Search Our Scientific Publications & Authors

Alzheimers Dement (Amst) 2020 9;12(1):e12057. Epub 2020 Jul 9.

Department of Neurology Washington University in St. Louis School of Medicine St. Louis Missouri USA.

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS. Read More

Alzheimers Dement (Amst) 2020 5;12(1):e12044. Epub 2020 Jul 5.

Department of Epidemiology School of Public Health Columbia University New York New York USA.

Introduction: Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) and its associated dementia, warranting the development of strategies to improve early detection when prevention is possible.

Methods: Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we evaluated the psychometrics of measures in a large sample of 561 adults with DS. We tracked longitudinal stability or decline in functioning in a subsample of 269 participants over a period of 3 years, all initially without indications of clinically significant aging-related decline. Read More

Contemp Clin Trials Commun 2020 Sep 30;19:100607. Epub 2020 Jun 30.

Department of Internal Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.

Nearly all individuals with Down Syndrome (DS) display pathology associated with Alzheimer's disease (AD) beginning as early as age 30. Previous research in typically developed adults suggests that increased moderate-to-vigorous physical activity (MVPA) may improve cognitive function and protect against age-related structural and functional changes in the brain; however, the potential impact of increased MVPA on the development of AD in adults with DS has not been evaluated. Despite the potential positive impact of MVPA on cognition and AD risk, participation in MVPA among young adults with DS is low. Read More

AIMS Neurosci 2020 22;7(2):168-193. Epub 2020 Jun 22.

University of Liège, Cognitive Sciences, Building 32, Sart Tilman, Liège 4000, Belgium.

Experimental work regarding corrective actions on chromosomes and genes, and control of gene products is yielding promising results. It opens the way to advances in dealing with the etiological aspects of Down syndrome and may lead to important changes in the life of individuals affected with this condition. A small number of molecules are being investigated in pharmacological research that may have positive effects on intellectual functioning. Read More

Alzheimers Dement 2020 07 16;16(7):1065-1077. Epub 2020 Jun 16.

Alzheimer's Therapeutics Research Institute and Department of Neurology, University of Southern California, Los Angeles, California, USA.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). Read More

Alzheimers Dement (Amst) 2020 16;12(1):e12020. Epub 2020 Apr 16.

University of Wisconsin-Madison Waisman Center Madison Wisconsin.

Introduction: Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load ( ) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.. Read More

Alzheimers Dement (Amst) 2020 5;12(1):e12028. Epub 2020 Apr 5.

Taub Institute for Research in Alzheimer's Disease and the Aging Brain Columbia University New York New York USA.

Introduction: Disruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).

Methods: We examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Read More

Neurosci Lett 2020 Apr 27;724:134876. Epub 2020 Feb 27.

Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Apartado Postal 70228, Cuidad Universitaria, CDMX, CP, 04510, Mexico. Electronic address:

In addition to the full-length beta-amyloid peptides (Aβ 1-40/42), several Aβ variants, truncated at their N- or C-termini and bearing different post-translational modifications, have been detected in the brain of Alzheimer´s disease (AD) patients. AβN3(pE), an Aβ peptide bearing an amino-terminal pyroglutamate at position 3, is a significant constituent of intracellular, extracellular and vascular Aβ deposits in brain tissue from individuals with AD and Down syndrome. Pioneering immunotherapy studies have primarily focused on the full-length Aβ peptide, disregarding the presence of N-truncated/modified species. Read More

Am J Intellect Dev Disabil 2020 03;125(2):97-99

Benjamin L. Handen, Western Psychiatric Hospital, Pittsburgh, PA.

Adults with Down syndrome are at high risk for Alzheimer's disease (AD), with most individuals developing clinical dementia by their late 60s. This increased risk for AD has been attributed, at least in part, to triplication and overexpression of the gene for amyloid precursor protein (APP) on chromosome 21 leading to elevated levels of amyloid β peptides. This article offers a brief overview of our current knowledge of AD in the DS population. Read More

Prog Brain Res 2020 20;251:209-243. Epub 2019 Nov 20.

Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

Down syndrome (DS) is the most frequent chromosomal disorder. It is caused by the triplication of human chromosome 21, leading to increased dosage of a variety of genes including APP (Amyloid Precursor Protein). Mainly for this reason, individuals with DS are at high risk to develop Alzheimer's disease (AD). Read More

Nat Rev Dis Primers 2020 02 6;6(1). Epub 2020 Feb 6.

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). DS is among the most genetically complex of the conditions that are compatible with human survival post-term, and the most frequent survivable autosomal aneuploidy. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the many clinical manifestations in DS. Read More

Glia 2020 Jul 16;68(7):1347-1360. Epub 2020 Jan 16.

Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Inflammation can be resolved by pro-homeostatic lipids called specialized pro-resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM-binding receptors were increased in patients with AD compared to age-matched controls. Read More

Clin Epigenetics 2019 12 16;11(1):195. Epub 2019 Dec 16.

Institut Jérôme Lejeune, CRB BioJeL, 37 rue des Volontaires, Paris, France.

Background: Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals. Read More

J Neurodev Disord 2019 12 16;11(1):39. Epub 2019 Dec 16.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Background: Adults with Down syndrome (DS) are at increased risk for Alzheimer disease dementia, and there is a pressing need for the development of assessment instruments that differentiate chronic cognitive impairment, acute neuropsychiatric symptomatology, and dementia in this population of patients.

Methods: We adapted a widely used instrument, the Clinical Dementia Rating (CDR) Scale, which is a component of the Uniform Data Set used by all federally funded Alzheimer Disease Centers for use in adults with DS, and tested the instrument among 34 DS patients recruited from the community. The participants were assessed using two versions of the modified CDR-a caregiver questionnaire and an in-person interview involving both the caregiver and the DS adult. Read More

Nihon Yakurigaku Zasshi 2019 ;154(6):335-339

Department of Pathological Biochemistry, Kyoto Pharmaceutical University.

Down syndrome caused by triplication of human chromosome 21 (HSA21) is the most frequent aneuploidy, resulting in mental retardation, intellectual disability and accelerated aging. Individuals with DS are at an increased risk of developing Alzheimer's disease (AD)-like dementia, with up to 75% of DS people in their 60s developing dementia. Oxidative stress is widely accepted as a mechanism underlying a number of DS symptoms, such as accelerated aging and cognitive decline. Read More

Handb Clin Neurol 2019 ;167:321-336

Department of Neurosciences, University of California San Diego, La Jolla, CA, United States. Electronic address:

Down syndrome (DS; Trisomy 21) is the most common chromosomal disorder in humans. It has numerous associated neurologic phenotypes including intellectual disability, sleep apnea, seizures, behavioral problems, and dementia. With improved access to medical care, people with DS are living longer than ever before. Read More

Neurobiol Dis 2020 02 31;134:104616. Epub 2019 Oct 31.

Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA.

The pontine nucleus locus coeruleus (LC) is the primary source of noradrenergic (NE) projections to the brain and is important for working memory, attention, and cognitive flexibility. Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) with high penetrance and often exhibit working memory deficits coupled with degeneration of LC-NE neurons early in the progression of AD pathology. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools that allow targeted manipulation of discrete neuronal populations in the brain without the confounds of off-target effects. Read More

JAMA Neurol 2019 Oct 28. Epub 2019 Oct 28.

Waisman Center, University of Wisconsin-Madison, Madison.

Am J Med Genet A 2020 01 22;182(1):104-114. Epub 2019 Oct 22.

Genetic Counseling Graduate Program, Division of Human Genetics, The Ohio State University, Columbus, Ohio.

Research about Alzheimer's disease (AD) in individuals with Down syndrome (DS) has predominantly focused on the underlying genetics and neuropathology. Few studies have addressed how AD risk impacts caregivers of adults with DS. This study aimed to explore the perceived impact of AD development in adults with DS on caregivers by assessing caregiver knowledge, concerns, effect on personal life, and resource utilization via a 40-question (maximum) online survey. Read More

Neurobiol Aging 2019 12 3;84:70-79. Epub 2019 Aug 3.

