Received: 9 March 2021 Revised: 21 July 2021 Accepted: 22 September 2021 DOI: 10.1002/alz.12512 F E AT U R E D A R T I C L E Characteristics of subjective cognitive decline associated with amyloid positivity Olin Janssen1 Willemijn J. Jansen1 Stephanie J.B. Vos1 Merce Boada28,29 Lucilla Parnetti11 Tomasz Gabryelewicz15 Tormod Fladby16 José Luis Molinuevo5 Sylvia Villeneuve37 Jakub Hort34,35 Stéphane Epelbaum19,20 Alberto Lleó36 Sebastiaan Engelborghs40 Wiesje M. van der Flier2 Susan Landau30 Julius Popp38,39 Anders Wallin12,33 Philip Scheltens2 Marcel Olde Rikkert14 Peter J. Snyder17,18 Chris Rowe21 Gaël Chételat31 Agustin Ruíz28,29 Marta Marquié28,29 Elena Chipi11 Steffen Wolfsgruber24,25 Michael Heneka25 Henning Boecker26 Oliver Peters27 Jonas Jarholm16 Lorena Rami5 Adrià Tort-Merino5 Alexa Pichet Binette37 Judes Poirier37 Pedro Rosa-Neto37 Jiri Cerman34,35 Bruno Dubois19 Marc Teichmann19 Daniel Alcolea36 Juan Fortea36 M. Belén Sánchez-Saudinós36 Jarith Ebenau2 Cornelia Pocnet39 Marie Eckerström33 Louisa Thompson17,18 Victor Villemagne21,22 Rachel Buckley8 Samantha Burnham11 Marion Delarue31 Yvonne Freund-Levi3 Åsa K. Wallin13 Inez Ramakers1 Magda Tsolaki6 Hilkka Soininen32 Harald Hampel7 Luiza Spiru9,10 for the Alzheimer’s Disease Neuroimaging Initiative FACEHBI study group PREVENT-AD research group Betty Tijms1 Rik Ossenkoppele2,4,5 Frans R. J. Verhey1 Frank Jessen23,24 Pieter Jelle Visser1,2,3 1 Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands 2 Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands 3 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden 4 Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden 5 Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain 6 Memory and Dementia Center, 3rd Department of Neurology, “G Papanicolau, ” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece 7 GRC no 21, Alzheimer Precision Medicine (AMP), AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France 8 Brigham and Women’s Hospital and Department of Neurology Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 9 Carol DAVILA University of Medicine and Pharmacy, Bucharest, Romania 10 Geriatrics- Gerontology and Old Age Psychiatry, Alzheimer Unit, Ana Aslan International Foundation – Memory Center and Longevity Medicine, Bucharest, Romania 11 Section of Neurology, Center for Memory Disturbances – Lab. of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy 12 CSIRO Health & Biosecurity, Parkville, Victoria, Australia 13 Department of Clinical Sciences Malmö, Clinical Memory Research Unit, Lund University, Lund, Sweden 14 Department of Geriatric Medicine, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, The Netherlands This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2021 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. 1832 wileyonlinelibrary.com/journal/alz Alzheimer’s Dement. 2022;18:1832–1845. 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1833 15 Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland 16 Department of Neurology, Akershus University Hospital, Lorenskog, Norway 17 Institute of Clinical Medicine, University of Oslo, Oslo, Norway 18 Kingston, The University of Rhode Island, Rhode Island, USA 19 AP-HP, Hôpital de la Pitié Salpêtrière, Institute of Memory and Alzheimer’s Disease (IM2A), Centre of excellence of neurodegenerative disease (CoEN), Department of Neurology, Paris, France 20 Inserm Sorbonne Université, Inria, Aramis project-team, Paris Brain Institute – Institut du Cerveau (ICM), Paris, France 21 Department of Molecular Imaging & Therapy, Austin Health, Melbourne, Australia 22 Department of Psychiatry, University of Pittsburgh, Pittsburgh, USA 23 Department of Psychiatry, University of Cologne, Cologne, Germany 24 German Center For Neurodegenerative Diseases/Clinical Research, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Zentrum für klinische Forschung/AG, Cologne, Germany 25 Department of Neurodegenerative Diseases and Psychiatry, University Hospital Bonn, Bonn, Germany 26 Functional Neuroimaging Group, Department of Radiology, University Hospital Bonn, Bonn, Germany 27 Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Berlin - CBF, Berlin, Deutschland 28 Fundació ACE, Institut Català de Neurociències Aplicades, Facultat de Medicina, Universitat