Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

[1]  Rafat Hussain,et al.  The four ages of Down syndrome. , 2007, European journal of public health.

[2]  M. Pritchard,et al.  Alzheimer's disease and endocytic dysfunction: Clues from the Down syndrome-related proteins, DSCR1 and ITSN1 , 2006, Ageing Research Reviews.

[3]  R. Mayeux,et al.  Bioavailable estradiol and age at onset of Alzheimer's disease in postmenopausal women with Down syndrome , 2006, Neuroscience Letters.

[4]  K. Sleegers,et al.  Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. , 2006, American journal of human genetics.

[5]  Hey-kyeong Jeong,et al.  DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects , 2006, Neurobiology of Disease.

[6]  Xin Gao,et al.  NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21 , 2006, Nature.

[7]  K. Davies,et al.  RCAN1 (DSCR1 or Adapt78) * stimulates expression of GSK‐3β , 2006, The FEBS journal.

[8]  P. Kahlem.  Gene-Dosage Effect on Chromosome 21 Transcriptome in Trisomy 21: Implication in Down Syndrome Cognitive Disorders , 2006, Behavior genetics.

[9]  J. C. Clemens,et al.  Dendritic patterning by Dscam and synaptic partner matching in the Drosophila antennal lobe , 2006, Nature Neuroscience.

[10]  K. Gardiner.  Transcriptional Dysregulation in Down Syndrome: Predictions for Altered Protein Complex Stoichiometries and Post-translational Modifications, and Consequences for Learning/Behavior Genes ELK, CREB, and the Estrogen and Glucocorticoid Receptors , 2006, Behavior genetics.

[11]  E. Peskind,et al.  Compensatory Changes in the Noradrenergic Nervous System in the Locus Ceruleus and Hippocampus of Postmortem Subjects with Alzheimer's Disease and Dementia with Lewy Bodies , 2006, The Journal of Neuroscience.

[12]  C. Siwak,et al.  The Canine Model of Human Brain Aging: Cognition, Behavior, and Neuropathology , 2006 .

[13]  D. Campion,et al.  APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy , 2006, Nature Genetics.

[14]  J. Carr.  Stability and change in cognitive ability over the life span: a comparison of populations with and without Down's syndrome. , 2005, Journal of intellectual disability research : JIDR.

[15]  D. Crawford,et al.  DSCR1 (ADAPT78) lethality: evidence for a protective effect of trisomy 21 genes? , 2005, Biochemical and biophysical research communications.

[16]  K. Min,et al.  Drosophila melanogaster homolog of Down syndrome critical region 1 is critical for mitochondrial function , 2005, Nature Neuroscience.

[17]  K. Davies,et al.  Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease , 2005, Cellular and Molecular Life Sciences CMLS.

[18]  Dean Nizetic,et al.  An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes , 2005, Science.

[19]  Fred H. Gage,et al.  Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice , 2005, The Journal of Neuroscience.

[20]  M. Davisson,et al.  Behavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome , 2005, Behavioural Brain Research.

[21]  C. Bramham,et al.  BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis , 2005, Progress in Neurobiology.

[22]  D. Borchelt,et al.  Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[23]  Victoria M Perreau,et al.  Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[24]  J. Wegiel,et al.  Dementia of the Alzheimer's type and accelerated aging in Down syndrome. , 2005, Science of aging knowledge environment : SAGE KE.

[25]  G. Schettini,et al.  The amyloid precursor protein and its network of interacting proteins: physiological and pathological implications , 2005, Brain Research Reviews.

[26]  Yuxiang Sun,et al.  Molecular endocrinology and physiology of the aging central nervous system. , 2005, Endocrine reviews.

[27]  K. Giese.  Faculty Opinions recommendation of Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. , 2005 .

[28]  Ilana S. Hairston,et al.  Environmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice , 2005, Cell.

[29]  D. Patterson,et al.  History of genetic disease: Down syndrome and genetics — a case of linked histories , 2005, Nature Reviews Genetics.

[30]  C. Epstein,et al.  Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome , 2004, The Journal of comparative neurology.

[31]  G. Johnson,et al.  Tau phosphorylation in neuronal cell function and dysfunction , 2004, Journal of Cell Science.