Center for Biomedical Technology, Laboratory of Cognitive and Computational Neuroscience, Technical University of Madrid, Campus Montegancedo, Madrid, Spain; Department of Legal Medicine, Psychiatry and Pathology, Complutense University of Madrid, Spain, Madrid, Spain.

Down syndrome (DS) has been considered a unique model for the investigation of Alzheimer's disease (AD) but intermediate stages in the continuum are poorly defined. Considering this, we investigated the neurophysiological (i.e. Read More

Dev Neurobiol 2019 07 26;79(7):622-638. Epub 2019 Aug 26.

Department of Neurology, The University of California, Irvine, Irvine, California.

Down syndrome (DS) is a well-known neurodevelopmental disorder most commonly caused by trisomy of chromosome 21. Because individuals with DS almost universally develop heavy amyloid burden and Alzheimer's disease (AD), biomarker discovery in this population may be extremely fruitful. Moreover, any AD biomarker in DS that does not directly involve amyloid pathology may be of high value for understanding broader mechanisms of AD generalizable to the neurotypical population. Read More

Brain Pathol 2020 03 8;30(2):319-331. Epub 2019 Sep 8.

Department of Anatomy & Neurobiology, University of California at Irvine, Irvine, CA, 92697-1275.

Reduced spine densities and age-dependent accumulation of amyloid β and tau pathology are shared features of Down syndrome (DS) and Alzheimer's disease (AD). Both spine morphology and the synaptic plasticity that supports learning depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders. The present study evaluated the synaptic levels of two proteins that promote filamentous actin stabilization, the Rho GTPase effector p21-activated kinase 3 (PAK3) and Arp2, in DS vs. Read More

Dev Neurobiol 2019 07 3;79(7):699-710. Epub 2019 Sep 3.

Department of Pharmacology & Neuroscience, Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, Texas.

Down syndrome (DS) occurs due to triplication of chromosome 21. Individuals with DS face an elevated risk for development of Alzheimer's disease (AD) due to increased amyloid beta (Aβ) resulting from the over-expression of the amyloid precursor protein found on chromosome 21. Diagnosis of AD among individuals with DS poses particular challenges resulting in an increased focus on alternative diagnostic methods such as blood-based biomarkers. Read More

Dev Neurobiol 2019 07 11;79(7):684-698. Epub 2019 Sep 11.

Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta-analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. Read More

Dev Neurobiol 2019 07 6;79(7):639-655. Epub 2019 Aug 6.

Department of Biological Sciences and the Knoebel Institute for Healthy Aging, University of Denver, Denver, Colorado.

Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Read More

J Neurosci 2019 07 1;39(27):5255-5268. Epub 2019 May 1.

Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, 10962,

Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer's disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the β cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/lysosomes. Read More

Neurobiol Aging 2019 06 11;78:186-194. Epub 2019 Mar 11.

Obsessive-Compulsive Spectrum Disorders Program, PROTOC, Department and Institute of Psychiatry, University of São Paulo School of Medicine, FMUSP, São Paulo, Brazil.

There is evidence that frontal-subcortical circuits play an important role in the initial presentation of dementia in Down syndrome (DS), including changes in behavior, a decline in working memory and executive dysfunction. We evaluated 92 individuals with DS (≥30 years of age), divided into 3 groups by diagnosis-stable cognition, prodromal dementia, and Alzheimer's disease. Each individual was evaluated with an executive protocol developed for people with intellectual disabilities and was rated for behaviors related to frontal lobe dysfunction (disinhibition, executive dysfunction, and apathy) by an informant using the Frontal Systems Behavior Scale. Read More

Nature 2019 04 20;568(7752):420-423. Epub 2019 Mar 20.

MRC Laboratory of Molecular Biology, Cambridge, UK.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. Read More

Int J Mol Sci 2019 Feb 25;20(4). Epub 2019 Feb 25.

Neurochemistry Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.

