Research JAMA Neurology | Original Investigation Association of Apolipoprotein E ε4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome Alexandre Bejanin, PhD; Maria Florencia Iulita, PhD; Eduard Vilaplana, PhD; Maria Carmona-Iragui, MD, PhD; Bessy Benejam, MSc; Laura Videla, MSc; Isabel Barroeta, MD, PhD; Susana Fernandez, MD; Miren Altuna, MD, PhD; Jordi Pegueroles, MSc; Victor Montal, MSc; Silvia Valldeneu, MSc; Sandra Giménez, MD, PhD; Sofía González-Ortiz, MD, PhD; Laia Muñoz, BSc; Concepción Padilla, PhD; Mateus Rozalem Aranha, MD; Teresa Estellés, MD; Ignacio Illán-Gala, MD, PhD; Olivia Belbin, PhD; Valle Camacho, MD, PhD; Liam Reese Wilson, PhD; Tiina Annus, PhD; Ricardo S. Osorio, MD; Sebastián Videla, MD, PhD; Sylvain Lehmann, MD, PhD; Anthony J. Holland, MD; Henrik Zetterberg, MD, PhD; Kaj Blennow, MD, PhD; Daniel Alcolea, MD, PhD; Jordi Clarimon, PhD; Shahid H. Zaman, MD, PhD; Rafael Blesa, MD, PhD; Alberto Lleó, MD, PhD; Juan Fortea, MD, PhD Editorial page 913 IMPORTANCE Alzheimer disease (AD) is the leading cause of death in individuals with Down Supplemental content syndrome (DS). Previous studies have suggested that the APOE ε4 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 ε4 allele with clinical and multimodal biomarkers of AD in adults with DS. DESIGN, SETTING, AND PARTICIPANTS This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ε4 allele carriers or noncarriers. MAIN OUTCOMES AND MEASURES Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18–labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ε4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume. RESULTS Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ε4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ε4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ε4 allele carriers. CONCLUSIONS AND RELEVANCE In this study, the APOE ε4 allele was associated with earlier Author Affiliations: Author clinical and biomarker changes of AD in DS. These results provide insights into the affiliations are listed at the end of this mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE article. genotype for future clinical trials in DS. Corresponding Authors: Alexandre Bejanin, PhD (abejanin@santpau. cat), and Juan Fortea, MD, PhD (jfortea@santpau.cat), Department of Neurology, Hospital de la Santa JAMA Neurol. 2021;78(8):937-947. doi:10.1001/jamaneurol.2021.1893 Creu i Sant Pau, Sant Antoni Maria Published online July 6, 2021. Claret, 167, 08025 Barcelona, Spain. (Reprinted) 937 Downloaded From: https://jamanetwork.com/ on 12/23/2022 Research Original Investigation Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome I ndividuals with Down syndrome (DS) constitute a popu- lation at ultrahigh risk of developing Alzheimer disease (AD) Key Points because of trisomy of chromosome 21, which harbors the Question What is the association of the apolipoprotein E (APOE) APP (amyloid precursor protein; OMIM 104760) gene. Recent ε4 allele with Alzheimer disease–related clinical and biomarker estimates indicate a lifetime dementia risk of more than 90% changes in Down syndrome? and identify Alzheimer dementia as the leading cause of death Findings In this cohort study of 464 adults with Down syndrome, in this population.1 This elevated risk has led to the concep- carriers of the APOE ε4 allele showed both earlier clinical tualization of DS as a genetically determined form of AD that symptoms of Alzheimer disease and earlier changes in amyloid is similar to autosomal dominant forms. This idea is further (cerebrospinal fluid Aβ1-42/1-40 and amyloid positron emission supported by a recent study that showed that the pattern of tomography), tau (plasma phosphorylated tau 181), and AD biomarker changes follows a similar temporal profile in DS neurodegeneration (cerebral glucose hypometabolism and as in autosomal dominant forms, with a long preclinical phase hippocampal atrophy) biomarkers. The APOE ε4 allele also altered the topography of neurodegeneration. and pathophysiological processes that are qualitatively com- parable to sporadic AD.2 Meaning Results of this study suggest that the APOE ε4 allele can The apolipoprotein E (APOE; OMIM 107741) ε4 allele is the modulate both the clinical expression and the biomarkers of most established genetic risk factor for sporadic AD and Alzheimer disease in a genetic form of the disease, such as in Down syndrome. has been consistently associated with earlier AD symptoms3,4 and pathology 5 -7 in the general population. A similar disease-accelerating feature might exist in DS given that stud- dividuals who were assessed; 2 individuals were excluded be- ies in this population have reported that ε4 allele carriers show cause of the absence of trisomy 21. an earlier onset of clinical symptoms8-11 and greater amyloid burden12 than noncarriers. However, little is known about the Clinical and Neuropsychological Assessment association of the APOE ε4 allele with the evolution of AD The Diagnostic and Statistical Manual of Mental Disorders, Fifth biomarkers. Edition was used to stratify the level of intellectual disability Using biochemical and neuroimaging measures for all 3 cat- as mild, moderate, or severe or profound. Participants were fur- egories of the ATN system13 (ie, amyloid, tau, and neurode- ther classified as having asymptomatic, prodromal, or AD de- generation), we conducted this cohort study to investigate the mentia in a consensus meeting between the neurologist or psy- association of the APOE ε4 allele with clinical and multi- chiatrist and neuropsychologist (eMethods in the Supplement). modal biomarker changes of AD in adults with DS. We also ex- Global cognition was assessed using the Cambridge Cog- amined the association of the APOE ε4 allele with the topog- nitive Examination for Older Adults with Down Syndrome raphy of structural and functional brain changes. (CAMCOG-DS),15 and episodic memory was evaluated with the modified Cued Recall Test (mCRT).16 The mCRT was adapted for people with intellectual disabilities and consisted of 3 trials of free and cued recall performed both immediately and