Articles Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study Juan Fortea, Eduard Vilaplana, Maria Carmona-Iragui, Bessy Benejam, Laura Videla, Isabel Barroeta, Susana Fernández, Miren Altuna, Jordi Pegueroles, Víctor Montal, Silvia Valldeneu, Sandra Giménez, Sofía González-Ortiz, Laia Muñoz, Teresa Estellés, Ignacio Illán-Gala, Olivia Belbin, Valle Camacho, Liam Reese Wilson, Tiina Annus, Ricardo S Osorio, Sebastián Videla, Sylvain Lehmann, Anthony J Holland, Daniel Alcolea, Jordi Clarimón, Shahid H Zaman, Rafael Blesa*, Alberto Lleó* Summary Lancet 2020; 395: 1988–97 Background Alzheimer’s disease and its complications are the leading cause of death in adults with Down syndrome. See Comment page 1951 Studies have assessed Alzheimer’s disease in individuals with Down syndrome, but the natural history of biomarker *Contributed equally changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers Barcelona Down Medical of Alzheimer’s disease in a population of adults with Down syndrome. Center, Fundació Catalana de Síndrome de Down, Barcelona, Methods We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population- Spain (J Fortea PhD, M Carmona-Iragui PhD, based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge B Benejam BSc, L Videla MSc, (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive S Fernández MD); Sant Pau Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate Memory Unit, Department of disability were included who had at least one of the following Alzheimer’s disease measures: apolipoprotein E allele Neurology, Hospital de la Santa Creu i Sant Pau, carrier status; plasma concentrations of amyloid β peptides 1–42 and 1–40 and their ratio (Aβ1–42/1–40), total tau protein, Biomedical Research Institute and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid Sant Pau, Universitat (CSF); and one or more of PET with ¹⁸F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy Autònoma de Barcelona, euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative Barcelona, Spain (J Fortea, E Vilaplana PhD, on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order M Carmona-Iragui, B Benejam, and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported L Videla, I Barroeta PhD, where appropriate. M Altuna MD, J Pegueroles MSc, V Montal MSc, S Valldeneu, L Muñoz BSc, T Estellés MD, Findings Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), I Illán-Gala PhD, O Belbin PhD, we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer’s D Alcolea PhD, J Clarimón PhD, disease, and 83 [21%] with Alzheimer’s disease dementia) and 242 euploid controls. CSF Aβ1–42/1–40 and plasma NFL R Blesa PhD, A Lleó PhD); Center values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake of Biomedical Investigation Network for changed in the fourth decade. ¹⁸F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth Neurodegenerative Diseases, decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Madrid, Spain (J Fortea, Alzheimer’s disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer’s disease E Vilaplana, M Carmona-Iragui, dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer’s disease prevalence increased with age in individuals B Benejam, L Videla, I Barroeta, M Altuna, J Pegueroles, V Montal, with Down syndrome, reaching 90–100% in the seventh decade of life. S Valldeneu, L Muñoz, T Estellés, I Illán-Gala, O Belbin, D Alcolea, Interpretation Alzheimer’s disease in individuals with Down syndrome has a long preclinical phase in which J Clarimón, R Blesa, A Lleó); biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and Multidisciplinary Sleep Unit, Respiratory Department autosomal dominant Alzheimer’s disease and the prevalence of Down syndrome make this population a suitable (S Giménez PhD), and Nuclear target for Alzheimer’s disease preventive treatments. Medicine Department (V Camacho PhD), Hospital de la Santa Creu i Sant Pau, Funding Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Barcelona, Spain; Parc de Salut, Council, and National Institutes of Health. Hospital del Mar, Barcelona, Spain (S González-Ortiz PhD); Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 Cambridge Intellectual and Developmental Disabilities license. Research Group, Department of Psychiatry, Douglas House, Introduction particularly Alzheimer’s disease. The lifetime risk of University of Cambridge, Down syndrome (also referred to as trisomy 21) is the Alzheimer’s disease in people with Down syndrome is Cambridge, UK (L R Wilson PhD, T Annus PhD, A J Holland MD, most frequent form of genetic developmental and now more than 90%,3 and the disease is the leading cause S H Zaman PhD); Center for intellectual disability, affecting 5·8 million people of death in this population.4 The strong association Sleep and Brain Health, worldwide.1 Life expectancy for people with Down between Down syndrome and Alzheimer’s disease has a Department of Psychiatry, syndrome has greatly increased because of improved genetic basis through a gene-dose effect of amyloid β (Aβ) New York University Langone Health, New York, NY, USA medical care, exceeding 60 years of age.2 Consequently, precursor protein, which is located on chromosome 21 (R S Osorio MD); Clinical age-related comorbidities in this group have emerged, and is overexpressed in people with Down syndrome.1 1988 www.thelancet.com Vol 395 June 27, 2020 Articles Research Support Unit, Research in context Bellvitge Biomedical Research Institute, Department of Evidence before this study in adults with Down syndrome. Biomarker changes begin more Clinical Pharmacology, We searched and reviewed the literature using PubMed, than two decades before Alzheimer’s disease dementia onset in University of Barcelona, meeting abstracts, and presentations. We searched PubMed on a strikingly similar order and timing to that described in Barcelona, Spain (Prof S Videla PhD); Institute for Nov 30, 2018, for research studies on established Alzheimer’s