International de Catalunya-Barcelona, Barcelona, Spain 29 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain 30 Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA 31 Institut National de la Sant. et de la Recherche M.dicale (Inserm), Caen, France 32 Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland 33 Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden 34 Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic 35 International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic 36 Neurology Department, Hospital de Sant Pau, Barcelona, Spain 37 Centre for Studies on Prevention of Alzheimer’s Disease (StOP-AD) Centre, Montreal, Quebec, Canada 38 Department of Geriatric Psychiatry, Psychiatric University Hospital, Zürich, Switzerland 39 Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland 40 Vrije Universiteit Brussel, (VUB) Brussels, and University of Antwerp, Antwerp, Belgium Correspondence Olin Janssen, Department of Psychiatry and Abstract Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Introduction: The evidence for characteristics of persons with subjective cognitive Maastricht University, P.O. Box 616, 6200 MD, decline (SCD) associated with amyloid positivity is limited. Maastricht, the Netherlands. Email: olin.janssen@maastrichtuniversity.nl Methods: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, Funding information domain-specific complaints, concerns, feelings of worse performance) demographics, National Institutes of Health; EMIF, Grant/Award Number: 115372; Euro- setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms pean Union’s Seventh Framework Program, with amyloid positivity. Grant/Award Number: FP7/2007-2013; Fun- dació ACE Institut Català de Neurociències Results: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Aplicades; CIBERNED; Instituto de Salud Car- Only older age, clinical setting, and APOE ε4 carriership showed univariate associations los III; Fondo Europeo de Desarrollo Regional; Fundación Española para el Fomento de la with increased amyloid positivity. After adjusting for these, lower education was also Investigación de la Esclerosis Lateral Amiotró- associated with increased amyloid positivity. Only within a research setting, informant- fica; Global Brain Health Institute; Fundació Catalana Síndrome de Down confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. Discussion: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals. KEYWORDS Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography, subjective cog- nitive decline 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1834 JANSSEN ET AL . 1 INTRODUCTION RESEARCH IN CONTEXT Cognitively normal persons with evidence of cerebral amyloidosis, as measured with positron emission tomography (PET) or cerebrospinal 1. Systematic review: Previous inconsistent findings on fluid (CSF), are considered an early stage of Alzheimer’s disease (AD), subjective cognitive decline (SCD) as a specific indicator that is, preclinical AD.1,2 These persons are at an increased risk of of amyloid positivity, with some studies reporting an asso- developing AD-type dementia.3,4 Identification of preclinical AD is ciation of SCD with amyloid and others reporting no asso- important for the development of treatments that aim to preserve cog- ciation, may be due to heterogeneity in the definition of nitive function. Cognitively unimpaired persons experiencing subjec- SCD and specific complaints. Improved understanding of tive cognitive decline (SCD) are also at an increased risk of developing associations of SCD-specific characteristics with amyloid dementia.5,6 SCD is characterized by perceived cognitive decline in the positivity is needed. absence of cognitive impairment.7 It has been hypothesized that SCD 2. Interpretation: We observed variability in the frequency may be an early manifestation of amyloidosis, and practical, low-cost of amyloid positivity between cohorts ranging from 10% characteristics of SCD could aid in the identification of potential at-risk to 76% when estimated at age 70, which was partly participants. However, previous studies have shown conflicting results attributable to setting and apolipoprotein E gene (APOE) on whether SCD is a specific indicator of amyloidosis, and improved ε4 carriership. In