ap- Methods proximately 15 to 20 minutes after the learning phase. Free and This cohort study was approved by the Clinical Research Eth- cued performances were summed to obtain total scores of im- ics Committee at Hospital Sant Pau and the University of Cam- mediate and delayed recall. To account for the association of bridge Research Ethics Committee and by the Administration intellectual disability with cognitive performances, we ex- of Radioactive Substances Advisory Committee. In Spain, all cluded severe or profound cases to prevent floor effects17 and study participants or their legally authorized representatives z-transformed the cognitive performances in the mild and mod- gave written informed consent before study enrollment. In the erate intellectual disability groups separately. United Kingdom, written consent was obtained from all adults with DS who had the capacity to consent. For participants in APOE Genotyping, Fluid Biomarkers, and Neuroimaging England and Wales who lacked the capacity to consent, the pro- DNA was extracted from peripheral blood by technicians who cedures in the Mental Capacity Act of 2005 were followed. were blinded to clinical and biomarker data, and APOE geno- Between June 1, 2009, and February 28, 2020, we re- typing was determined by polymerase chain reaction cruited adults with DS. In Barcelona, Spain, adults with DS were amplification.18 Participants were dichotomized according to recruited from a population-based health plan that was de- the presence of at least 1 ε4 allele. veloped for the screening of AD from which the Down Alzhei- Cerebrospinal fluid (CSF) and blood samples were ac- mer Barcelona Neuroimaging Initiative cohort was formed.2,18 quired, as previously described.18,19 Plasma levels of phos- In Cambridge, UK, participants were selected from a conve- phorylated tau 181 (pTau181) and neurofilament light chain nience sample that was recruited from services for people with (NfL) were measured using single molecule array technology intellectual disabilities in England and Scotland.14 (Simoa; Quanterix). The pTau181 analyses were carried out at The study included adults with DS who were screened for the University of Gothenburg (Sweden) using a validated the APOE genotype and underwent a comprehensive clinical assay.20 The analysis of NfL was performed at the Centre Hos- evaluation. Most, but not all, of these individuals had at least pitalier Universitaire de Montpellier (France) and Hospital Sant 1 biochemical or imaging AD biomarker assessment. Genetic Pau (Spain).2,18 The CSF levels of amyloid-β peptide 1-40 (Aβ1- screening confirmed complete trisomy 21 in 98.3% of the in- 40), Aβ1-42, pTau181, and total tau were quantified using a fully 938 JAMA Neurology August 2021 Volume 78, Number 8 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/23/2022 Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome Original Investigation Research automated platform (Lumipulse; Fujirebio), following the pub- pants (n = 158; eTable 1 in the Supplement) from the Sant Pau lished protocol.21 The CSF NfL levels were measured with en- Initiative on Neurodegeneration cohort21 was included in the zyme-linked immunosorbent assay (NF-Light Assay; Uman- analyses as a visual reference of the biomarker changes occur- Diagnostics) according to the manufacturer recommendations. ring in individuals without trisomy 21. In addition to the lo- A subset of participants underwent 3-T magnetic reso- cally estimated scatterplot smoothing analyses, we con- nance imaging (MRI; n = 175), fluorine 18–labeled (18F) fluo- ducted between-group comparisons for each biomarker and rodeoxyglucose (FDG) positron emission tomography (PET; each decade using Mann-Whitney tests (eFigures 2-4 in the n = 132), and/or amyloid PET (n = 75). The Computational Supplement). Anatomy Toolbox (CAT12; Christian Gaser and Robert Dahnke) We used voxelwise linear models to compare the topog- for the SPM12 software (Wellcome Centre for Human Neuro- raphy of gray matter metabolism and volume in ε4 allele car- imaging, University College London, Queen Square Institute riers vs noncarriers. Analyses were performed in a mask that of Neurology) was used to preprocess the structural, 3-dimen- excluded non–gray matter voxels, and the statistical models sional, T1-weighted MRI and extract the hippocampal and total were corrected for age and sex as well as for total intracranial intracranial volumes. The 18F-FDG PET images were intensity volume and recruitment center for the models that included scaled by the pons-vermis region and spatially normalized volume. Voxelwise results are presented at an uncorrected using the SPM12 software. The standardized uptake value ra- threshold of P < .001 (cluster size k >100 mm3). tios were extracted from the region of interest in Landau et al.23 Both the 18F-FDG PET and the segmented and modulated gray matter maps were smoothed using an 8-mm full-width at half- maximum Gaussian kernel for voxelwise analyses. The amy- Results loid PET data were collected using 18F-florbetapir in Barce- Of the 464 adults with DS included, 97 (20.9%) were APOE lona and carbon 11–labeled Pittsburg compound B in ε4 allele carriers (ε2/4: n = 7; ε3/4: n = 86; and ε4/4: n = 4) Cambridge. Images were spatially normalized using the MRI and 367 (79.1%) were noncarriers. The 2 groups did not dif- transformations computed with Advanced Normalization fer significantly in age (median [interquartile range (IQR)], Tools24 and scaled using the whole cerebellum as the refer- 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56), sex ence region.2,25,26 The mean cortical standardized uptake value distribution (male participants: 51 [52.6%] vs 199 [54.2%]; ratio22 was then transformed into centiloid units according to female participants: 46 [47.4%] vs 168 [45.8%]; P = .86), standard procedures.27 level of intellectual disability (mild: 23 [23.7%] vs 82 [22.5%]; moderate: 50 [51.6%] vs 190 [52.2%]; and severe or Statistical Analysis profound: 24 [24.7%] vs 92 [25.3%]; P = .97), or the most All statistical analyses were performed with