patients with autosomal dominant Alzheimer’s disease. Regenerative Medicine & disease biomarkers in the plasma and cerebrospinal fluid Biotherapy, Université de Implications of all the available evidence (CSF; amyloid β (Aβ), tau protein, and neurofilament light Montpellier, INSERM, Centre Our study supports people with Down syndrome as a suitable Hospitalier Universitaire de protein [NFL]), MRI, or PET in people with Down syndrome population for clinical trials for Alzheimer’s disease. Montpellier, (LBPC-PPC), using the search terms “biomarker” OR “plasma” OR “CSF” OR The description of the natural history of Alzheimer’s disease in Montpellier,France “MRI” OR “PET” AND “Down Syndrome” AND (“Alzheimer’s” or (Prof S Lehmann MD); and this population would have an immediate effect on the design “dementia”). Several previous studies in Down syndrome have Cambridgeshire & of such trials. It would also have implications in clinical practice Peterborough NHS Foundation assessed Aβ brain deposition with PET tracers, studied plasma because it supports the concept of Down syndrome as a form of Trust, Fulbourn Hospital, and CSF biomarkers, or described the atrophy and cerebral Elizabeth House, Cambridge, genetically determined Alzheimer’s disease with a predictable metabolic Alzheimer’s disease patterns. However, we found no UK (S H Zaman) sequence of biomarker changes. previous multimodal studies assessing the natural history of Correspondence to: Alzheimer’s disease in individuals with Down syndrome. Dr Juan Fortea, Department of Neurology, Hospital de la Added value of this study Santa Creu i Sant Pau, To our knowledge, this is the first large multimodal biomarker 08025 Barcelona, Spain jfortea@santpau.cat study to characterise the natural history of Alzheimer’s disease Consequently, Down syndrome is now conceptualised as of Cambridge, UK). Adults aged 18 years or older with a form of genetically determined Alzheimer’s disease, Down syndrome in Barcelona were recruited from a similar to its autosomal dominant form.5 population-based health plan designed to screen for Alzheimer’s disease pathology has been described in Alzheimer’s disease dementia, which includes yearly all adults with full trisomy 21 by the age of 40 years, and neurological and neuropsychological assessments. Indi­ its hallmarks are qualitatively similar to those of sporadic viduals in this plan interested in research studies are Alzheimer’s disease.6 Increasing evidence from bio­ included in the Down Alzheimer Barcelona Neuroimaging marker studies also suggest that the pathophysiology of Initiative cohort.14 In Cambridge, participants with Down the disease in Down syndrome is similar to that of the syndrome were recruited through services for people sporadic and autosomal dominant forms of Alzheimer’s with intellectual disabilities in England and Scotland, disease.7,8 Several studies in individuals with Down with the support of the UK Down Syndrome Association.12 syndrome have assessed Aβ brain deposition with PET We included all adults with Down syndrome who had at tracers, studied plasma and cerebrospinal fluid (CSF) least one biochemical or imaging Alzheimer’s disease biomarkers, or described the atrophy and cerebral biomarker. For euploid controls, we recruited non- metabolic patterns of Alzheimer’s disease.9–14 Although trisomic individuals aged 18 years or older up to 75 years longitudinal studies of Alzheimer’s disease in individuals from the Sant Pau Initiative on Neurodegeneration.20 with Down syndrome exist,15 the natural history of Euploid controls underwent a structured neurological biomarker changes in Down syndrome has not been assessment and a comprehensive battery of neuropsy­ established.1,8,16–18 In this study, we assessed the order and chological tests to establish normal cognitive health. timing of Alzheimer’s disease biomarker changes in a Inclusion criteria were normal neuropsychological results large cohort of adults with Down syndrome. We used for their age and education level, a Clinical Dementia For the Clinical Dementia biochemical, neuroimaging, and cognitive measures Rating Scale score of 0, and normal levels of Alzheimer’s Rating Scale see https://www. madrc.org/clinical-dementia- covering all three categories of the AT(N) biomarker disease biomarkers in CSF.20 rating-cdr-scale system (assessing deposition of Aβ, hyperphosphory­ The study was approved by the Sant Pau and the lated tau, and neurodegeneration).19 Understanding this Cambridge Research Ethics Committees, following pattern of changes is crucial for the design of trials in the standards for medical research in humans recom­ Down syndrome aimed at preventing or moderating the mended by the Declaration of Helsinki. All participants progression of Alzheimer’s disease.8 or their legally authorised representative gave written informed consent before enrolment. Methods Study design and participants Procedures We did a dual-centre cross-sectional study of adults with For the purpose of dementia diagnosis, we provided the Down syndrome and euploid controls in Barcelona participants’ caregivers with a semi-structured adapted (Hospital of Sant Pau, Spain) and Cambridge (University health questionnaire, the Cambridge Examination for www.thelancet.com Vol 395 June 27, 2020 1989 Articles Mental Disorders of Older People with Down Syndrome platform (Lumipulse, Fujirebio-Europe, Ghent, Belgium).20 and others with intellectual disabilities (CAMDEX-DS) CSF NFL concentrations were measured with a commer­ developed in Cambridge, with a version adapted for the cial ELISA (UmanDiagnostics, Umeå, Sweden), following Spanish population. The CAMDEX-DS includes a com­ the manufacturer’s recommendations. All CSF samples prehensive cognitive battery of neuropsychological tests, were analysed at Hospital Sant Pau (appendix p 7). Methods the Cambridge Cognitive Examination for Older Adults and findings from plasma and CSF biomarkers have been with