addition to age, setting, and APOE-ε4 understanding of the association of SCD-specific characteristics with carriership, we found associations between amyloid posi- amyloid positivity is needed. tivity and informant confirmation of complaints, memory Some studies reported an association between memory complaints complaints, attention/concentration complaints, feelings or concerns and presence of amyloid pathology,8–11 whereas others of worse performance, and depressive symptoms. These reported similar levels of amyloid pathology in cognitively normal indi- associations were found mainly in a research setting. viduals with and without SCD.3,12 These inconsistent findings may be 3. Future directions: Future research areas are longitudi- due to heterogeneity in the definition and assessment of SCD and spe- nal relationships of SCD characteristics with amyloid and cific complaints13 and in the underlying causes of SCD. In an attempt other AD biomarkers, and associations with clinical pro- to reduce part of this heterogeneity between studies, Jessen et al.13,14 gression. suggested characteristics to be collected in studies on SCD that are assumed to increase the likelihood of the presence of amyloid pathol- ogy in persons with SCD, such as memory complaints rather than attention/concentration complaints, concerns associated with SCD, and informant confirmation of complaints.13,14 It remains unknown HIGHLIGHTS whether these SCD-specific enrichment characteristics for preclinical ∙ We examined subjective cognitive decline characteristics AD are associated with amyloid positivity across studies. Furthermore, associated with amyloid. the characteristics suggested for studies on SCD also included more ∙ Large variability exists in amyloid positivity between general risk factors for amyloidosis such as older age,15,16 apolipopro- cohorts of persons with subjective cognitive decline (SCD). tein E gene (APOE) ε4 carriership,15 and the presence of neuropsychi- ∙ Older age, memory clinic setting, and apolipoprotein E atric symptoms,17 which may further influence the potential associa- gene (APOE) ε4 carriership were related to amyloid posi- tions between SCD characteristics and amyloid positivity, as well as tivity. study setting.6,18 Previous studies examining the association of charac- ∙ A number of SCD-specific characteristics were also teristics of persons with SCD with amyloid positivity were performed related to amyloid positivity. within a single cohort19,20 or focused on age and APOE ε4 carriership ∙ SCD-specific characteristics may facilitate identifying as characteristics of persons with SCD.10,11 amyloid-positive persons. This study investigates which general and SCD-specific characteris- tics are associated with amyloid positivity using individual participant- level data from 20 cohorts included in the Amyloid Biomarker Study.3,21 In addition, sources of heterogeneity in amyloid positivity cohorts using amyloid biomarkers on PET or CSF.3,21 The aim of between cohorts are examined. the Amyloid Biomarker Study is to obtain a better understanding of the pathophysiology of AD. Study selection and data collection are 2 METHODS described in Jansen et al.3 For the current analyses, we included 1640 participants with SCD from 20 cohorts (Table 1). All participants expe- 2.1 Participants rienced cognitive decline in the absence of objective decline on neu- ropsychological assessment, and each participant was classified as SCD Participants were selected from the Amyloid Biomarker Study, an either based on presentation to a memory clinic or upon assessment. In ongoing worldwide data-pooling initiative that collects data from research settings, participants were typically classified as SCD based 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1835 TA B L E 1 Data availability for the different measures memory-specific complaints, attention/concentration-specific com- plaints, informant confirmation of complaints, concerns about the Measure N individuals N cohorts complaints, and feelings of worse cognitive performance compared to Age 1640 20 others of the same age group. Not all characteristics were available Sex 1640 20 for all cohorts, as shown in Table 1. Education was dichotomized as Education 1481 20 lower or higher than the total