasma from older Down syndrome (DS) persons and age-matched controls. Persons with DS (35 years and older) have neuropathological changes characteristic of AD. Studies have shown that plasma Aβ40 and Aβ42 levels are higher in older persons with DS than in controls. However, none examined Aβ38 levels in DS. Our quantitation data showed that, like Aβ40 and Aβ42 plasma levels, Aβ38 plasma levels were higher in DS than in controls. Longitudinal studies will determine whether plasma Aβ38 levels in combination with levels of Aβ40 and Aβ42 are useful to predict early signs of AD in DS.

Serum MHPG strongly predicts conversion to Alzheimer's disease in behaviorally characterized subjects with Down syndrome.

Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimer's disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items. Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n = 51), DS subjects without AD (n = 50), non-demented DS individuals that converted to AD over time (n = 50), and, finally, healthy non-DS controls (n = 22). Serum MHPG levels were significantly lower in demented and converted DS subjects (p < 0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS.

Hippocampal glutamate-glutamine (Glx) in adults with Down syndrome: a preliminary study using in vivo proton magnetic resonance spectroscopy ((1)H MRS).

BackgroundDown syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. People with DS have intellectual disability (ID) and are at significantly increased risk of developing Alzheimer’s disease (AD). The biological associates of both ID and AD in DS are poorly understood, but glutamate has been proposed to play a key role. In non-DS populations, glutamate is essential to learning and memory and glutamate-mediated excitotoxicity has been implicated in AD. However, the concentration of hippocampal glutamate in DS individuals with and without dementia has not previously been directly investigated. Proton magnetic resonance spectroscopy (1H MRS) can be used to measure in vivo the concentrations of glutamate-glutamine (Glx). The objective of the current study was to examine the hippocampal Glx concentration in non-demented DS (DS-) and demented DS (DS+) individuals.MethodsWe examined 46 adults with DS (35 without dementia and 11 with dementia) and 39 healthy controls (HC) using 1H MRS and measured their hippocampal Glx concentrations.ResultsThere was no significant difference in the hippocampal Glx concentration between DS+ and DS-, or between either of the DS groups and the healthy controls. Also, within DS, there was no significant correlation between hippocampal Glx concentration and measures of overall cognitive ability. Last, a sample size calculation based on the effect sizes from this study showed that it would have required 6,257 participants to provide 80% power to detect a significant difference between the groups which would indicate that there is a very low likelihood of a type 2 error accounting for the findings in this study.ConclusionsIndividuals with DS do not have clinically detectable differences in hippocampal Glx concentration. Other pathophysiological processes likely account for ID and AD in people with DS.

Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR deregulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.

Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease

Down syndrome (DS) is the most common genetic cause of intellectual disability, due to partial or complete triplication of chromosome 21. DS subjects are characterized by a number of abnormalities including premature aging and development of Alzheimer disease (AD) neuropathology after approximately 40 years of age. Several studies show that oxidative stress plays a crucial role in the development of neurodegeneration in the DS population. Increased lipid peroxidation is one of the main events causing redox imbalance within cells through the formation of toxic aldehydes that easily react with DNA, lipids, and proteins. In this study we used a redox proteomics approach to identify specific targets of 4-hydroxynonenal modifications in the frontal cortex from DS cases with and without AD pathology. We suggest that a group of identified proteins followed a specific pattern of oxidation in DS vs young controls, probably indicating characteristic features of the DS phenotype; a second group of identified proteins showed increased oxidation in DS/AD vs DS, thus possibly playing a role in the development of AD. The third group of comparison, DS/AD vs old controls, identified proteins that may be considered specific markers of AD pathology. All the identified proteins are involved in important biological functions including intracellular quality control systems, cytoskeleton network, energy metabolism, and antioxidant response. Our results demonstrate that oxidative damage is an early event in DS, as well as dysfunctions of protein-degradation systems and cellular protective pathways, suggesting that DS subjects are more vulnerable to oxidative damage accumulation that might contribute to AD development. Further, considering that the majority of proteins have been already demonstrated to be oxidized in AD brain, our results strongly support similarities with AD in DS.

Abnormal Protein Profiles in Hippocampus of Mouse Models of Down Syndrome: Similarities with Alzheimers Disease