Down Syndrome (CAMCOG-DS), that covers seven published previously,14 but the age-related changes were different cognitive domains.21 We classified participants not assessed. All participants from our paper assessing the with Down syndrome into asymptomatic, having prodro­ diagnostic performance5 have been included in this Article. mal Alzheimer’s disease, or having Alzheimer’s disease Notably, the methods for CSF biomarker measurement dementia, in a consensus meeting between the neurol­ differs between the two studies (we used a commercially ogist or psychiatrist and the neuropsychologists who available ELISA in the previous study, but the Lumipulse assessed the participants while masked to biomarker fully automated platform for this study). Additionally, in data, as previously described.14 Because of the floor effects this study, we have included 66 new plasma samples and of the CAMCOG-DS in adults with Down syndrome with 47 new CSF samples from adults with Down syndrome severe and profound levels of intellectual disability,21 and 56 new plasma samples and 160 new CSF samples we only included participants with mild or moderate from control participants. intellectual disability in this analysis. We stratified the level of intellectual disability according to the Diagnostic Statistical analysis and Statistical Manual of Mental Disorders (fifth edition)22 We assessed differences in baseline characteristics as mild, moderate, or severe or profound (which were between the diagnostic groups with the Kruskal-Wallis grouped together) on the basis of the individuals’ best- test and a pairwise Wilcoxon test corrected for multiple ever level of functioning, as determined from carers’ comparisons. To determine the order and temporality of reports. The information was obtained through family the biomarker changes and cognitive decline in partic­ interviews and review of medical or educational records ipants with Down syndrome, we fitted a first-order locally for past assessment results. estimated scatterplot smoothing curve for controls and We screened patients for trisomy 21 using the Illumina adults with Down syndrome indepen­ dently.16,28 The Infinium Global Screening Array (Illumina, San Diego, model uses a standard tricubic weight function with a CA, USA) as previously described.14 We also determined span parameter to 0·75. The exact age at which the apolipoprotein E (APOE)-ε4 allele carrier status through intervals diverge is dependent on intrinsic limitations of detection of polymorphisms rs429358 and rs7412 in exon studies assessing the natural history of biomarkers, such 4 via Sanger sequencing.7,14 as the nature of the variable, the sensitivity of the assay, A subset of participants underwent a 3 Tesla MRI, a the slope of the association, and, in our study, the uneven ¹⁸F-fluorodeoxyglucose PET, amyloid PET, or a combi­ sample sizes for the different biomarkers. Therefore, nation of these acquisitions. The amyloid tracer used was we defined biomarker change as the age at which the ¹⁸F-florbetapir in Barcelona and ¹¹C-Pittsburg compound groups appear to start diverging visually. Nonetheless, B in Cambridge. Structural T1 MRI was processed with we also provide the lower age at which the 95% CIs For Freesurfer see https://surfer. Freesurfer (version 6)23 to extract the adjusted hippocampal between groups did not overlap. When neurodevelop­ nmr.mgh.harvard.edu/ volumes (appendix pp 3–4).24 ¹⁸F-fluorodeoxyglucose and mental differences were present (different offsets such as See Online for appendix ¹⁸F-florbetapir PET images were co-registered to the hippocampal volumes in the youngest individuals) individual MRI, and standardised uptake value ratios were or when no data were available for the controls (eg, extracted from the corresponding Landau regions.25,26 CAMCOG-DS scores), we visually described only the Methods and findings from amyloid PET or CT scans in trajectory in adults with Down syndrome. the Cambridge cohort have been published previously,12 To compare the timing of changes in Down syndrome but data were reanalysed and converted to the Centiloid and autosomal dominant Alzheimer’s disease, we scale and combined with the Barcelona ¹⁸F-florbetapir data presented the biomarker changes both according to the following standard procedures (appendix pp 5–6).27 chronological age and with respect to the median age of CSF and blood samples were acquired concurrently on diagnosis of prodromal Alzheimer’s disease (referred in the same day. Plasma concentrations of Aβ 1–42 (Aβ1–42) this study as expected symptom onset). and Aβ1–40, total tau protein, and neurofilament light chain All statistical analyses were done with R statistical (NFL) were measured using single molecule array (Simoa; software. Further details for the statistical methods can Quanterix, Billerica, MA, USA) at Centre Hospitalier be found in the appendix (pp 7–8). Universitaire Montpellier (Montpellier, France)14 or at Hospital of Sant Pau (Barcelona, Spain). CSF concen­ Role of the funding source trations of Aβ1–42, Aβ1–40, tau phosphorylated at threonine The funders of the study had no role in study design, data 181 (p-tau), and total tau were quantified with a com­ collection, data analysis, data interpretation, or writing of mercially available immunoassay in a fully auto­ mated the report. The corresponding author had full access to all 1990 www.thelancet.com Vol 395 June 27, 2020 Articles the data in the study and had final responsibility for the 53·7 years (49·5–57·2) for Alzheimer’s disease dementia. decision to submit for publication. The prevalence of symptomatic Alzheimer’s disease (prodromal Alzheimer’s disease and Alzheimer’s disease Results dementia combined) increased exponentially from age Between Feb 1, 2013, and June 28, 2019 (Barcelona), and 40 years onwards, reaching 90–100% prevalence by the between June 1, 2009, and Dec 31, 2014 (Cambridge), we end of the seventh decade of life (figure 1). The evolution recruited participants with Down syndrome and euploid of the different bio­markers along the Alzheimer’s dis­ controls (appendix p 3). We recruited and included ease continuum (asymptomatic, pro­dromal Alzheimer’s 388 adults with Down syndrome (347 in Barcelona and disease, and Alzheimer’s disease dementia) is shown in 41 in Cambridge) and 242 euploid controls (recruited in the appen­dix (p 11). Barcelona) in our study. 