R software, ver- common health conditions observed in DS (eg, hypothyroid- sion 4.0.4 (R Foundation for Statistical Computing). Differ- ism: 29 [44.6% of those evaluated] vs 124 [51.2% of those ences in baseline characteristics, percentage of sympto- evaluated]; P = .42) (Table; eTable 2 in the Supplement has matic cases across age intervals, and age at diagnosis were details on the subsamples for each biomarker). Similar to analyzed using χ2 tests (or Fisher exact tests, when appro- the general population, the ε3 allele was the most prevalent, priate) for categorical data, and Mann-Whitney or 2-sample, followed by ε4 and ε2 alleles. When comparing recruiting unpaired, 2-tailed t tests were used for continuous vari- sites, we found no demographic, genetic, or clinical differ- ables. Survival analysis with a log-rank test was also con- ences between the Barcelona and Cambridge cohorts except ducted to assess between-group differences in the age at the for intellectual disability (eTable 3 in the Supplement). first diagnosis of symptomatic AD (which combines prodro- mal and dementia cases). The threshold for significance was Clinical and Neuropsychological Findings set at P < .05. The overall proportion of individuals with DS with a diagno- To compare the age-associated changes in cognition and sis of symptomatic AD was similar between APOE ε4 allele car- biomarkers between APOE ε4 allele carriers and noncarriers, riers and noncarriers (36.8% vs 29.9%; χ 21,460 = 1.4; P = .24). we fitted a first-order locally estimated scatterplot smooth- However, an age-stratified analysis by 5-year intervals re- ing curve, with a tricubic weight function and a span param- vealed 2 key differences (Figure 1A). First, in the 40 to 45 years eter of 0.75, in each group independently. Given that no ε4 al- of age range, the prevalence of symptomatic AD was 40% in lele carriers were older than 60 years, the curves did not include carriers and 12% in noncarriers (χ 21,75 = 4.9; P = .03). Second, noncarriers older than carriers for a more uniform compari- in contrast to the noncarrier group in which 18 individuals were son. The exact age at which the intervals diverge depends on older than 60 years, we found no individuals carrying the ε4 the intrinsic limitations of the study, such as the nature of the allele who were older than 60 years, even when examining data variable, the sensitivity of the assay, the slope of the associa- from follow-up visits. tion, and, in the present case, the uneven sample sizes for the Next, we used baseline and follow-up data to examine the different measurements. Therefore, we defined cognitive or age at which individuals with DS had been diagnosed with biomarker change as the age at which the groups’ curves ap- symptomatic AD. The survival curve showed a significant dif- peared to start diverging visually and provided the age range ference in the distributions of the 2 groups (log-rank test, at which the 95% CIs between groups did not overlap. A con- P = .01), with the carrier group showing a greater probability venience sample of cognitively unimpaired euploid partici- of being diagnosed with symptomatic AD at an earlier age jamaneurology.com (Reprinted) JAMA Neurology August 2021 Volume 78, Number 8 939 Downloaded From: https://jamanetwork.com/ on 12/23/2022 Research Original Investigation Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome Table. Study Participantsa APOE ε4 allele Variable noncarrier APOE ε4 allele carrier P value All participants (n = 464), No. (%) 367 (79.1) 97 (20.9) NA Age, median (IQR), y 43.7 (34.9-50.2) 45.9 (36.4-50.2) .56 Sex, No. (%) Female 168 (45.8) 46 (47.4) .86 Male 199 (54.2) 51 (52.6) Level of intellectual disability, No. (%)b Mild 82 (22.5) 23 (23.7) Moderate 190 (52.2) 50 (51.6) .97 Severe or profound 92 (25.3) 24 (24.7) Diagnostic group, No. (%)b Asymptomatic AD 256 (70.1) 60 (63.2) .24 Symptomatic AD 109 (29.9) 35 (36.8) Abbreviations: Aβ1-40, amyloid-β APOE alleles, No. NA peptide 1-40; Aβ1-42, amyloid-β peptide 1-42; AD, Alzheimer disease; ε2/ε2 1 0 APOE, apolipoprotein E; ε2/ε3 47 0 CAMCOG-DS, Cambridge Cognitive ε2/ε4 0 7 Examination for Older Adults with Down Syndrome; CSF, cerebrospinal ε3/ε3 319 0 fluid; 18F FDG, fluorine 18–labeled ε3/ε4 0 86 fluorodeoxyglucose; IQR, interquartile range; mCRT, modified ε4/ε4 0 4 Cued Recall Test; NA, not applicable; Medical conditions, No. (%)b NfL, neurofilament light chain; PET, Hypothyroidism (n = 307) 124 (51.2) 29 (44.6) .42 positron emission tomography; pTau181, phosphorylated tau 181; Epilepsy (n = 289) 19 (8.3) 8 (13.3) .35 SUVR, standardized uptake value Sleep apnea (n = 297) 27 (11.4) 11 (18.3) .22 ratio; TIV, total intracranial volume. Depression (n = 330) 34 (13.1) 13 (18.3) .36 a Unless otherwise indicated, values Cognition, median (IQR) c were number (%) or median (IQR). All fluid biomarker concentration CAMCOG-DS score (n = 301) 74.0 (59.0-85.0) 73.5 (63.0-83.0) .68 units, except for the CSF Aβ1-42 to mCRT immediate recall (n = 263) 35.0 (33.0-36.0) 35.0 (31.0-36.0) .14 Aβ1-40 ratio, were picograms per mCRT delayed recall (n = 262) 12.0 (10.0-12.0) 12.0 (9.0-12.0) .30 milliliter. P values refer to analyses of χ2 tests for categorical variables Fluid biomarkers, median (IQR) and Mann-Whitney tests for CSF Aβ1-42/1-40 (n = 156) 0.1 (<0.1-0.1) 0.1 (<0.1-0.1) .08 continuous variables. b CSF NfL (n = 139) 493.7 (305.6-791.9) 663.9 (372.5-880.0) .47 Percentages for intellectual disability, diagnostic group, and CSF pTau181 (n = 158) 44.2 (25.8-122.3) 71.8 (32.0-119.7) .29 medical conditions were calculated CSF total tau (n = 158) 398.5 (247.8-755.0) 516.0 (236.0-749.0) .82 according to the total of patients Plasma NfL (n = 354) 9.6 (5.3-15.3) 10.7 (6.3-16.8) .11 with available data in each group. c Plasma pTau181 (n = 354) 12.5 (8.6-22.2) 17.8 (11.4-25.8) .007 Cognition included cognitive performances only for individuals Imaging biomarkers, median (IQR) with DS who had mild or moderate Centiloid amyloid PET (n = 75)d 7.6 (0.3-33.8) 17.4 (5.0-67.7) .08 intellectual disability. 