[32]  H. Potter,et al.  Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable &bgr;-amyloid deposition , 2004, Neuroreport.

[33]  R. Holder,et al.  The Adaptive Behaviour Dementia Questionnaire (ABDQ): screening questionnaire for dementia in Alzheimer's disease in adults with Down syndrome. , 2004, Research in developmental disabilities.

[34]  K. Yamakawa,et al.  Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. , 2004, Human molecular genetics.

[35]  A. Scaloni,et al.  Growth Factor Receptor-bound Protein 2 Interaction with the Tyrosine-phosphorylated Tail of Amyloid β Precursor Protein Is Mediated by Its Src Homology 2 Domain* , 2004, Journal of Biological Chemistry.

[36]  J. Wuu,et al.  Increased proNGF Levels in Subjects with Mild Cognitive Impairment and Mild Alzheimer Disease , 2004, Journal of neuropathology and experimental neurology.

[37]  E. Head,et al.  Down syndrome and beta-amyloid deposition , 2004, Current opinion in neurology.

[38]  J. Rimmer,et al.  Improvements in physical fitness in adults with Down syndrome. , 2004, American journal of mental retardation : AJMR.

[39]  N. Beail,et al.  Risk factors for dementia in people with down syndrome: issues in assessment and diagnosis. , 2004, American journal of mental retardation : AJMR.

[40]  P. Doevendans,et al.  MCIP1 Overexpression Suppresses Left Ventricular Remodeling and Sustains Cardiac Function After Myocardial Infarction , 2004, Circulation research.

[41]  K. Yutzey,et al.  DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. , 2004, Developmental biology.

[42]  K. Becker,et al.  DSCR1(Adapl78) modulates expression of SOD1 , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  C. Howe,et al.  Trafficking the NGF signal: implications for normal and degenerating neurons. , 2004, Progress in brain research.

[44]  J. Padovan,et al.  Mnb/Dyrk1A phosphorylation regulates the interaction of dynamin 1 with SH3 domain-containing proteins. , 2004, Biochemistry.

[45]  P. Doevendans,et al.  MCIP 1 Overexpression Suppresses Left Ventricular Remodeling and Sustains Cardiac Function After Myocardial Infarction , 2004 .

[46]  D. Tappa,et al.  Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification : a two-year longitudinal study , 2004 .

[47]  Melina R. Uncapher,et al.  Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia , 2003, Neurology.

[48]  G. Alexander,et al.  Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[49]  D. Borchelt,et al.  Environmental Enrichment Exacerbates Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease , 2003, Journal of neuropathology and experimental neurology.

[50]  B. Tycko,et al.  Onset of dementia is associated with age at menopause in women with Down's syndrome , 2003, Annals of neurology.

[51]  C. Cotman,et al.  Parallel Compensatory and Pathological Events Associated with Tau Pathology in Middle Aged Individuals with Down Syndrome , 2003, Journal of neuropathology and experimental neurology.

[52]  Nathan S White,et al.  A voxel-based morphometric study of nondemented adults with Down Syndrome , 2003, NeuroImage.

[53]  David P. Wolfer,et al.  Does cAMP Response Element-Binding Protein Have a Pivotal Role in Hippocampal Synaptic Plasticity and Hippocampus-Dependent Memory? , 2003, The Journal of Neuroscience.

[54]  X. Estivill,et al.  Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. , 2003, Cerebral cortex.

[55]  Z. Galdzicki,et al.  Understanding mental retardation in Down's syndrome using trisomy 16 mouse models , 2003, Genes, brain, and behavior.

[56]  J. Cerón,et al.  Expression patterns and subcellular localization of the Down syndrome candidate protein MNB/DYRK1A suggest a role in late neuronal differentiation , 2003, The European journal of neuroscience.

[57]  M. Johnston,et al.  Learning, Memory, and Transcription Factors , 2003, Pediatric Research.

[58]  S. Black,et al.  Evidence from Functional Neuroimaging of a Compensatory Prefrontal Network in Alzheimer's Disease , 2003, The Journal of Neuroscience.

[59]  N. Cairns,et al.  Increased RNA levels of the 25 kDa synaptosomal associated protein in brain samples of adult patients with Down Syndrome , 2003, Neuroscience Letters.

