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Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome. We enrolled adults (aged 16–34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711. The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: −4·58 s [–8·54 to −0·62], p=0·024; d −0·27 [–0·72 to −0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [–0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups. EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

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. 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. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30–61 years) were analysed for markers of amyloid β (Aβ1–40, Aβ1–42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30–61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aβ1–42 to Aβ1–40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms). CSF biomarker profiles are useful for identifying and tracking Alzheimer's disease-related processes in Down syndrome and, as such, are likely to have use in clinical trial design in this understudied population at risk. National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.

Explains this genetic abnormality, its characteristics and how scientists are studying and treating it.

Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1–42 and 1–40 and their ratio (Aβ1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ1–42/1–40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life. Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

Recovering from surgery, Paul Clements and his wife, Felicity, spent a year in a remote cottage in the woodlands of Montalto Estate, Co. Down. Through the lens of a curious observer and a budding bird watcher, Clements describes in exquisite detail his discovery of the restorative power of nature.

Individuals with Down syndrome have a genetically determined form of Alzheimer's disease, due to an additional copy of the APP gene. Nearly all individuals with Down syndrome develop Alzheimer's disease pathology by age 40 years, and approximately 70% are diagnosed with dementia by around age 54 years, with an overall lifetime risk of 95%. Moreover, Alzheimer's disease is the leading cause of death in adults with Down syndrome older than 35 years. The intersection of Down syndrome and Alzheimer's disease has garnered substantial attention in the past 10 years as research indicates that the trajectory of clinical symptoms and biomarker changes in adults with Down syndrome closely resembles that seen in late-onset Alzheimer's disease and autosomal-dominant Alzheimer's disease (ADAD). The predictive nature of dementia onset in genetically determined populations allows precise staging of disease in individuals along the Alzheimer's disease continuum. The high prevalence of Alzheimer's disease pathology combined with the few age-related comorbidities in these cohorts, makes them ideal for understanding the biological mechanisms related to late-onset Alzheimer's disease. The more rapid disease progression seen in people with Down syndrome-related Alzheimer's disease compared with people with ADAD or late-onset Alzheimer's disease provides important insights and supports the rationale for new clinical trials. The Alzheimer's Clinical Trials Consortium–Down Syndrome is ushering in a new era of therapies for individuals with Down syndrome. Three ongoing clinical trials, in close collaboration with industry partners, specifically designed for this population, are focused on testing disease-modifying treatments. These innovative efforts mark a considerable stride in bringing groundbreaking therapies to a group that has long been excluded from clinical trials in Alzheimer's disease.