174 (45%) of 388 participants We plotted the scores on the CAMCOG scale as a with Down syndrome and 162 (67%) of 242 controls were function of age in individuals with mild and moderate women (table). 308 participants with Down syndrome intellectual disability separately (figure 1). Although were screened for trisomy 21; genetic confirmation neuropsychological performance cannot be directly of trisomy 21 was not available for 80 participants. Of compared between individuals with Down syndrome participants with Down syndrome, 72 (19%) had mild and controls, a visual inspection showed a decline in intellectual disability, 175 (45%) had moderate, and CAMCOG scores starting at about age 40 years in 98 (25%) had severe or profound. The number of adults individuals with Down syndrome, particularly in partic­ with Down syndrome and controls was different for each ipants with moderate intellectual disability, which is biomarker method (appendix p 9). 10 years before the median age of diagnosis of prodromal We observed no clinical evidence of dementia in Alzheimer’s disease (figure 1). 257 (66%) of the 388 participants with Down syndrome. We compared the pattern of cortical atrophy in Of the remaining, 48 (12%) had prodromal Alzheimer’s individuals with Down syndrome who had symptomatic disease and 83 (21%) had Alzheimer’s disease demen­ Alzheimer’s disease with that in individuals who were tia. The median age of diagnosis was 50·2 years asymptomatic (figure 2). Compared with participants who (IQR 47·5–54·1) for prodromal Alzheimer’s disease and were asymptomatic, those who were symptomatic showed Asymptomatic Prodromal Alzheimer’s Alzheimer’s disease dementia Controls p value (n=257) disease (n=48) (n=83) (n=242) Age, years 38·7 (31·1 to 48·2) 50·2 (47·5 to 54·1) 53·7 (49·5 to 57·2) 56·6 (50·4 to 63·8) <0·0001 Sex ·· ·· ·· ·· <0·0001 Men 144 (56%) 26 (54%) 44 (53%) 80 (33%) NA Women 113 (44%) 22 (46%) 39 (47%) 162 (67%) NA APOE-ε4 carriers 46 (19%) 11 (23%) 15 (20%) 67 (29%) 0·10 Level of intellectual disability ·· ·· ·· ·· <0·0001 Mild 62 (27%) 6 (14%) 4 (5%) NA NA Moderate 114 (50%) 19 (45%) 42 (56%) NA NA Severe or profound 52 (22%) 17 (40%) 29 (38%) NA NA CAMCOG-DS score (n=225) Mild (n=67) 88 (82 to 91) 80 (76 to 82) 70 (66 to 75) NA <0·0001 Moderate (n=158) 75 (65 to 82) 65 (60 to 73) 41 (18 to 55) NA <0·0001 CSF Aβ1–42/1–40 (n=265) 0·078 (0·062 to 0·093) 0·042 (0·046 to 0·050) 0·046 (0·042 to 0·055) 0·106 (0·101 to 0·111) <0·0001 CSF NFL (n=230) 368·7 (233·7 to 523·1) 667·4 (484·0 to 1013·6) 1139·2 (757·3 to 1436·3) 400·0 (338·6 to 544·6) <0·0001 CSF p-tau (n=272) 30·0 (18·5 to 59·0) 110·4 (67·3 to 186·2) 155·3 (100·4 to 192·8) 32·5 (26·1 to 43·7) <0·0001 Plasma Aβ1–42 (n=435) 14·2 (12·2 to 16·4) 14·1 (11·9 to 15·8) 14·5 (12·5 to 17·0) 9·0 (7·7 to 10·1) <0·0001 Plasma NFL (n=431) 6·0 (4·6 to 10·3) 13·3 (10·7 to 18·5) 22·3 (17·2 to 30·0) 4·4 (3·3 to 6·2) <0·0001 Plasma total tau (n=427) 2·5 (2·0 to 3·1) 3·3 (2·4 to 4·0) 4·0 (2·9 to 5·0) 2·2 (1·7 to 3·4) <0·0001 Centiloid amyloid PET (n=108)* 6·4 (2·0 to 15·7) 64·7 (44·9 to 84·8) 72·6 (53·6 to 97·8) –1·9 (–10·9 to 4·4) <0·0001 FDG SUVR (n=197) 1·3 (1·3 to 1·4) 1·2 (1·1 to 1·3) 0·9 (0·8 to 1·1) 1·4 (1·3 to 1·5) <0·0001 Adjusted hippocampal volume 3 –0·14 (–0·50 to 0·27) –0·87 (–1·50 to –0·59) –1·86 (–2·37 to –1·03) 0·86 (0·35 to 1·40) <0·0001 Tesla MRI (n=330)† Data are n (%) or median (IQR). The n values on each row are the total number of assessments, including for both individuals with Down syndrome and controls. Percentages of APOE-ε4 carriers and level of intellectual disability were calculated according to the total of patients with available data in each group. CAMCOG-DS=Cambridge Cognitive Examination for Older Adults with Down Syndrome. Aβ1–40=amyloid β peptide 1–40. Aβ1–42=amyloid β peptide 1–42. CSF=cerebrospinal fluid. NFL=neurofilament light chain. p-tau=tau phosphorylated at threonine 181. FDG=¹⁸F-fluorodeoxyglucose. NA=not applicable. SUVR=standardised uptake value ratio. *n=74 with ¹⁸F-florbetapir and n=34 with ¹¹C-Pittsburg compound B. †With MRI. Table: Clinical, cognitive, imaging, and biochemical markers in individuals with Down syndrome and controls www.thelancet.com Vol 395 June 27, 2020 1991 Articles A decreased cortical thickness in the temporoparietal, Asymptomatic Prodromal Dementia precuneus-posterior cingulate, and frontal areas. 100 In the assessment of hippocampal atrophy with age, 90 adults with Down syndrome had smaller hippocampi across the whole lifespan than did controls (figure 3G). 80 A visual inspection of the data showed a steeper decline 70 in hippocampal volumes at the beginning of the fifth 60 decade of life in participants with Down syndrome, about Prevalence (%) 10 years before expected symptom onset. 50 A comparison of the pattern of cortical hypometabolism 40 in individuals who were symptomatic with those without 30 symptoms showed decreased glucose metabolism in the temporoparietal, precuneus-posterior cingulate, and 20 frontal areas in participants who were symptomatic 10 (figure 2). We assessed the trajectory with age of 0 the cerebral glucose metabolism as measured in the 18 20 25 30 35 40 45 50 55 60 65 70 Landau signature, which tracks early changes in sporadic Alzheimer’s disease (figure 3H).26 Visually, brain meta­ B bolism decreased in participants with Down syn­drome 100 starting from the earliest observed age. We observed a substantial further decrease in cerebral metabolism at 90 age 37·5 years (12·7 years before expected symptom 80 onset). 