[60]  J. Galceran,et al.  The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications. , 2003, Journal of neural transmission. Supplementum.

[61]  G. Small,et al.  Use of neuroimaging to detect early brain changes in people at genetic risk for Alzheimer's disease. , 2002, Advanced drug delivery reviews.

[62]  R. Hussain,et al.  The changing survival profile of people with Down's syndrome: implications for genetic counselling , 2002, Clinical genetics.

[63]  X. Chen,et al.  Hippocampal CRE-mediated gene expression is required for contextual memory formation , 2002, Nature Neuroscience.

[64]  Mara Dierssen,et al.  Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome , 2002, Behavioural Brain Research.

[65]  Tony Wyss-Coray,et al.  Inflammation in Neurodegenerative Disease—A Double-Edged Sword , 2002, Neuron.

[66]  P. Mcgeer,et al.  Innate immunity, local inflammation, and degenerative disease. , 2002, Science of aging knowledge environment : SAGE KE.

[67]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[68]  T. Nabeshima,et al.  CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning , 2002, Behavioural Brain Research.

[69]  C. Cotman,et al.  Exercise: a behavioral intervention to enhance brain health and plasticity , 2002, Trends in Neurosciences.

[70]  N. Schupf,et al.  Genetic and host factors for dementia in Down's syndrome. , 2002, The British journal of psychiatry : the journal of mental science.

[71]  N. Schupf,et al.  Incidence and temporal patterns of adaptive behavior change in adults with mental retardation. , 2002, American journal of mental retardation : AJMR.

[72]  S. Rasmussen,et al.  Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study , 2002, The Lancet.

[73]  S. Krinsky-McHale,et al.  Changes in explicit memory associated with early dementia in adults with Down's syndrome. , 2002, Journal of intellectual disability research : JIDR.

[74]  E. Carmeli,et al.  Effects of a treadmill walking program on muscle strength and balance in elderly people with Down syndrome. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[75]  M. Starkey,et al.  Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study , 2002, The Lancet.

[76]  B. Lawlor,et al.  Dementia in people with Down's syndrome , 2001, International journal of geriatric psychiatry.

[77]  L. Hyde,et al.  Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease. , 2001, Behavioral neuroscience.

[78]  K. Yamakawa,et al.  Dscam is associated with axonal and dendritic features of neuronal cells , 2001, Journal of neuroscience research.

[79]  K. Chung,et al.  Protein Kinase Dyrk1 Activates cAMP Response Element-binding Protein during Neuronal Differentiation in Hippocampal Progenitor Cells* , 2001, The Journal of Biological Chemistry.

[80]  X. Estivill,et al.  Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. , 2001, Human molecular genetics.

[81]  R. Davis,et al.  The Role of Drosophila Mushroom Body Signaling in Olfactory Memory , 2001, Science.

[82]  C. Cotman,et al.  Complement Association with Neurons and β-Amyloid Deposition in the Brains of Aged Individuals with Down Syndrome , 2001, Neurobiology of Disease.

[83]  G. Alexander,et al.  Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[84]  K. Yamakawa,et al.  DSCAM, a highly conserved gene in mammals, expressed in differentiating mouse brain. , 2001, Biochemical and biophysical research communications.

[85]  M. Konstantareas,et al.  Alzheimer dementia in Down's syndrome: the relevance of cognitive ability. , 2001, Journal of intellectual disability research : JIDR.

[86]  E. Masliah,et al.  Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease , 2001, Neurology.

[87]  C. Cotman,et al.  Neurobiological Models of Aging in the Dog and Other Vertebrate Species , 2001 .

[88]  N. Cairns.  Molecular neuropathology of transgenic mouse models of Down syndrome. , 2001, Journal of neural transmission. Supplementum.

[89]  M. Sofroniew,et al.  Nerve growth factor signaling, neuroprotection, and neural repair. , 2001, Annual review of neuroscience.

[90]  M. Han,et al.  Grb2 dominantly associates with dynamin II in human hepatocellular carcinoma HepG2 cells , 2001, Journal of cellular biochemistry.

[91]  Racial disparities in median age at death of persons with Down syndrome--United States, 1968-1997. , 2001, MMWR. Morbidity and mortality weekly report.