sample median of 14 years. Setting APOE ε4 carriership 1354 16 was defined as clinical if patients presented with cognitive complaints Setting 1639 20 at a health care facility or as research if participants were asked to Memory-specific complaints 1133 18 participate in research and recruited through advertisements or from Attention/concentration-specific 688 11 other departments within the health care facility. All SCD-specific complaints characteristics were dichotomized as present or absent. Supplemental Informant confirmation of complaints 693 12 Tables 3 and 4 show the definition of SCD and measurement details for Concerns or worries about the 684 9 each of these characteristics for the different cohorts. complaints Feelings of worse performance 1144 13 compared to others of the same age 2.3 Statistical analyses group Symptoms of depression 1257 19 Differences in AD risk factors and SCD-specific characteristics Symptoms of anxiety 1015 17 between amyloid-positive and amyloid-negative participants were Abbreviation: APOE, apolipoprotein E gene. analyzed using independent samples t tests for continuous vari- ables and χ2 tests for categorical variables. Generalized estimat- ing equations (GEEs) were used to examine the combined individ- on an interview or questionnaire. In clinical settings, SCD was clas- ual participant-level data from different cohorts, and GEEs allow for sified based on a clinical interview, a questionnaire, or a multidisci- modeling non-independencies in the data such as clustering of par- plinary consensus meeting (Supplemental Table 3). Characteristics of ticipants within cohorts.21–23 A logit link function for binary outcome the included cohorts are displayed in Supplemental Table 1. Written with an exchangeable correlation structure was assumed to account informed consent to participate was obtained from all participants for within-cohort correlation. First, we examined heterogeneity in and data were de-identified by the respective cohorts. Study protocols amyloid-positivity frequencies between the different cohorts. Second, were approved by the respective local ethics committees. we examined the association of each AD risk factor and SCD-specific characteristic with the frequency of amyloid positivity in separate, uncorrected GEE analyses. Third, we combined all significant charac- 2.2 Measures teristics in one GEE model and examined the effect of the remain- ing characteristics by adding them one-by-one separately to the GEE 2.2.1 Amyloid assessment model and by testing two-way interaction effects with the significant characteristics from analysis 2. For any interaction effect with one of Our primary outcome measure was amyloid beta (Aß) deposition mea- the significant characteristics from analysis 2, we calculated stratified sured by PET or CSF biomarkers, dichotomized as normal and abnor- mean predicted values for various levels of the individual character- mal using study-specific cut-offs or upon visual read for PET (Supple- istics (eg, for different ages, for APOE ε4 carriers vs non-carriers, or mental Table 2). Amyloid positivity was assessed using amyloid-PET for research vs clinical settings). Nonsignificant terms were removed in 499 participants (six cohorts) and using amyloid ß1-42 level in CSF step by step for each model based on the highest P-values. Terms were in 1141 participants (15 cohorts). When both PET and CSF amyloid retained in each model equation when the Wald statistic was signifi- measures were available, we selected the modality that resulted in the cant (P < .05). Significant terms in each model are described in Sup- greatest number of participants for each cohort for the primary analy- plemental Table 5. Additional analyses included examining discrepan- ses. cies in amyloid positivity between PET and CSF measures and exam- ining discrepancies between self- and informant-reported complaints. All analyses were performed using SPSS statistical software, version 26 2.2.2 AD risk factors and SCD-specific (IBM Corp). characteristics We examined risk factors previously associated with AD and SCD- 3 RESULTS specific characteristics. The AD risk factors included age, sex, education, setting, presence of APOE ε4 genotype, and symptoms We included 1640 participants with SCD (mean age 