70 We compared the pattern of Aβ deposition in individuals who were symptomatic with that of indi­ CAMCOG-DS score 60 viduals without symptoms (figure 2). Participants who 50 were symptomatic showed increased global cerebral 40 Aβ deposition, with a relative sparing in sensory and motor areas. Amyloid PET uptake started to increase in 30 the latter half of the fourth decade of life, about 20 Moderate intellectual disability 12–15 years before expected symptom onset (figure 3I). Mild intellectual disability 10 Asymptomatic Notably, the curves for ¹¹C-Pittsburg compound B and Symptomatic ¹⁸F-florbetapir followed similar trajectories and had 0 18 20 25 30 35 40 45 50 55 60 65 70 overlapping CIs in the whole age span (appendix p 6). Age (years) Conversely, CSF Aβ1–42/1–40 values decreased in individuals with Down syndrome starting from the earliest observed Figure 1: Clinical and neuropsychological changes with age in adults with Down syndrome ages (third decade of life) and were significantly different (A) Point prevalence of Alzheimer’s disease dementia, prodromal Alzheimer’s disease, and no clinical symptoms of Alzheimer’s disease in individuals with Down syndrome. (B) Age-related changes in CAMCOG-DS scores in from those of controls from age 28 years onwards (22 years individuals with Down syndrome with mild or moderate intellectual disability (analysed separately), with bands before prodromal Alzheimer’s disease diagnosis), levelling representing 95% CIs. The vertical dashed line at 50·2 years represents the median age at the expected symptom off in the sixth decade of life (figure 3A). CSF concentrations onset (ie, prodromal Alzheimer’s disease diagnosis). CAMCOG-DS=Cambridge Cognitive Examination for Older of p-tau and NFL showed similar trajectories: visually, the Adults with Down Syndrome. concentrations of both biomarkers started increasing in the fourth decade of life in individuals with Down Atrophy Hypometabolism Amyloid β deposition syndrome (figures 3B, 3C). The CIs no longer overlapped for p-tau at age 39 years and for NFL at age 40 years (11–10 years before prodromal Alzheimer’s disease diagnosis). Total tau concentrations in participants with Down syndrome evolved similarly to p-tau (appendix p 10), showing differences at age 36 years. Plasma Aβ1–42 concentrations were 58% higher in p value p value p value adults with Down syndrome than in controls across the 10–2 10–12 10–2 10–10 10–2 10–8 whole age span (figure 3D) and did not differ between diagnostic groups (plasma Aβ1–42/1–40 concentrations are Figure 2: Imaging signature of Alzheimer’s disease in adults with Down syndrome for brain structure, shown in the appendix [p 10]). Plasma NFL concen­ glucose metabolism, and amyloid β deposition All panels compare individuals with Down syndrome with symptomatic Alzheimer’s disease with those with trations also increased visually from the earliest no clinical evidence of dementia. The left panel represents loss of cortical thickness, the middle panel loss of brain observed ages and were significantly different at age glucose metabolism, and the right panel the increase in cerebral fibrillar amyloid β deposition. 30 years (20 years before prodromal Alzheimer’s disease 1992 www.thelancet.com Vol 395 June 27, 2020 Articles A B C 0·125 300 2000 0·100 CSF phosphorylated tau (pg/mL) 200 CSF NFL (pg/mL) CSF Aβ1–42/1–40 0·075 1000 100 0·050 Down 0 syndrome 0 0·025 Controls D E F 30 15 60 Plasma total tau (pg/mL) 20 10 Plasma Aβ1–42 (pg/mL) Plasma NFL (pg/mL) 40 10 5 20 0 0 0 G H I 120 2·0 1·50 Adjusted hippocampal volume (cm3) 80 1·25 FDG-PET SUVR Centiloid scale 0 40 1·00 –2·0 0·75 0 0·50 20 30 40 50 60 70 80 20 30 40 50 60 70 80 20 30 40 50 60 70 80 Age (years) Age (years) Age (years) Figure 3: Biomarker changes with age in adults with Down syndrome and control participants Shading represents 95% CIs. The vertical dashed lines at 50·2 years represent the age at the expected symptom onset (eg, median age of prodromal Alzheimer’s disease diagnosis). Aβ1–40=amyloid β peptide 1–40. Aβ1–42=amyloid β peptide 1–42. CSF=cerebrospinal fluid. FDG=¹⁸F-fluorodeoxyglucose. NFL=neurofilament light chain. SUVR=standardised uptake value ratio. www.thelancet.com Vol 395 June 27, 2020 1993 Articles 3 CSF Aβ1–42/1–40 Alzheimer’s disease dementia, in a strikingly similar CSF p-tau order and timing to that described in autosomal dominant Plasma NFL Alzheimer’s disease.16,18 2 Hippocampal volume Amyloid β deposition Symptomatic Alzheimer’s disease prevalence in indi­ Glucose metabolism viduals with Down syndrome increased exponentially Standardised difference 1 CAMCOG-DS score with age in our study, reaching 90–100% in the seventh decade of life. The median age of diagnosis of prodromal 0 Alzheimer’s disease and clinical Alzheimer’s disease dementia in our study are in agreement with a large –1 study that used clinical records in the UK (mean age at dementia onset of 55·8 years, SD 6·3).29 The variability –2 in dementia onset in both ours and the UK-only study was less than that reported in the Colombian Kindred –3 study (mean age 38·5 years, SD 8·6), and similar to 0 20 30 40 50 60 70 those reported for the other mutations in autoso­ - Age (years) mal dominant Alzheimer’s disease.30 The prevalence Figure 4: Integrated model of the natural history of Alzheimer’s disease in estimates for Alzheimer’s disease dementia in cross- individuals with Down syndrome sectional and longitudinal studies show substantial Comparison of structural, metabolic, and biochemical biomarker changes as variability.1,3 Our study is among those with the highest a function of age by use of the standardised differences between participants estimates, probably because of our research protocol with Down syndrome and controls fitted with a locally estimated scatterplot smoothing curve. Positive standardised differences represent higher biomarker with comprehensive neuropsychological and neurological values in participants with Down syndrome than in euploid controls, and assessments, which allowed us to detect individuals with negative values represent lower biomarker values. The vertical dashed line at prodromal Alzheimer’s disease. 