[92]  F. Huppert,et al.  Incidence and course of dementia in people with Down's syndrome: findings from a population-based study. , 2001, Journal of intellectual disability research : JIDR.

[93]  S. Krinsky-McHale,et al.  Sequence of cognitive decline in dementia in adults with Down's syndrome. , 2000, Journal of intellectual disability research : JIDR.

[94]  K. Arima,et al.  The developmental and aging changes of Down’s syndrome cell adhesion molecule expression in normal and Down’s syndrome brains , 2000, Acta Neuropathologica.

[95]  Mark S. Cohen,et al.  Patterns of brain activation in people at risk for Alzheimer's disease. , 2000, The New England journal of medicine.

[96]  B. Winblad,et al.  The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample. , 2000, Archives of neurology.

[97]  G. Reid,et al.  Physical Fitness of Adults with an Intellectual Disability: A 13-Year Follow-up Study , 2000, Research quarterly for exercise and sport.

[98]  A. Dalton,et al.  Prevalence of dementia and impact on intellectual disability services. , 2000, Mental retardation.

[99]  Roberta F. White,et al.  The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort. , 2000, Archives of neurology.

[100]  J. Mazziotta,et al.  Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[101]  E. Aylward,et al.  Test battery for the diagnosis of dementia in individuals with intellectual disability. Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Intellectual Disability. , 2000, Journal of intellectual disability research : JIDR.

[102]  D. Davies,et al.  Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice , 2000, Brain Research.

[103]  A. Granholm,et al.  Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down's Syndrome , 2000, Experimental Neurology.

[104]  S. Deb,et al.  Comparison of rating scales for the diagnosis of dementia in adults with Down's syndrome. , 2001, Journal of intellectual disability research : JIDR.

[105]  C. Epstein,et al.  Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome , 1999, Neuropharmacology.

[106]  T J Sejnowski,et al.  Running enhances neurogenesis, learning, and long-term potentiation in mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[107]  N L Foster,et al.  Discordance between Traditional Pathologic and Energy Metabolic Changes in Very Early Alzheimer's Disease: Pathophysiological Implications , 1999, Annals of the New York Academy of Sciences.

[108]  M. Mesulam.  Neuroplasticity Failure in Alzheimer's Disease Bridging the Gap between Plaques and Tangles , 1999, Neuron.

[109]  X. Estivill,et al.  Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome. , 1999, Genomics.

[110]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[111]  J. Wands,et al.  Neuritic sprouting with aberrant expression of the nitric oxide synthase III gene in neurodegenerative diseases , 1999, Journal of the Neurological Sciences.

[112]  S. Ohara,et al.  On the occurrence of neuronal sprouting in the frontal cortex of a patient with Down’s syndrome , 1999, Acta Neuropathologica.

[113]  S. Cooper,et al.  Maladaptive behaviours and symptoms of dementia in adults with Down's syndrome compared with adults with intellectual disability of other aetiologies. , 2002, Journal of intellectual disability research : JIDR.

[114]  D. Mash,et al.  Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. , 1998, Journal of neuropathology and experimental neurology.

[115]  A. Holland,et al.  A four year prospective study of age-related cognitive change in adults with Down's syndrome , 1998, Psychological Medicine.

[116]  W. Griffin,et al.  Life-long overexpression of S100β in Down’s syndrome: implications for Alzheimer pathogenesis , 1998, Neurobiology of Aging.

[117]  N. B. Phillips,et al.  Dementia in adults with Down syndrome: diagnostic challenges. , 1998, American journal of mental retardation : AJMR.

[118]  F. Huppert,et al.  Population-based study of the prevalence and presentation of dementia in adults with Down's syndrome , 1998, British Journal of Psychiatry.

[119]  M. Raskind,et al.  Early Amyloid Deposition in the Medial Temporal Lobe of Young Down Syndrome Patients: A Regional Quantitative Analysis , 1998, Experimental Neurology.

[120]  B. Tycko,et al.  Earlier onset of Alzheimer's disease in men with Down syndrome , 1998, Neurology.

[121]  K. Yamakawa,et al.  DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system. , 1998, Human molecular genetics.

[122]  S. Soraci,et al.  Perspectives on fundamental processes in intellectual functioning , 1998 .