The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer's disease (AD) caused by APP gene duplications (Dup⁻APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5'untranslated region (5'UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. Read More

J Intellect Disabil Res 2019 06 27;63(6):614-623. Epub 2019 Feb 27.

School of Health Solutions, Arizona State University, Phoenix, AZ, USA.

Background: The high prevalence of cognitive dysfunction is well documented in individuals with Down syndrome. However, only a few studies have focused on the effect of exercise on cognitive performance in this population. In particular, verbal fluency has been shown to be relevant to the early onset of Alzheimer's disease in individuals with Down syndrome. Read More

Nat Rev Neurol 2019 03;15(3):135-147

Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. Amyloid-β accumulates in the brain across the lifespan of people with DS, which provides a unique opportunity to understand the temporal progression of AD and the epigenetic factors that contribute to the age of dementia onset. Read More

Alzheimers Dement (N Y) 2018 13;4:703-713. Epub 2018 Dec 13.

Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.

The discovery that adults with Down syndrome (DS) have neuropathological features identical to individuals with sporadic Alzheimer's disease (AD) played a key role in the identification of the amyloid precursor protein gene on chromosome 21 and resulted in the amyloid cascade hypothesis. Individuals with DS have a lifetime risk for dementia in excess of 90%, and DS is now acknowledged to be a genetic form of AD similar to rare autosomal-dominant causes. Just as DS put the spotlight on amyloid precursor protein mutations, it is also likely to inform us of the impact of manipulating the amyloid pathway on treatment outcomes in AD. Read More

Alzheimers Dement 2019 02 28;15(2):245-257. Epub 2018 Nov 28.

Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Division of Psychiatry, University College London, London, UK; The LonDownS Consortium, London, UK.

Introduction: Down syndrome (DS) is associated with an almost universal development of Alzheimer's disease. Individuals with DS are therefore an important population for randomized controlled trials to prevent or delay cognitive decline, though it is essential to understand the time course of early cognitive changes.

Methods: We conducted the largest cognitive study to date with 312 adults with DS to assess age-related and Alzheimer's disease-related cognitive changes during progression from preclinical to prodromal dementia, and prodromal to clinical dementia. Read More

JAMA Neurol 2019 02;76(2):152-160

Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England.

Importance: This work quantifies the fatal burden of dementia associated with Alzheimer disease in individuals with Down syndrome (DS).

Objective: To explore the association of dementia associated with Alzheimer disease with mortality and examine factors associated with dementia in adults with DS.

Design, Settings And Participants: Prospective longitudinal study in a community setting in England. Read More

JAMA Neurol 2019 02;76(2):142-143

Down Syndrome Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

J Alzheimers Dis 2019 ;67(1):103-112

Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Cerebrovascular pathology is a significant mediator in Alzheimer's disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2-83 years). Read More

Transl Neurodegener 2018 6;7:28. Epub 2018 Nov 6.

1Department of Biochemical Sciences, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Read More

Brain Behav Immun 2019 01 25;75:163-180. Epub 2018 Oct 25.

The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel; The Paul Feder Laboratory on Alzheimer's Disease Research, Bar-Ilan University, Ramat Gan 5290002, Israel. Electronic address:

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Read More

Neurobiol Aging 2019 01 27;73:171-176. Epub 2018 Sep 27.

Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA. Electronic address:

Down syndrome (DS) predisposes individuals to early Alzheimer's disease (AD). Using Pittsburgh Compound B ([C]PiB), a pattern of striatal amyloid beta (Aβ) that is elevated relative to neocortical binding has been reported, similar to that of nondemented autosomal dominant AD mutation carriers. However, it is not known whether changes in striatal and neocortical [C]PiB retention differ over time in a nondemented DS population when compared to changes in a nondemented elderly (NDE) population. Read More

Tijdschr Gerontol Geriatr 2018 Oct 20;49(5):187-205. Epub 2018 Sep 20.

Afdeling Neurologie en Alzheimer Onderzoekscentrum, Universitair Medisch Centrum Groningen, Rijksuniversiteit Groningen, postbus 30.001, 9700 RB, Groningen, Nederland.