18 d F-FDG PET SUVR (n = 132) 1.3 (1.1-1.4) 1.2 (0.9-1.4) .44 Forty-five participants had amyloid PET with fluorine 18–labeled Bilateral hippocampal volume (n = 175) 6.8 (6.2-7.4) 6.5 (5.1-7.4) .20 florbetapir, and 30 participants had Bilateral hippocampal volume per TIV (n = 175) 0.0059 0.0057 .16 amyloid PET with carbon 11–labeled (0.0053-0.0062) (0.0047-0.0062) Pittsburgh compound B. (Figure 1B). The between-group comparison further con- age regardless of APOE genotype. Visually, the change seemed firmed this earlier age at diagnosis in carriers compared with earlier and steeper in APOE ε4 allele carriers compared with noncarriers (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; noncarriers starting from age 40 years, but the CIs did not di- P = .02) (Figure 1C). verge (Figure 1D). Carriers also showed a decrease in both the We also evaluated the performance on the CAMCOG-DS immediate and delayed recall scores of the mCRT at an earlier and mCRT tests (immediate and delayed recall) expressed as age compared with noncarriers (Figure 1E and F). The differ- z scores and as a function of age (eFigures 1 and 2 in the ence between the 2 groups was evident from age 40 years (non- Supplement have raw data and analyses in participants with overlapping CIs from age 44 years). These age-associated dif- mild and moderate levels of intellectual disability). All par- ferences were not reflected by significant group differences, ticipants with DS showed decreased CAMCOG-DS z scores with when the mCRT scores were compared between the whole 940 JAMA Neurology August 2021 Volume 78, Number 8 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/23/2022 Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome Original Investigation Research Figure 1. Association of Apolipoprotein E (APOE) ε4 Allele With Clinical Diagnosis and Cognitive Performance in Adults With Down Syndrome (DS) A Point prevalence of symptomatic AD B Probability by age of developing symptomatic AD C Age at diagnosis of symptomatic AD 100 1.0 70 APOE ε4 allele noncarriers 0.8 Symptoms, probability APOE ε4 allele Symptomatic cases, % 80 Age at diagnosis, y carriers 60 60 0.6 0.4 40 50 0.2 20 0 40 0 30 35 40 45 50 55 >60 30 40 50 60 70 APOE ε4 allele APOE ε4 allele 5-y Age interval Age, y noncarriers carriers APOE status D CAMCOG-DS E mCRT immediate recall F mCRT delayed recall 2 2 2 0 0 0 z Score z Score z Score –2 –2 –2 –4 –4 –4 20 30 40 50 60 20 30 40 50 60 20 30 40 50 60 Age, y Age, y Age, y The horizontal lines in panel C represent the mean values, and the error bars Cambridge Cognitive Examination for Older Adults with Down Syndrome; and represent the nonparametric bootstrapped 95% CIs. Bands in panels D to F mCRT, modified Cued Recall Test. represent the 95% CIs. AD indicates Alzheimer disease; CAMCOG-DS, group of carriers and noncarriers (median (IQR) immediate re- Neurodegeneration Biomarkers call: 35.0 [31.0-36.0] vs 35.0 [33.0-36.0]; P = .14; median (IQR) No between-group differences in the levels of NfL were found delayed recall: 12.0 [9.0-12.0] vs 12.0 [10.0-12.0]; P = .30) in CSF or in plasma as seen by the overlapping CIs across all (Table). ages and in the analyses by decade (Figure 2E and F; eFig- ure 3E and F in the Supplement). The CSF total tau likewise Amyloid and Tau Pathology Biomarkers showed no differences between groups (eFigure 4C and F in The CSF Aβ1-42 to Aβ1-40 ratio was lower in APOE ε4 allele the Supplement). carriers than in noncarriers among the youngest partici- By contrast, neuroimaging biomarkers revealed signifi- pants (20s to 30s) and overlapped with noncarriers starting cant differences between APOE genotypes. Specifically, the ε4 from age 40 years (Figure 2A and eFigure 3A in the Supple- allele carriers showed lower brain metabolism than noncarri- ment). This result was driven by the lower levels of CSF ers starting at age 40 years. This difference was sustained un- Aβ1-42 in carriers (eFigure 4A and D in the Supplement). til the sixth decade, and the CIs of both groups diverged from Similarly, carriers showed an earlier and greater increase in age 45 to 53 years (Figure 2G and eFigure 3G in the Supple- cortical amyloid PET uptake than noncarriers (mid-30s vs ment). Similarly, carriers showed an earlier loss of hippocam- early 40s), with nonoverlapping CIs throughout the older pal volume starting from age 40 years and with nonoverlap- ages (41 to 54 years) (Figure 2B) up to when amyloid uptake ping CIs from age 48 to 52 years (Figure 2H and eFigure 3H in seemed to plateau. the Supplement). The age-assoc iated trajec tories of CSF pTau181 (Figure 2C) did not differ between ε4 allele carriers and non- Topography of Brain Hypometabolism and Atrophy carriers. However, when analyzing this biomarker in plasma The voxelwise analysis that was adjusted by age and sex re- in a larger sample, carriers showed higher levels starting vealed lower metabolism in the APOE ε4 allele carriers com- from the mid-40s and with CIs not overlapping by age 50 pared with noncarriers in subcortical structures (caudate, len- years (Figure 2D). tiform nucleus, and thalamus), posterior insula, medial, and jamaneurology.com (Reprinted) JAMA Neurology August 2021 Volume 78, Number 8 941 Downloaded From: https://jamanetwork.com/ on 12/23/2022 Research Original Investigation Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome Figure 2. Association of Apolipoprotein E (APOE) ε4 Allele With Age-Related Changes in Alzheimer Disease (AD) Biomarkers APOE ε4 allele noncarriers APOE ε4 allele carriers A CSF Aß1-42/1-40 ratio B Cortical amyloid PET uptake 0.125 120 0.100 80 CSF Aß1-42/1-40 Centiloid 0.075 40 0.050 0 0.025 20 30 40 50 60 20 30 40 50 60 Age, y Age, y C CSF pTau181 D Plasma pTau181 400 80 300 Plasma pTau181, pg/mL 60 CSF pTau181, pg/mL 200 40 100 20 0 0 20 30 40 50 60 20 30 40 50 60 Age, y Age, y E CSF NfL F Plasma NfL 3000 60 50 Plasma NfL, pg/mL 2000 40 CSF Nfl, pg/mL 30 1000 20 10 0 0 20 30 40 50 60 20 30 40 50 60 Age, y Age, y G Brain glucose metabolism H Hippocampal volume 1.75 0.008 Shading represents 95% CIs, and the dashed lines represent the Hippocampal volume per TIV 1.50 age-related changes in euploid individuals for visual reference. 