[123]  Hui Zheng,et al.  The β-Amyloid Precursor Protein of Alzheimer’s Disease Enhances Neuron Viability and Modulates Neuronal Polarity , 1997, The Journal of Neuroscience.

[124]  T. Chowdhury,et al.  ApoE genotype and Alzheimer's disease in adults with Down syndrome: meta-analysis. , 1997, American journal of mental retardation : AJMR.

[125]  A. Gatherer,et al.  Sarcoma of the Larynx , 1958, The Journal of Laryngology & Otology.

[126]  Jan-Fang Cheng,et al.  Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome , 1997, Nature Genetics.

[127]  E. Aylward,et al.  Diagnosis of dementia in individuals with intellectual disability. , 1997, Journal of intellectual disability research : JIDR.

[128]  S. Gauthier,et al.  Lymphocyte content of amyloid precursor protein is increased in Down's syndrome and aging , 1997, Neurobiology of Aging.

[129]  A. V. van Huffelen,et al.  Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome. , 1997, American journal of mental retardation : AJMR.

[130]  P Pietrini,et al.  Brain cognition and metabolism in Down syndrome adults in association with development of dementia , 1996, Neuroreport.

[131]  D. Holtzman,et al.  Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[132]  X. Estivill,et al.  A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. , 1996, Human molecular genetics.

[133]  H. Evenhuis,et al.  Further evaluation of the Dementia Questionnaire for Persons with Mental Retardation (DMR). , 1996, Journal of intellectual disability research : JIDR.

[134]  C. Cotman,et al.  Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain , 1996, Brain Research.

[135]  P. Johannsen,et al.  The prevalence of dementia in Down syndrome. , 1996, Dementia.

[136]  R. Eyman,et al.  Mortality of people with mental retardation in California with and without Down syndrome, 1986-1991. , 1996, American journal of mental retardation : AJMR.

[137]  S. Thibodeau,et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. , 1996, The New England journal of medicine.

[138]  J. Price,et al.  Cerebral amyloid deposition and diffuse plaques in ``normal'' aging , 1996, Neurology.

[139]  D. Selkoe,et al.  Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation , 1996, Neurobiology of Disease.

[140]  N. Schupf,et al.  Prevalence of dementia in adults with and without Down syndrome. , 1996, American journal of mental retardation : AJMR.

[141]  S. Pillai,et al.  Innate immunity. , 1996, Current opinion in immunology.

[142]  V. Prasher,et al.  Behavioural disturbance in people with Down's syndrome and dementia. , 1995, Journal of intellectual disability research : JIDR.

[143]  R. Bronson,et al.  A mouse model for Down syndrome exhibits learning and behaviour deficits , 1995, Nature Genetics.

[144]  D. Mann,et al.  The extent of amyloid deposition in brain in patients with Down's syndrome does not depend upon the apolipoprotein E genotype , 1995, Neuroscience Letters.

[145]  D. Neill.  Alzheimer's disease: maladaptive synaptoplasticity hypothesis. , 1995, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[146]  G. Dawson,et al.  β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity , 1995, Cell.

[147]  P. Satz,et al.  Detection of Alzheimer disease in individuals with Down syndrome. , 1995, American journal of mental retardation : AJMR.

[148]  B. Hyman,et al.  Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. , 1995, Archives of neurology.

[149]  Richard J. Haier,et al.  Brain size and cerebral glucose metabolic rate in nonspecific mental retardation and down syndrome , 1995 .

[150]  D. Selkoe,et al.  Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[151]  M Heisenberg,et al.  minibrain: A new protein kinase family involved in postembryonic neurogenesis in Drosophila , 1995, Neuron.

[152]  P. Greengard,et al.  Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[153]  O Nalcioglu,et al.  Magnetic resonance imaging analysis of age‐related changes in the brains of individuals with Down's syndrome , 1994, Neurology.

[154]  B. Ames,et al.  Oxidants, antioxidants, and the degenerative diseases of aging. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[155]  V. Prasher,et al.  Mental disorders and adaptive behaviour in people with Down's syndrome , 1993, British Journal of Psychiatry.