Behavioral and psychological symptoms of dementia (BPSD) have not been comprehensively studied in people with Down syndrome, despite their high risk on dementia. A novel evaluation scale was developed to identify the nature, frequency and severity of behavioral changes (83 behavioral items in 12 clinically defined sections). Central aim was to identify items that change in relation to the dementia status. Read More

Mol Psychiatry 2018 12 31;23(12):2363-2374. Epub 2018 Aug 31.

Mitchell Center for Alzheimer's Disease and Related Brain Disorders. Department of Neurology, University of Texas Medical School at Houston, Houston, TX, USA.

The typical abnormalities observed in the brain of Alzheimer's disease (AD) patients include synaptic alterations, neuronal death, brain inflammation, and the accumulation of protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Despite the development of many animal and in vitro models for AD, there is a lack of an experimental approach that fully recapitulates essential aspects of the disease in human cells. Here, we report the generation of a new model to study AD, consisting of cerebral organoids (COs) produced from human-induced pluripotent stem cells (iPSCs). Read More

Brain Dev 2019 Jan 4;41(1):106-110. Epub 2018 Aug 4.

Department of Child Neurology, Tokyo Metropolitan Tobu Medical Center for Persons with Developmental/Multiple Disabilities, Japan.

The average lifespan of individuals with Down syndrome has approximately doubled over the past three decades to 55-60 years. To reveal the pathogenic process of Alzheimer-type dementia in individuals with Down syndrome, we immunohistochemically examined senile plaque formation in the cerebral cortex in the autopsy brain and compared findings with our previous studies. We described a 52-year-old female with Down syndrome who developed progressively more frequent myoclonus following cognitive decline and died at the age of 59 years. Read More

JAMA Neurol 2018 11;75(11):1399-1406

Global Brain Health Institute, University of California, San Francisco.

Importance: As the life expectancy of people with Down syndrome (DS) has markedly increased over the past decades, older adults with DS may be experiencing a higher incidence of aging conditions. In addition to longevity, the amyloid precursor protein gene located on chromosome 21 places individuals with DS at a high risk for developing Alzheimer disease. Yet, few studies have determined prevalence of dementia and comorbidities among older people with DS. Read More

Acta Neuropathol Commun 2018 07 4;6(1):56. Epub 2018 Jul 4.

Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences University of Manchester, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, England.

While post mortem studies have identified the major cell types and functional systems affected in Alzheimer's disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal 'model system' in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored. In the present study we have examined the brains of 56 individuals with DS ranging from new-born to 76 years for the presence of amyloid and tau pathology in key cortical and subcortical regions. Read More

Mol Genet Genomic Med 2018 09 3;6(5):855-860. Epub 2018 Jul 3.

KTO-Special Welfare District of Varsinais-Suomi, Paimio, Finland.

Background: Intellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups.

Methods: Using the British Present Psychiatric State-learning Disabilities assessment (PPS-LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35 year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively. Read More

Brain 2018 08;141(8):2457-2474

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG UK.

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. Read More

Neuroimage Clin 2018 28;18:160-166. Epub 2018 Jan 28.

Specialized Service in Mental Health and Intellectual Disability, Institut Assistència Sanitària (IAS), Parc Hospitalari Martí i Julià, 17190 Girona, Spain.

Background: We longitudinally assessed Down syndrome individuals at the age of risk of developing dementia to measure changes in brain anatomy and their relationship to cognitive impairment progression.

Methods: Forty-two Down syndrome individuals were initially included, of whom 27 (mean age 46.8 years) were evaluable on the basis of completing the 2-year follow-up and success in obtaining good quality MRI exams. Read More

Alzheimers Dement (Amst) 2018 23;10:99-111. Epub 2017 Nov 23.

Department of Neurology and Alzheimer Research Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Introduction: People with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS.

Methods: Noradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Read More

Acta Neuropathol 2018 10 16;136(4):569-587. Epub 2018 May 16.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, UK.

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Read More

Brain Behav Immun 2018 10 31;73:235-251. Epub 2018 May 31.

Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain. Electronic address:

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e. Read More