18F-FDG PET SUVR 0.006 1.25 Aβ1-40 indicates amyloid-β peptide 1-40; Aβ1-42, amyloid-β peptide 1-42; 1.00 CSF, cerebrospinal fluid; 18F-FDG, 0.004 fluorine 18–labeled 0.75 fluorodeoxyglucose; NfL, neurofilament light chain; PET, positron emission tomography; 0.50 0.002 pTau181, phosphorylated tau 181; 20 30 40 50 60 20 30 40 50 60 SUVR, standardized uptake value Age, y Age, y ratio; and TIV, total intracranial volume. 942 JAMA Neurology August 2021 Volume 78, Number 8 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/23/2022 Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome Original Investigation Research Figure 3. Association of Apolipoprotein E (APOE) ε4 Allele With Gray Matter Metabolism and Volume A Decreased gray matter glucose metabolism in APOE ε4 allele carriers 0.3 0.2 0.1 Adjusted metabolism 0 –0.1 –0.2 –0.3 3.1 3.3 APOE ε4 allele APOE ε4 allele T values noncarriers carriers B Decreased gray matter volume in APOE ε4 allele carriers 0.10 0.05 Adjusted volume 0 The boxplots illustrate the voxelwise results and represent the metabolism (A) and volume (B) adjusted for the covariates within the significant –0.05 clusters. For each boxplot, the box represents the interquartile range, the band represents the median value, and the dots represent –0.10 individual values. Results are presented in neurological convention and were generated using the Surf Ice tool (https://www.nitrc.org/projects/ –0.15 3.1 3.3 surfice/). eFigures 5 and 6 in the APOE ε4 allele APOE ε4 allele T values noncarriers carriers Supplement show a slice-by-slice display of the results. lateral parietal and occipital cortices (Figure 3A and eFigure 5 ε4 allele carriers (1) presented an earlier decline in episodic in the Supplement). No brain region showed higher metabo- memory and were diagnosed with symptomatic AD a mean of 2 lism in carriers than in noncarriers. years before noncarriers, (2) exhibited earlier changes in AD bio- In addition, carriers showed lower gray matter volume in markers, and (3) showed differences in the topography of struc- the hippocampus bilaterally and right superior parietal cor- tural and functional brain changes. These results demonstrate that tex compared with noncarriers (Figure 3B and eFigure 6 in the the APOE ε4 allele can modulate both the clinical expression and Supplement). No brain region showed greater volume in car- changes in AD biomarkers in a genetic form of the disease. riers than in noncarriers. It has been well established that the APOE ε4 allele is as- sociated with an increased risk of sporadic AD and younger age at onset.3,4 This association is also true in autosomal domi- nant forms, in which the ε4 allele is associated with earlier Discussion diagnoses.28 In line with this finding, we observed an asso- To our knowledge, this is the first large, multimodal biomarker ciation of the APOE ε4 allele with earlier decline in episodic study to characterize the association of the APOE ε4 allele with memory and earlier clinical AD diagnoses in individuals with clinical and biomarker changes of AD in DS. We found that APOE DS. This observation is in agreement with previous findings jamaneurology.com (Reprinted) JAMA Neurology August 2021 Volume 78, Number 8 943 Downloaded From: https://jamanetwork.com/ on 12/23/2022 Research Original Investigation Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome in other DS cohorts that showed greater cognitive impair- Alternatively, the biochemical measurements across different ment among ε4 allele carriers29 and a similar 2-year advance- biofluids may not consistently capture the pathological changes ment in symptomatic AD diagnosis.8,11 that occur in some specific brain structures, such as the higher We observed this earlier age at symptom onset despite no tau pathology in the medial temporal lobe previously reported significant difference in the overall proportion of ε4 allele car- in ε4 allele carriers with sporadic AD.40 A similar explanation riers between asymptomatic and symptomatic individuals. Dis- might account for the lack of association that we observed with crepant results in DS have been reported concerning the ε4 al- biochemical markers of neurodegeneration (plasma and CSF NfL; lele proportions in these clinical groups, with some studies CSF total tau), despite differences in neuroimaging biomarkers showing more carriers in the symptomatic group and others (18F-FDG PET and MRI). finding no differences.10,30 Although no overall group differ- Both neuroimaging biomarkers showed diverging trajec- ences were found, the age-stratified analysis that we con- tories between APOE ε4 allele carriers and noncarriers around ducted revealed an increased prevalence of symptomatic AD age 40 years. The voxelwise analyses further indicated that the in carriers aged 40 to 45 years. This result further emphasizes APOE ε4 allele was associated with not only accelerated on- that age and sample composition are critical variables to in- set of biomarker changes but also differences in the extent and terpreting results in the context of DS, wherein AD is inexo- topography of the pattern of neurodegeneration. Carriers had rable. Note that no individuals with DS older than 60 years were lower glucose metabolism in subcortical structures and sev- found in the ε4 allele carrier group, a finding that is consis- eral cortical areas, including the medial parietal region. More- tent with previous studies that associated the ε4 allele with over, they presented with less medial temporal volume com- lower life expectancy.8,11 pared with noncarriers. These results mirror previous findings The results also provided new in vivo pathophysiological in sporadic AD that showed decreased parietal metabolism and data with which to interpret the clinical findings. We found that hippocampal volume in carriers.41 In addition, we found an ear- the APOE ε4 allele was associated with age-associated changes lier decline in episodic memory in carriers starting at age 40 in the 3 categories of the ATN system (amyloid, tau, and