[156]  B. Fernhall.  Physical fitness and exercise training of individuals with mental retardation. , 1993, Medicine and science in sports and exercise.

[157]  M. Mattson,et al.  Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein , 1993, Neuron.

[158]  D. Drachman,et al.  Alzheimer's disease and aging: Effects on perforant pathway perikarya and synapses , 1992, Neurobiology of Aging.

[159]  Michael Alford,et al.  Patterns of aberrant sprouting in alzheimer's disease , 1991, Neuron.

[160]  M. Franceschi,et al.  Prevalence of dementia in adult patients with trisomy 21. , 2005, American journal of medical genetics. Supplement.

[161]  H. Evenhuis,et al.  The natural history of dementia in Down's syndrome. , 1990, Archives of neurology.

[162]  J. Haxby,et al.  Regional Cerebral Glucose Metabolism is Normal in Young Adults with down Syndrome , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[163]  C. Cotman,et al.  Axon sprouting in the rodent and Alzheimer's disease brain: a reactivation of developmental mechanisms? , 1990, Progress in brain research.

[164]  G. Cole,et al.  The regulation of amyloid β protein precursor secretion and its modulatory role in cell adhesion , 1989, Neuron.

[165]  R. S. Williams,et al.  A prospective study of Alzheimer disease in Down syndrome. , 1989, Archives of neurology.

[166]  D. Mann,et al.  The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome , 1989, Journal of the Neurological Sciences.

[167]  P. Davies,et al.  Reexpression of a developmentally regulated antigen in Down syndrome and Alzheimer disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[168]  David M. A. Mann,et al.  The pathological association between down syndrome and Alzheimer disease , 1988, Mechanisms of Ageing and Development.

[169]  R. Katzman.,et al.  Clinical, pathological, and neurochemical changes in dementia: A subgroup with preserved mental status and numerous neocortical plaques , 1988, Annals of neurology.

[170]  N. Cutler.  Cerebral metabolism as measured with positron emission tomography (PET) and [18F] 2-deoxy-d-glucose: Healthy aging Alzheimer's disease and down syndrome , 1986, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[171]  H. Wiśniewski,et al.  Discrepancy between Alzheimer‐Type Neuropathology and Dementia in Persons with Down's Syndrome a , 1986, Annals of the New York Academy of Sciences.

[172]  C. Cotman,et al.  Plasticity of hippocampal circuitry in Alzheimer's disease. , 1985, Science.

[173]  H. Wiśniewski,et al.  Alzheimer's disease in Down's syndrome , 1985, Neurology.

[174]  H. Wiśniewski,et al.  Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome , 1985, Annals of neurology.

[175]  C. Grady,et al.  Down's syndrome in adults: brain metabolism. , 1983, Science.

[176]  M. Thase.  Longevity and mortality in Down's syndrome. , 2008, Journal of mental deficiency research.

[177]  M. Thase,et al.  Clinical evaluation of dementia in Down's syndrome: a preliminary report. , 2008, Journal of mental deficiency research.

[178]  I. Lott,et al.  Dementia in Down's syndrome: observations from a neurology clinic. , 1982, Applied research in mental retardation.

[179]  A. Ropper,et al.  Relationship between plaques, tangles, and dementia in Down syndrome , 1980, Neurology.

[180]  P. Huttenlocher.  Synaptic density in human frontal cortex - developmental changes and effects of aging. , 1979, Brain research.

[181]  H. Wiśniewski,et al.  Precocious aging and dementia in patients with Down's syndrome. , 1978, Biological psychiatry.

[182]  B. Cragg,et al.  The density of synapses and neurons in normal, mentally defective ageing human brains. , 1975, Brain : a journal of neurology.

[183]  G. Schlotterer,et al.  Alzheimer's disease in Down's syndrome: visual retention deficits. , 1974, Cortex; a journal devoted to the study of the nervous system and behavior.

[184]  E. Niebuhr,et al.  Down's syndrome , 1974, Humangenetik.

[185]  Peter Secretan.  Learning , 1965, Mental Health.

[186]  J. Down.  Observations on an Ethnic Classification of Idiots , 1867 .

[187]  M. Low,et al.  Disruption of neurotransmission in Drosophila mushroom body blocks retrieval but not acquisition of memory , 2022 .