Down syndrome (DS) is caused by an extra copy of the long arm of human chromosome 21 (HSA21) and the increased expression, due to dosage, of HSA21 encoded genes. In addition to intellectual disability, all individuals with DS develop the neuropathology of Alzheimer’s Disease (AD) by age 30-40. The amyloid precursor protein gene, APP, that is mutated or duplicated in some familial AD (FAD), is encoded by HSA21, over expressed in DS, and a candidate for causing AD in DS. However, only half of those with DS will develop the AD-like dementia by age 50-60, suggesting that additional HSA21 genes may modulate the effects of APP triplication, and/or protect the DS brain from early onset progression to dementia in spite of neuropathology. In sporadic AD and mouse models of FAD, abnormal levels of a diverse set of proteins, including receptors, scaffold proteins, kinases, phosphatases and cytokines, have been documented, but nothing is known about their possible roles in AD in DS. Here, we compare expression of 26 AD-related proteins in hippocampus of four mouse models of DS, the Ts65Dn, Tc1, Dp (10)1Yey and Dp (17)1Yey, that together provided trisomy of partially overlapping subsets of all HSA21 genes or mouse orthologs. In the Dp(10)1Yey, that is trisomic for HSA21 orthologs mapping to mouse chromosome 10, twelve of 26 AD-related proteins were elevated, while in the Tc1, Dp(17)1Yey and the popular Ts65Dn, six, four and two differed from littermate controls. These data suggest that genes mapping to the HSA21 orthologous regions of mouse chromosomes 10 and 17 contribute to protein perturbations in the DS brain, and possibly AD in DS. Considering the different phenotypic features of the four DS mouse models further suggests that some protein abnormalities may be compensatory and protective for brain function and/or that learning and memory deficits may be age-dependent.

Treatment of Alzheimer disease in Down syndrome

Down syndrome (DS) is associated with early onset of neuropathology that is indistinguishable from Alzheimer disease (AD), and is typically followed by cognitive decline two decades later. A recent study has reported that the AD drug memantine failed to improve cognitive performance and function in middle-aged patients with DS.

An Intron 7 Polymorphism in APP Affects the Age of Onset of Dementia in Down Syndrome

People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt5−8, in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt5−8 and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD.

The Extended Tau Haplotype and the Age of Onset of Dementia in Down Syndrome

Background/Aims: Most people with Down syndrome (DS) develop Alzheimer’s disease (AD). The extended tau haplotype has been linked to AD. In this study, we examined the haplotype’s effect on the age of onset of AD in DS. Methods: People with DS were assessed for dementia. Genotyping was performed for the extended tau haplotype, APOE anda polymorphism in APP, attt_5–8. Results: Haplotype frequencies vary between those developing AD before 45 and those developing dementia after this age (p = 0.03). H1/H2 individuals are more likely to develop dementia before 45 than H1/H1 individuals (OR = 3, 95% CI = 1.01–8.91). Conclusion: Even in a condition driven by excess amyloid pathology, factors affecting tau are also important and should be considered as potential treatment targets.

Executive dysfunction and its association with personality and behaviour changes in the development of Alzheimer's disease in adults with Down syndrome and mild to moderate learning disabilities

Recent research suggests that preclinical Alzheimer's disease (AD) in people with Down syndrome (DS) is characterized by changes in personality/behaviour and executive dysfunction that are more prominent than deterioration in episodic memory. This study examines the relationship between executive dysfunction and the clinical and preclinical features of AD in DS. To determine the specificity of this relationship, performance on executive function (EF) measures is contrasted with performance on memory measures. One hundred and three people with DS (mean age 49 years, range 36-72) with mild to moderate learning disabilities (LD) took part. Dementia diagnosis was based on the CAMDEX informant interview conducted with each participant's main carer. Reported changes in personality/behaviour and memory were recorded. Participants completed six EF and six memory measures (two of which also had a strong executive component) and the BPVS (as a measure of general intellectual ability). First, performance was compared between those with and without established dementia of Alzheimer's type (DAT), controlling for age and LD severity using ANCOVA. Next, the degree to which informant-reported changes predicted cognitive test performance was examined within the non-DAT group using multiple regression analyses. The DAT group (N=25) showed a consistent pattern of impaired performance relative to the non-DAT group (N=78), across all measures. Within the non-DAT group, number of informant-reported personality/behaviour changes was a significant predictor of performance on two EF and two 'executive memory' tests (but not on episodic memory tests). Informant-reported memory changes, however, were associated with impaired performance on a delayed recall task only. These findings provide further evidence for a specific impairment in frontal-lobe functioning in the preclinical stages of AD in DS. Implications for the assessment, diagnosis, and management of dementia in DS are discussed.

An experimental approach to detecting dementia in Down syndrome: A paradigm for Alzheimer’s disease

Measures developed from animal models of aging may detect dementia of the Alzheimer’s type in a population at-risk for Alzheimer’s disease (AD). Although, by middle age, individuals with Down syndrome (DS) show an extraordinarily high prevalence of AD-type pathology, their severe idiopathic cognitive deficits tend to confound the clinical diagnosis of AD. The current study was designed to improve detection of AD in DS by using measures of learning and memory derived from animal models of aging. Adults with DS ( N = 34) were assessed and reassessed ( n = 19) approximately one year later using stimulus–response (S–R) test methods derived from experimental literature, as well as standardized informant-based tests. Results demonstrated high validity and reliability of select tests. The implication of early symptom detection in a population at-risk for AD-type dementia was discussed in terms of potential brain regions of interest.