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Front Neurosci 2022 7;16:909669. Epub 2022 Jun 7.

UK Dementia Research Institute at University College London, London, United Kingdom.

There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. Read More

Biomedicines 2022 Jun 10;10(6). Epub 2022 Jun 10.

CNRS, UMR 8251, Biologie Fonctionnelle et Adaptative (BFA), Université Paris Cité, 75013 Paris, France.

Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of developing early onset Alzheimer's disease dementia. DYRK1A, a proline-directed serine/threonine kinase, whose gene is located on chromosome 21, has recently emerged as a promising plasma biomarker in patients with sporadic Alzheimer's disease (AD). Read More

Alzheimers Dement (Amst) 2022 25;14(1):e12324. Epub 2022 May 25.

Department of Psychiatry and Human Behavior University of California Irvine Irvine California USA.

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. Read More

J Neurodev Disord 2022 May 24;14(1):33. Epub 2022 May 24.

Institute for Behavioral Genetics, University of Colorado Boulder, 1480 30th Street, Boulder, CO, 80309-0447, USA.

Background: Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer's disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology that appear symptomatic of DS, AD, and aging. Read More

JAMA Netw Open 2022 May 2;5(5):e2212910. Epub 2022 May 2.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Importance: People with Down syndrome have a high risk of developing Alzheimer disease dementia. However, penetrance and age at onset are considered variable, and the association of this disease with life expectancy remains unclear because of underreporting in death certificates.

Objective: To assess whether the variability in symptom onset of Alzheimer disease in Down syndrome is similar to autosomal dominant Alzheimer disease and to assess its association with mortality. Read More

PLoS One 2022 11;17(5):e0262558. Epub 2022 May 11.

UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom.

Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer's disease, characterised by the accumulation in the brain of amyloid-β plaques. Amyloid-β is a product of the processing of the amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-β accumulation is within endosomes, and changes to endosome biology occur early in Alzheimer's disease. Read More

JAMA Neurol 2022 Jun;79(6):565-574

Department of Neuroscience, University of California, San Diego, San Diego.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Read More

J Alzheimers Dis 2022 ;87(2):595-607

Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada.

Background: Down syndrome (DS) is frequently associated with Alzheimer's disease (AD)-related neuropathological changes. There are few observations on the spectrum of mixed proteinopathies in DS patients.

Objective: This study aimed to evaluate multiple disease-associated proteinopathies in a series of DS cases. Read More

Int J Geriatr Psychiatry 2021 Dec 24;37(2). Epub 2021 Dec 24.

Little Bookham, Surrey, UK.

Background: Individuals with Down syndrome (DS) are at significant risk for early onset Alzheimer's disease (AD), likely due to the triplication of genes on chromosome 21 that facilitate AD neuropathology. To aid the effective early diagnosis of dementia in DS, we demonstrate the strategy of using single point assessment of cognitive performance with scoring normed for degree of intellectual disability to generate age related prevalence data for acquired mild cognitive impairment (AMCI).

Methods: Four hundred and twelve adults with DS were assessed using the Neuropsychological Assessment of dementia in adults with Intellectual Disability. Read More

Acta Neuropathol Commun 2022 01 4;10(1). Epub 2022 Jan 4.

Center for Cognitive Neurology, Departments of Neurology, Pathology and Psychiatry, NYU Grossman School of Medicine, New York, NY, 10016, USA.

The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21-linked early-onset Alzheimer's disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26-72 years of age were to identify the magnitude of brain region-specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. Read More

Front Psychiatry 2021 14;12:749046. Epub 2021 Dec 14.

Research Unit Developmental Psychology, Department of Developmental and Educational Psychology, Faculty of Psychology, University of Vienna, Vienna, Austria.

Down syndrome (DS) is the most prevalent neurodevelopmental disorder, with a known genetic cause. Besides facial dysmorphologies and congenital and/or acquired medical conditions, the syndrome is characterized by intellectual disability, accelerated aging, and an increased likelihood of an early onset Alzheimer's disease in adulthood. These common patterns of DS are derived from the long-held standard in the field of DS research, that describes individuals with DS as a homogeneous group and compares phenotypic outcomes with either neurotypical controls or other neurodevelopmental disorders. Read More

Acta Neuropathol Commun 2021 12 27;9(1):201. Epub 2021 Dec 27.

Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA, 94158, USA.

Amyloid beta (Aβ) is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). Prion-like Aβ polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aβ that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Read More

Res Dev Disabil 2022 Feb 27;121:104148. Epub 2021 Dec 27.

Faculty of Psychology, University of Vienna, Vienna, Austria.

Background: Dementia in people with intellectual disability (ID) is frequent but hard to recognise. Evidence-based recommendations for suitable instruments are lacking.

Aims: The present study set out to evaluate informant-based dementia assessment instruments and to provide evidence-based recommendations for instruments most suitable in clinical practice and research. Read More

Neuroimage Clin 2022 10;33:102908. Epub 2021 Dec 10.