neuro- years. This observation corroborates the literature on the as- degeneration). The associations with amyloid pathology ap- sociation of the APOE ε4 allele with episodic memory in the peared to be the earliest (differences in the early 20s for CSF general population,42 which has also been suggested in DS.43 Aβ1-42 to Aβ1-40 ratio and in the mid-30s for amyloid PET), the Given the crucial role of the hippocampus in episodic memory, greatest (highest magnitude), and the most consistent across the its greater atrophy likely underlies the earlier memory defi- different biomarkers. Specifically, we found lower levels of CSF cits in carriers. Carriers also showed a lower metabolism in the Aβ1-42 and CSF Aβ1-42 to Aβ1-40 ratio associated with the APOE striatum. This finding, which is not typically reported in spo- ε4 allele. This finding reproduces previous observations in both radic AD, might reflect the greater vulnerability of the stria- sporadic AD5,31-33 and autosomal dominant AD.34,35 It also fits tum to AD pathology in genetically determined forms of with the lower age-adjusted level of CSF Aβ1-42 reported in ε4 AD.44,45 allele carriers with DS.36 The early decrease in CSF Aβ1-42 to Overall, this study provided evidence that the APOE ε4 al- Aβ1-40 ratio in carriers supports the finding that cerebral Aβ dep- lele exerts a similar association with AD pathophysiological pro- osition occurs at a young age in DS and is consistent with the cesses in DS as in the general population. The association with abundant Aβ42-immunoreactive diffuse plaques reported in amyloid pathology and the concurrent shift toward greater hip- teenagers and young adults in this population.37 pocampal atrophy and memory impairments in APOE ε4 al- The differences in CSF amyloid biomarkers were con- lele carriers resemble the association of the APOE ε4 allele with cordant with the earlier and higher increase in amyloid PET the earlier clinical symptoms and pathogenesis of sporadic uptake in ε4 allele carriers (mid-30s) compared with non- AD.41 Several molecular mechanisms have been proposed by carriers (mid-40s). As in sporadic and other genetic forms of which the ε4 isoform may alter AD pathology, including the AD,5,32 the APOE ε4 allele might be associated with an ear- impairment of amyloid clearance and the promotion of its dep- lier and greater brain amyloid accumulation in DS. This idea osition into amyloid plaques.46 Growing evidence also sug- is supported by postmortem data showing a greater burden gests that the APOE ε4 allele might contribute to tau aggrega- of amyloid plaques in carriers with DS than noncarriers.12 tion that is independent of amyloid-β,47 and an autopsy study Besides the association with amyloid pathology, the ε4 al- supports an association between truncated APOE forms and lele altered the age-related trajectory of plasma, but not CSF, tau pathology in DS.48 Future studies that use ultrasensitive pTau181. This association was noticeable around age 50 years, methods may explore these truncated forms in body fluids only a few years before AD symptom onset. Controversial re- from people with DS. sults have been reported concerning the association between bio- Overall, this study capitalized on the largest cohort of chemical measures of pTau181 and the APOE ε4 allele, with some adults with DS with clinical assessments and multimodal bio- studies finding an association 38 but others finding no markers to inform on the age-related association of the APOE association.5,32,33,35 In the present study, the differences in ε4 allele with in vivo AD biomarkers, increasing the under- sample sizes between plasma pTau181 and CSF pTau181 mea- standing of the mechanisms that link APOE to the accelera- sures (354 vs 158 participants) may partially account for the dif- tion of disease in genetically at-risk populations. We believe ferent results. The discrepancy may also be explained by the exis- that this work is timely in the emerging landscape of preven- tence of other variables that modulate the association between tive trials for dementia in DS given that consideration of APOE the APOE ε4 allele and tau pathology, such as biological sex.38,39 genotype might be important for drugs that are designed to 944 JAMA Neurology August 2021 Volume 78, Number 8 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 12/23/2022 Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome Original Investigation Research lower amyloid burden and/or trials that use MRI as a surro- gate marker of improved outcomes. Conclusions Limitations In this cohort study, APOE ε4 allele carriers (compared with This study has limitations. The cross-sectional design and the noncarriers) showed an earlier decline in episodic memory, relatively small sample sizes for some biomarkers (eg, amy- earlier clinical diagnosis of symptomatic AD, earlier changes loid PET) did not allow for an investigation of the differences in AD biomarkers, and differences in the pattern of neuro- between each of the APOE genotypes. Nevertheless, note that degeneration. These findings demonstrate that the APOE ε4 age can be used as a proxy for disease progression in geneti- allele can modulate both the clinical expression and bio- cally determined AD, and the results remained essentially simi- markers of AD in a genetic form of the disease, such as in lar when sensitivity analyses were performed in the subsample DS, and emphasize the importance of the APOE genotype with the ε3 and ε4 polymorphisms. for future clinical trials in DS. ARTICLE INFORMATION Disease, UCL Queen Square Institute of Neurology, the Medical Research Council UK and Alzheimer's Accepted for Publication: April 16, 2021. London, United Kingdom (Zetterberg); Research UK during the conduct of the study as Cambridgeshire and Peterborough National Health well as nonfinancial support from the Down Published Online: July 6, 2021. Service (NHS) Foundation Trust, Fulbourn Hospital, Syndrome Association UK outside the submitted doi:10.1001/jamaneurol.2021.1893 Elizabeth House, Cambridge, United Kingdom work. Dr Zetterberg reported