50·2 years represents the age at the expected symptom onset (median age Early clinicopathological studies and recent biomarker of prodromal Alzheimer’s disease diagnosis). Aβ1–40=amyloid β peptide 1–40. Aβ1–42=amyloid β peptide 1–42. CAMCOG-DS=Cambridge Cognitive studies have shown that Alzheimer’s disease pathology Examination for Older Adults with Down Syndrome. CSF=cerebrospinal fluid. and CSF and plasma biomarker changes in individuals NFL=neurofilament light chain. p-tau=tau phosphorylated at threonine 181. with Down syndrome are qualitatively the same as in sporadic Alzheimer’s disease.6,14 On one hand, the diagnosis; figure 3F). Plasma tau concentrations in patterns of cerebral Aβ deposition, atrophy, and hypo­ participants with Down syndrome and controls over­ metabolism in our study are similar to those found in lapped widely (figure 3E). The group comparisons previous reports, indicating that Alzheimer’s disease in for all the biomarkers along the Alzheimer’s disease individuals with Down syndrome targets the same continuum (asymptomatic vs prodromal Alz­ heimer’s cortical regions affected in the sporadic and autosomal disease vs Alzheimer’s disease dementia) are shown in dominant forms.9 On the other hand, cognitive perfor­ the appendix (p 11). mance and other biomarkers, such as plasma Aβ1–42 The changes in cognitive, biochemical, and imaging concentrations or hippocampal volumes, had clear biomarkers in individuals with Down syndrome different starting points in the youngest individuals expanded for more than 20 years (figure 4). At age (and throughout all ages). These abnormalities, which 30 years, the early decrease in CSF Aβ1–42/1–40 values was have been consistently reported in the literature,9,31 accompanied by increases in plasma NFL concentrations, underscore the importance of considering the neuro­ increases in CSF p-tau concentrations, and reductions in developmental differences in individuals with Down brain metabolism. At age 40 years, changes in Centiloid syndrome and the level of baseline intellectual disability Aβ scale scores and brain atrophy occurred together when interpreting cognitive and biomarker results. with cognitive impairment, followed by prodromal In our study, the CSF Aβ1–42/1–40 ratios and plasma NFL Alzheimer’s disease and Alzheimer’s disease dementia concentrations were the first biomarkers to change at the beginning of the fifth decade of life in these by age 28–30 years, more than 20 years before prodro­ individuals. mal Alzheimer’s disease diagnosis. Fibrillar amyloid deposition was not detectable with PET until almost Discussion 10 years after the Aβ1–42/1–40 and NFL changes. This onset To our knowledge, this was the first large multimodal is similar to those reported in DIAN16 or in the Colombian biomarker study to characterise the natural history of E280A PSEN1 kindred18 studies and is in agreement with Alzheimer’s disease in adults with Down syndrome. We evidence showing the reduced sensitivity of amyloid found sequential changes in biomarkers over decades, as PET in the earliest stages of amyloid deposition in well as progressive cognitive impairment. In accordance individuals with Down syndrome.32 Additionally, the with the conceptualisation of Down syndrome as a form change in CSF Aβ1–42 concentrations might occur earlier of genetically determined Alzheimer’s disease,5 these than reported in this study because, at younger ages, changes began more than two decades before the onset of both children with Down syndrome33 and children with 1994 www.thelancet.com Vol 395 June 27, 2020 Articles a presenilin-1 mutation16,34 have shown higher CSF even before fibrillar Aβ deposition is detectable by PET. Aβ1–42 concentrations than those of age-matched controls. These results reinforce the adequacy of the unbiased Changes in brain metabolism in individuals with Down descriptive classification scheme for Alzheimer’s disease syndrome was the biomarker that followed a more biomarkers of the AT(N) system.19 Third, our results linear decrease, compared with that of other biomarkers, showed that the biochemical changes in their direction and we observed significant differences at about age and magnitude are similar to those described in sporadic 37·5 years, nearly 13 years before prodromal Alzheimer’s and autosomal dominant Alzheimer’s disease. The disease diagnosis. CSF p-tau and NFL concentrations atrophy, hypometabolic, and Aβ deposition maps were began to increase at about age 40 years, 10 years before also similar to those described in the sporadic and prodromal Alzheimer’s disease diagnosis, similar to autosomal dominant forms of the disease. Finally, autosomal dominant Alzheimer’s disease.16 Hippo­ our finding of a long preclinical phase supports the campal atrophy was evident from an early age, probably consideration of people with Down syndrome as a reflecting neurodevelopmental differences. Nonetheless, suitable population for clinical trials of Alzheimer’s hippocampal volumes decreased faster at about age disease. 