School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Waisman Center, Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA.

Introduction: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. Read More

Alzheimers Dement 2021 Nov 23. Epub 2021 Nov 23.

Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Rome, Italy.

Introduction: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing.

Methods: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. Read More

J Intellect Disabil Res 2021 12 16;65(12):1085-1096. Epub 2021 Nov 16.

Department of Neurology, University of Kentucky, Lexington, KY, USA.

Background: Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer's disease. However, many measures regularly used for the detection of dementia in the general population are not suitable for individuals with DS due in part to floor effects. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT) and Dementia Scale for People with Learning Disabilities (DLD), have been used in clinical trials and other research with this population. Read More

J Alzheimers Dis 2022 ;85(1):153-165

Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.

Background: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS.

Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS?

Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51. Read More

F1000Res 2020 5;9:1299. Epub 2020 Nov 5.

BioScience Project, PO Box 352, Wakefield, MA, 01880, USA.

People with Down Syndrome (DS) are born with an extra copy of Chromosome (Chr) 21 and many of these individuals develop Alzheimer's Disease (AD) when they age. This is due at least in part to the extra copy of the APP gene located on Chr 21. By 40 years, most people with DS have amyloid plaques which disrupt brain cell function and increase their risk for AD. Read More

Res Dev Disabil 2021 Nov 28;118:104068. Epub 2021 Aug 28.

Institut Jérôme Lejeune, Paris, France.

Background: People with Down Syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD) relatively early in life. The dementia screening questionnaire for individuals with intellectual disabilities (DSQIID) has been developed for people with intellectual disabilities and was shown to have high discriminative power to distinguish between people with and without dementia. The objective of this study was to verify if the French version of the DSQIID (DSQIID-F) had a good diagnostic specificity and to determine the optimal cut-off for screening people with DS for dementia. Read More

Sci Rep 2021 08 30;11(1):17377. Epub 2021 Aug 30.

Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Down syndrome (DS) is caused by the trisomy of chromosome 21. Among the many disabilities found in individuals with DS is an increased risk of early-onset Alzheimer's disease (AD). Although higher oxidative stress and an upregulation of amyloid β (Aβ) peptides from an extra copy of the APP gene are attributed to the AD susceptibility, the relationship between the two factors is unclear. Read More

Mol Syndromol 2021 Jul 20;12(4):202-218. Epub 2021 May 20.

Boston University, Boston, Massachusetts, USA.

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Read More

Med Hypotheses 2021 Sep 19;154:110645. Epub 2021 Jul 19.

Harvard Medical School Multi-Campus Geriatric Fellowship, Boston, Massachusetts, USA. Electronic address:

Alzheimer's disease (AD) is a progressive incurable neurodegenerative disease of the brain afflicting a third of the population aged 85 and older. Pathologic hallmarks include extracellular plaques of amyloid-beta (Aß), intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein, synaptic destruction, neuronal death, and brain atrophy. Neuroinflammation, mediated by microglia, is a central component of the disease, and is intricately connected with peripheral inflammation. Read More

Lancet Neurol 2021 08;20(8):615-626

Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease.

Methods: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. Read More

Lancet Neurol 2021 08;20(8):605-614

Sant Pau Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain; Horizon 21 Consortium, Paris, France. Electronic address:

Background: Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.

Methods: We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Read More

J Clin Med 2021 Jul 15;10(14). Epub 2021 Jul 15.

Department of Neurology, Harvard Medical School, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA.

Adults with Down syndrome (DS) have an exceptionally high prevalence of Alzheimer disease (AD), with an earlier age of onset compared with the neurotypical population. In addition to beta amyloid, immunological processes involved in neuroinflammation and in peripheral inflammatory/autoimmune conditions are thought to play important roles in the pathophysiology of AD. Individuals with DS also have a high prevalence of autoimmune/inflammatory conditions which may contribute to an increased risk of early AD onset, but this has not been studied. Read More

Nat Commun 2021 07 14;12(1):4304. Epub 2021 Jul 14.

Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. Read More

JAMA Neurol 2021 08;78(8):937-947

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce.

Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. Read More

Neuroimage Clin 2021 24;31:102740. Epub 2021 Jun 24.

University of Wisconsin-Madison Waisman Center, Madison, WI, USA; University of Wisconsin-Madison Department of Medical Physics, Madison, WI, USA.

Introduction: Adults with Down syndrome are genetically predisposed to develop Alzheimer's disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. Read More

Dement Geriatr Cogn Dis Extra 2021 May-Aug;11(2):140-150. Epub 2021 Jun 8.

Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, accounting for 50-75% of all cases. While older maternal and paternal age at childbirth are established risk factors for Down syndrome which is associated with later AD, it is still not entirely clear whether parental age is a risk factor for AD. Previous studies have suggested contradictory findings. Read More

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. Read More