receiving personal Open Access: This is an open access article (Zaman). fees for service on the scientific advisory boards of distributed under the terms of the CC-BY License. Author Contributions: Drs Bejanin and Fortea had Denali, Roche Diagnostics, Wave, Samumed, © 2021 Bejanin A et al. JAMA Neurology. full access to all of the data in the study and take Siemens Healthineers, Pinteon Therapeutics, and Author Affiliations: Sant Pau Memory Unit, responsibility for the integrity of the data and the CogRx; receiving personal fees for giving lectures in Department of Neurology, Hospital de la Santa Creu accuracy of the data analysis. Drs Bejanin and Iulita symposia sponsored by Fujirebio, Alzecure, and i Sant Pau, Biomedical Research Institute Sant Pau, share first authorship. Biogen; and being the cofounder of Brain Universitat Autònoma de Barcelona, Barcelona, Concept and design: Bejanin, Iulita, Vilaplana, Biomarker Solutions in Gothenburg AB (part of the Spain (Bejanin, Iulita, Vilaplana, Carmona-Iragui, Wilson, S. Videla, Zaman, Blesa, Fortea. GU Ventures Incubator Program) outside the L. Videla, Barroeta, Fernandez, Altuna, Pegueroles, Acquisition, analysis, or interpretation of data: submitted work. Dr Blennow reported serving as a Montal, Valldeneu, Muñoz, Padilla, Aranha, Estellés, Bejanin, Iulita, Vilaplana, Carmona-Iragui, Benejam, consultant at advisory boards or at data monitoring Illán-Gala, Belbin, Alcolea, Clarimon, Blesa, Lleó, L. Videla, Barroeta, Fernandez, Altuna, Pegueroles, committees for Abcam, Axon, Biogen, JOMDD/ Fortea); Center of Biomedical Investigation Montal, Valldeneu, Giménez, González-Ortiz, Shimadzu, Julius Clinical, Eli Lilly and Company, Network for Neurodegenerative Diseases Muñoz, Padilla, Aranha, Estellés, Illán-Gala, Belbin, MagQu, Novartis, Roche Diagnostics, and Siemens (CIBERNED), Madrid, Spain (Bejanin, Iulita, Camacho, Wilson, Annus, Osorio, Lehmann, Healthineers as well as being the cofounder of Brain Vilaplana, Carmona-Iragui, L. Videla, Barroeta, Holland, Zetterberg, Blennow, Alcolea, Clarimon, Biomarker Solutions in Gothenburg AB (part of the Altuna, Pegueroles, Montal, Valldeneu, Muñoz, Lleó, Fortea. GU Ventures Incubator Program) outside the Padilla, Aranha, Estellés, Illán-Gala, Belbin, Alcolea, Drafting of the manuscript: Bejanin, Iulita, Vilaplana, submitted work. Dr Alcolea reported receiving Clarimon, Blesa, Lleó, Fortea); Barcelona Down L. Videla, Altuna, Fortea. personal fees for advisory board services and/or Medical Center, Fundació Catalana Síndrome de Critical revision of the manuscript for important speaker honoraria from Fujirebio-Europe, Roche Down, Barcelona, Spain (Carmona-Iragui, Benejam, intellectual content: Bejanin, Iulita, Vilaplana, Diagnostics, Nutricia, Krka Farmacéutica SL, and L. Videla, Fortea); Multidisciplinary Sleep Unit, Carmona-Iragui, Benejam, Barroeta, Fernandez, Esteve Pharmaceuticals SA outside the submitted Respiratory Department, Hospital de la Santa Creu i Altuna, Pegueroles, Montal, Valldeneu, Giménez, work as well as holding a patent for WO2019175379 Sant Pau, Barcelona, Spain (Giménez); Hospital del González-Ortiz, Muñoz, Padilla, Aranha, Estellés, A1 markers of synaptopathy in neurodegenerative Mar, Barcelona, Spain (González-Ortiz); Nuclear Illán-Gala, Belbin, Camacho, Wilson, Annus, Osorio, disease (licensed to ADx). Dr Zaman reported Medicine Department, Hospital de la Santa Creu i S. Videla, Lehmann, Holland, Zetterberg, Blennow, receiving nonfinancial support from the National Sant Pau, Barcelona, Spain (Camacho); Cambridge Alcolea, Clarimon, Zaman, Blesa, Lleó, Fortea. Institute for Health Research (NIHR) Cambridge Intellectual and Developmental Disabilities Statistical analysis: Bejanin, Vilaplana. Dementia Biomedical Research Unit and personal Research Group, Department of Psychiatry, Obtained funding: Benejam, Annus, Holland, fees for a short-term advisory role from Lundbeck University of Cambridge, Douglas House, Blennow, Alcolea, Zaman, Lleó, Fortea. outside the submitted work. Dr Fortea reported Cambridge, United Kingdom (Wilson, Annus, Administrative, technical, or material support: Iulita, receiving personal fees for service on the advisory Holland, Zaman); Healthy Brain Aging and Sleep Vilaplana, Carmona-Iragui, Benejam, Barroeta, boards or adjudication committees of AC Immune, Center, Department of Psychiatry, New York Altuna, Montal, Valldeneu, Giménez, Muñoz, Novartis, Lundbeck, Roche Diagnostics, and Merck University Grossman School of Medicine, New York Padilla, Aranha, Camacho, Wilson, Annus, Zaman, outside the submitted work; receiving conference (Osorio); Clinical Research Support Unit, Bellvitge Fortea. fees from Esteve, Novo Nordisk, Roche Diagnostics, Biomedical Research Institute Department of Supervision: Iulita, Barroeta, Altuna, Belbin, Osorio, Fujirebio, and Biogen; and holding a patent for Clinical Pharmacology, University of Barcelona, S. Videla, Holland, Clarimon, Blesa, Lleó, Fortea. markers of synaptopathy in neurodegenerative Barcelona, Spain (S. Videla); Le Laboratoire de Other - Clinical assessment of the participants: disease (licensed EP18382175.0). No other Biochimie et Protéomique Clinique, Université Estellés. disclosures were reported. Montpellier, Centre Hospitalier Universitaire Conflict of Interest Disclosures: Dr Funding/Support: This study was funded in part by Montpellier, Institut National de la Santé et de la Carmona-Iragui reported receiving grant the Fondo de Investigaciones Sanitario; Instituto de Recherche Médicale, Montpellier, France GBHI_ALZ-18-543740 from the Alzheimer's Salud Carlos III (grants PI14/01126 and PI17/01019 (Lehmann); Department of Psychiatry and Association and Global Brain Health Institute to Dr Fortea, grants PI13/01532 and PI16/01825 to Neurochemistry, Institute of Neuroscience and Project and grant Project No. 1913 Cycle 2019B from Dr Blesa, grant PI18/00335 to Dr Carmona-Iragui, Physiology, the Sahlgrenska Academy at the the Jérôme Lejeune Foundation outside the grants PI18/00435 and INT19/00016 to Dr Alcolea, University of Gothenburg, Mönldal, Sweden