40 years, 10 years before prodromal Alzheimer’s disease Regrettably, individuals with Down syndrome have yet diagnosis, in parallel with a decline in CAMCOG-DS to be included in preventive clinical trials. Such trials scores. Dementia diagnosis occurred approximately would, admittedly, pose additional challenges compared 3 years after prodromal Alzheimer’s disease diagnosis. with those done in the general population regarding This sequence of changes, summarised in the combined informed consent and concerns about the feasibility of model (figure 4), is again strikingly similar to that completing all assessments. However, our study shows described in autosomal dominant Alzheimer’s disease.16 that a substan­ tial proportion of adults with Down The main strengths of this study are the large syndrome are capable and willing to do all the population size, with a wide age range, and the multimodal studies required in a trial. Clinical trials in comprehensive and multimodal nature of the assess­ this population have obvious advantages: the ultra-high ment. The main lim­ itations are its cross-sectional risk for developing symptomatic Alzheimer’s disease design and the differences in sample sizes for the and, as we showed here, a predictable sequence of events different biomarker tests. The unequal sample size of make this population ideal for preventive trials in each biomarker affects the CI calculations and the exact Alzheimer’s disease, together with individuals with its estimates of the ages for the biomarker changes. For autosomal dominant form. Notably, Down syndrome this reason, and because of the intrinsic limitations of is much more common than autosomal dominant studies assessing the natural history of biomarkers Alzheimer’s disease. Given the similarities between (eg, different nature of the variables with different both sporadic and autosomal dominant Alz­ heimer’s slopes and different sensitivities of the assays), we used disease and Alzheimer’s disease in individuals with a descriptive analysis, which we complemented with the Down syndrome, such therapies could prove ben­eficial mathematical approach previously used in studies of for all of these groups.35 Future studies should assess autosomal dominant Alzheimer’s disease.16 This limi­ the effects of potential genetic modifiers (including the tation is clearly exemplified by the differences between APOE haplotype and polygenic risk factors), the potential the estimates for plasma and CSF NFL concentrations. differences between individuals with full trisomy 21 The neurodevelopmental and biological differences as­ and those with partial translocations or mosaicism and, sociated with Down syndrome also complicate the importantly, the relationships between biomarkers. The deter­mination of the estimates, as exemplified in the different biomarkers do indeed show correlations, and cog­nitive performance assessment and in other bio­ multimodal studies are certainly needed to assess the markers, such as hippocampal volumes or plasma Aβ1–42 effect of pathophysiological biomarkers on topographical concentrations. Finally, as in previous studies in biomarkers.5 Additional studies specifically investigating individuals with Down syndrome,29 we used age at cognition are also needed to assess whether the differ­ diagnosis as proxy of age of onset, but we acknowledge ences in the CAMCOG-DS rate of decline in individuals that this approach might have underestimated age of with mild versus moderate intellectual disability are due onset. to insufficient test sensitivity for highly functioning Our results have several important implications. First, individuals, differences in underlying biology supportive they support the concept of Down syndrome as a form of the cognitive reserve hypothesis, or the population of genetically determined Alzheimer’s disease,5 which composition in our study. has been shown to have a profound effect in patient Contributors management and family counselling for autosomal JF, RB, and AL developed the study concept and design. JF, EV, MC-I, dominant Alzheimer disease. Second, neurodegenera­ BB, LV, IB, SF, MA, JP, VM, SVa, SG, SG-O, TE, II-G, VC, OB, LM, SL, LRW, TA, AJH, and SHZ acquired the data. JF and EV analysed and tive changes, as measured by plasma NFL increases or interpreted the data, did the statistical analysis, and drafted the brain hypometabolism, might occur much earlier than manuscript. All authors revised and edited the manuscript and critically previously thought in individuals with Down syndrome, revised it for important intellectual content. www.thelancet.com Vol 395 June 27, 2020 1995 Articles Declaration of interests References JF reports grants from Instituto de Salud Carlos III, Generalitat de 1 Ballard C, Mobley W, Hardy J, Williams G, Corbett A. Dementia Catalunya, National Institute on Aging of the US National Institutes in Down’s syndrome. Lancet Neurol 2016; 15: 622–36. of Health, and Fundació La Marató de TV3, during the conduct of the 2 Bittles AH, Bower C, Hussain R, Glasson EJ. The four ages of study; personal fees from AC Inmune, Merck, and Novartis, outside Down syndrome. Eur J Public Health 2007; 17: 221–25. the submitted work; and a patent titled markers of synaptopathy in 3 McCarron M, McCallion P, Reilly E, Dunne P, Carroll R, Mulryan N. neurodegenerative disease (EP18382175.0 pending). MC-I reports grants A prospective 20-year longitudinal follow-up of dementia in persons from Instituto de Salud Carlos III, during the conduct of the study. with Down syndrome. J Intellect Disabil Res 2017; 61: 843–52. OB reports personal fees from ADx Neurosciences, outside the 4 Hithersay R, Startin CM, Hamburg S, et al. Association of dementia submitted work; and a patent (WO 2019/175379 A1 markers of with mortality among adults with Down syndrome older than synaptopathy in neurodegenerative disease) pending to ADx 35 years. JAMA Neurol 2019; 76: 152–60. Neurosciences NV. DA reports grants from Instituto de Salud Carlos III 5 Dubois B, Feldman HH, Jacova C, et al. Advancing research and Generalitat de Catalunya, during the conduct of the study; personal diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 2014; 13: 614–29. fees from Fujirebio-Europe, Krka Farmaceutica, Nutricia, and Roche Farma, outside the submitted work; and a patent titled markers of 6 Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease synaptopathy in neurodegenerative disease (EP18382175.0 pending). in Down’s syndrome. Ann Neurol 1985; 17: 278–82. AL reports grants from Instituto de Salud Carlos III, BBVA foundation, 7 Carmona-Iragui M, Balasa M, Benejam B, et al. Cerebral amyloid