submitted work. Dr Belbin reported receiving grant PI18/00327 to Dr Belbin, and grants PI14/1561 (Zetterberg, Blennow); Clinical Neurochemistry personal fees from ADx NeuroSciences outside the and PI17/01896 to Dr Lleó); Center of Biomedical Laboratory, Sahlgrenska University Hospital, submitted work. Dr Annus reported being a current Investigation Network for Neurodegenerative Mölndal, Sweden (Zetterberg, Blennow); UK employee at Johnson & Johnson. Dr Lehmann Diseases (CIBERNED) Program 1, Alzheimer Disease Dementia Research Institute at University College reported receiving personal fees for service on the (Dr Lleó) and SIGNAL study, which was partly jointly London (UCL), London, United Kingdom scientific advisory boards of Roche Diagnostics and funded by Fondo Europeo de Desarrollo Regional, (Zetterberg); Department of Neurodegenerative Fujirebio. Dr Holland reported receiving grants from Unión Europea, and Una Manera de Hacer Europa; jamaneurology.com (Reprinted) JAMA Neurology August 2021 Volume 78, Number 8 945 Downloaded From: https://jamanetwork.com/ on 12/23/2022 Research Original Investigation Association of APOE ε4 With Biomarker Changes of Alzheimer Disease in Down Syndrome National Institutes of Health (NIH; grants the East of England at Cambridgeshire and disease: impact of APOE ε4 genotype. Brain. 2018; 1R01AG056850-01A1, R21AG056974, and Peterborough NHS Foundation Trust and grant 141(6):1828-1839. doi:10.1093/brain/awy103 R01AG061566 to Dr Fortea); Departament de Salut 98480 from the Medical Research Council. 8. Prasher VP, Sajith SG, Rees SD, et al. Significant de la Generalitat de Catalunya, Pla Estratègic de Dr Fortea was supported by grants from the Jérome effect of APOE epsilon 4 genotype on the risk of Recerca i Innovació en Salut (grant SLT002/16/ Lejeune Foundation. dementia in Alzheimer’s disease and mortality in 00408 to Dr Lleó); Fundació La Marató de TV3 Role of the Funder/Sponsor: The funders had no persons with Down syndrome. Int J Geriatr Psychiatry. (grant 20141210 to Dr Fortea and grant 044412 to role in the design and conduct of the study; 2008;23(11):1134-1140. doi:10.1002/gps.2039 Dr Blesa); Fundació Catalana Síndrome de Down collection, management, analysis, and and Fundació Víctor Grífols i Lucas (Dr Fortea); 9. Schupf N, Kapell D, Lee JH, et al. Onset of interpretation of the data; preparation, review, or dementia is associated with apolipoprotein E Generalitat de Catalunya (grant SLT006/17/00119 approval of the manuscript; and decision to submit to Dr Fortea, grant SLT006/17/95 to Dr Vilaplana, epsilon4 in Down’s syndrome. Ann Neurol. 1996;40 the manuscript for publication. (5):799-801. doi:10.1002/ana.410400518 and grant SLT006/17/00125 to Dr Alcolea); Fundació Bancaria La Caixa to Dr Blesa; NIHR Disclaimer: The views expressed herein are those 10. Deb S, Braganza J, Norton N, et al. APOE Cambridge Biomedical Research Centre; NIHR of the authors and do not reflect the official policy epsilon 4 influences the manifestation of Collaborations in Leadership for Applied Health or position of the funders. Alzheimer’s disease in adults with Down’s Research and Care (CLAHRC) for the East of Additional Contributions: We thank all of the syndrome. Br J Psychiatry. 2000;176:468-472. England; NIHR Cambridge Dementia Biomedical participants with Down syndrome, their families, doi:10.1192/bjp.176.5.468 Research Unit; Down Syndrome Association; and and their caregivers for their support and 11. Coppus AM, Evenhuis HM, Verberne GJ, et al. the Health Foundation. Dr Bejanin was supported dedication to this research. We acknowledge the The impact of apolipoprotein E on dementia in by a Juan de la Cierva Incorporación grant Fundació Catalana Síndrome de Down and the UK persons with Down’s syndrome. Neurobiol Aging. (IJCI-2017-32609) from the Spanish Ministry of Down's Syndrome Association for their support; 2008;29(6):828-835. doi:10.1016/j.neurobiolaging. Economy and Competitiveness and by a Miguel Soraya Torres, CLT, Shaimaa El Bounasri, CLT, and 2006.12.013 Servet I grant (CP20/00038) from the Carlos III Raúl Núñez, BSc, Sant Pau Memory Unit, Barcelona, Health Institute. Dr Iulita was supported by the Spain, for providing laboratory and sample 12. Hyman BT, West HL, Rebeck GW, et al. Jérôme Lejeune Foundation and Sisley D’Ornano handling; Reyes Alcoverro at Fundació Catalana Quantitative analysis of senile plaques in Alzheimer Foundations. Dr Estellés was supported by grant Síndrome de Down as well as Marta Salinas and disease: observation of log-normal size distribution CM19/00017 from Pío del Río Hortega. Dr Padilla Tania Martínez at Sant Pau Hospital, Barcelona, and molecular epidemiology of differences was supported as a Sara Borrell Postdoctoral Fellow Spain, for administrative support; and Concepción associated with apolipoprotein E genotype and (CD20/00133) at the Carlos III Health Institute. Dr Escola, RN, and Diana Garzón, RN, MSc, Sant Pau trisomy 21 (Down syndrome). Proc Natl Acad Sci U S Illán-Gala was supported by a Juan Rodés contract Hospital, for nursing handling. We also thank the A. 1995;92(8):3586-3590. doi:10.1073/pnas.92.8. (JR21-00018) and the Pilot Award for Global Brain positron emission tomography imaging 3586 Health Leaders (GBHI ALZ UK-21-720973). Dr technologist, radiographers, technicians, and 13. Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: Belbin was supported by a Miguel Servet II grant radiochemists at the Wolfson Brain Imaging Centre an unbiased descriptive classification scheme for (CP18/00011). Dr Osorio was supported by grants as well as the clinicians for their help in acquiring Alzheimer disease biomarkers. Neurology. 2016;87 R01AG056031, R01AG056531, R01AG066870, and the data reported in this article. These individuals (5):539-547. doi:10.1212/WNL. R21AG067549 from the NIH and grant 98480 from received no additional compensation, outside of 0000000000002923 the Medical Research Council. Dr Lehmann was their usual salary, for their contributions. 14. Annus T, Wilson LR, Hong YT, et al. 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