Fundació la Marato de TV3, and Generalitat de Catalunya, during angiopathy in Down syndrome and sporadic and autosomal- the conduct of the study; personal fees from FujirebioEurope, Biogen, dominant Alzheimer’s disease. Alzheimer’s Dement 2017; Nutricia, and Roche, outside the submitted work; and a patent titled 13: 1251–60. markers of synaptopathy in neurodegenerative disease (EP18382175.0 8 Lott IT, Head E. Dementia in Down syndrome: unique insights pending). All other authors declare no competing interests. for Alzheimer disease research. Nat Rev Neurol 2019; 15: 135–47. Data sharing 9 Neale N, Padilla C, Fonseca LM, Holland T, Zaman S. We would consider sharing de-identified, individual participant-level Neuroimaging and other modalities to assess Alzheimer’s disease data that underlie the results reported in this Article. Data will be in Down syndrome. NeuroImage Clin 2018; 17: 263–71. available with the publication of our main manuscript on receipt of 10 Rafii MS, Wishnek H, Brewer JB, et al. The down syndrome a request detailing the study hypothesis and statistical analysis plan. biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer’s disease biomarkers in down syndrome. All requests should be sent to the corresponding author. The steering Front Behav Neurosci 2015; 9: 1–11. committee of this study will discuss all requests and decide on the 11 Handen BL, Cohen AD, Channamalappa U, et al. Imaging brain basis of the novelty and scientific rigor of the proposal whether data amyloid in nondemented young adults with Down syndrome using sharing is appropriate. All applicants are asked to sign a data access Pittsburgh compound B. Alzheimer’s Dement 2012; 8: 496–501. agreement. 12 Annus T, Wilson LR, Hong YT, et al. The pattern of amyloid Acknowledgments accumulation in the brains of adults with Down syndrome. This study was supported by the Fondo de Investigaciones Sanitario, Alzheimer’s Dement 2016; 12: 538–45. Instituto de Salud Carlos III, and the CIBERNED programme, partly 13 Lao PJ, Betthauser TJ, Hillmer AT, et al. The effects of normal aging jointly funded by the EU European Regional Development Fund. on amyloid-β deposition in nondemented adults with Down This work was also supported by the National Institutes of Health, syndrome as imaged by carbon 11-labeled Pittsburgh compound B. Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Alzheimer’s Dement 2016; 12: 380–90. Recerca i Innovacio en Salut, and Fundació La Marató de TV3. I. 14 Fortea J, Carmona-Iragui M, Benejam B, et al. Plasma and CSF II-G is supported by the Rio Hortega grant from Acción Estratégica en biomarkers for the diagnosis of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet Neurol 2018; Salud 2013–2016, and the Global Brain Health Institute. Fundació 17: 860–69. Catalana Síndrome de Down, Fundació Víctor Grífols i Lucas, 15 Devenny DA, Silverman WP, Hill AL, Jenkins E, Sersen EA, and the Jérôme Lejeune Foundation also partly supported this work. Wisniewski KE. Normal ageing in adults with Down’s syndrome: Finally, this work was supported by Generalitat de Catalunya and a a longitudinal study. J Intellect Disabil Res 1996; 40: 208–21. grant from the Fundació Bancaria La Caixa to RB. We thank all the 16 Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical and biomarker participants with Down’s syndrome, their families, and their carers for changes in dominantly inherited Alzheimer’s disease. N Engl J Med their support of, and dedication to, this research. We also acknowledge 2012; 367: 795–804. the Fundació Catalana Síndrome de Down for global support; 17 Jack CR Jr, Lowe VJ, Weigand SD, et al. Serial PIB and MRI in Soraya Torres and Raúl Núñez for laboratory and sample handling; normal, mild cognitive impairment and Alzheimer’s disease: Reyes Alcoverro, Marta Salinas, and Tania Martínez for administrative implications for sequence of pathological events in Alzheimer’s support; and Concepción Escola and Diana Garzón for nursing disease. Brain 2009; 132: 1355–65. handling. We also thank the PET imaging technologist, radiographers, 18 Fleisher AS, Chen K, Quiroz YT, et al. Associations between technicians, and radiochemists at the Wolfson Brain Imaging Centre, biomarkers and age in the presenilin 1 E280A autosomal dominant as well as the clinicians for their help in acquiring the data reported in Alzheimer disease kindred: a cross-sectional study. JAMA Neurol this Article. We are grateful to the Medical Research Council for 2015; 72: 316–24. generously providing a grant to support this research. Additional 19 Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research support came from the National Institute for Health Research (NIHR) Framework: toward a biological definition of Alzheimer’s disease. Cambridge Biomedical Research Centre, the NIHR Collaborations in Alzheimer’s Dement 2018; 14: 535–62. Leadership for Applied Health Research and Care (CLAHRC) for 20 Alcolea D, Clarimón J, Carmona-Iragui M, et al. The Sant Pau the East of England, the NIHR Cambridge Dementia Biomedical Initiative on Neurodegeneration (SPIN) cohort: a dataset for Research Unit, the Down Syndrome Association, and the Health biomarker discovery and validation in neurodegenerative disorders. Foundation. AJH was supported during the preparation of this Alzheimers Dement 2019; 5: 597–609. manuscript by the NIHR CLAHRC East of England at Cambridgeshire 21 Esteba-Castillo S, Dalmau-Bueno A, Ribas-Vidal N, Vilà-Alsina M, and Peterborough National Health Service Foundation Trust. Novell-Alsina R, García-Alba J. Adaptacion y validacion del Cambridge Examination for Mental Disorders of Older People The manuscript describes independent research, and the views with Down’s Syndrome and Others with Intellectual Disabilities expressed are those of the authors and not necessarily those of the (CAMDEX-DS) en poblacion espanola con discapacidad intelectual. funders. 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