66.8 (SD 7.95) of depression and anxiety. SCD-specific characteristics included13 years), of which 863 (53%) were women and 363 (21%) were 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1836 JANSSEN ET AL . TA B L E 2 Sample characteristics according to amyloid status All Amyloid negative Amyloid positive N individuals 1640 1277 363 Age, y (SD) 66.8 (7.95) 66.1 (7.91) 69.2 (7.61)** Education, N (%) low (< 14 years) 810/1481 (55) 618/1144 (54) 192/337 (57) MMSE, N, mean (SD) 1141, 28.6 (1.64) 849, 28.6 (1.62) 292, 28.6 (1.69) Sex, N (%) women 863/1640 (53) 677/1277 (53) 186/363 (51) p-tau positive, N (%) 357/1093 (33) 237/839 (28) 120/254 (47)** APOE ε4 carrier, N (%) 464/1354 (34) 303/1074 (28) 161/208 (58)** Setting, N (%) memory clinic 1108/1639 (68) 822/1276 (64) 286/363 (79)** Memory-specific complaints, N (%) yes 702/1133 (62) 534/884 (60) 168/249 (68) Attention/concentration-specific complaints, N (%) yes 261/952 (38) 193/553 (35) 68/135 (50)* Informant confirmation of complaints, N (%) yes 377/693 (54) 292/559 (52) 85/134 (63)* Concerns or worries about the complaints, N (%) yes 492/684 (72) 399/558 (72) 93/126 (74) Feelings of worse performance compared to others of 501/1144 (44) 349/901 (44) 107/243 (44) the same age group, N (%) yes Symptoms of depression, N (%) yes 227/1257 (18) 185/980 (19) 42/277 (15) Symptoms of anxiety, N (%) yes 166/1015 (16) 132/791 (17) 34/224 (15) Note: N is displayed as N/total available N for each characteristic, % is the percentage within the available N. SD, standard deviation; APOE, apolipoprotein E; p-tau, phosphorylated tau. *P < .05 or. **P < .001 for difference between amyloid positive persons and amyloid-negative persons. Data availability for the different measures is shown in Table 1. amyloid positive. This is comparable to the observed prevalence of istics were associated with amyloid positivity in these univariate anal- amyloid positivity in 697 participants with SCD included in our pre- yses. vious study (22% in CSF and 23% in PET).23 Table 2 shows sample Because the AD risk factors age, setting, and APOE ε4 carriership characteristics according to amyloid status. Compared with amyloid- were associated with amyloid positivity in the univariate analyses, we negative persons, amyloid-positive persons were older, more often CSF next performed multivariate analyses including age, setting, and APOE phosphorylated tau (p-tau) positive, more often APOE ε4 carriers, more ε4 carriership, and we tested separately for each variable that was not often recruited from a memory clinic setting, more often had atten- significant in the univariate analyses whether they had an association tion/concentration complaints, and informants more often confirmed with amyloid positivity or an interaction effect with one of these three their complaints. factors. We found a higher frequency of amyloid positivity in persons with a lower education (28% at age 70, vs 23% for higher education, P < .001, Figure 3E and Supplemental Table 5, analysis 3). 3.1 Heterogeneity in amyloid positivity In addition, the associations of informant confirmation of com- plaints, memory complaints, attention/concentration complaints, and Figure 1 demonstrates heterogeneity between cohorts in age-related depressive symptoms with amyloid positivity were dependent on set- frequencies of amyloid positivity for persons with SCD. There was con- ting (P < .001 for informant confirmation of complaints, P < .001 for siderable heterogeneity, as mean amyloid positivity estimates at age 70 memory complaints, P < .001 for attention/concentration complaints, ranged from 10% to 76% (Supplemental Table 6). and P = .035 for depressive symptoms, Supplemental Table 5, analy- sis 3). Within a research setting, amyloid positivity was higher if com- plaints were confirmed by an informant (21% at age 70) compared to 3.2 Associations with amyloid positivity those without confirmation (8%, Figure 3A and Supplemental Figure 1A), higher in persons with complaints specific to memory (25% at age In univariate analyses with AD risk factors, older age (18% at age 60, 70) compared to persons without complaints specific to memory (9%, 27% at age 70, and 39% at age 80; P < .001), a memory clinic setting Figure 3B and Supplemental Figure 1B), higher in persons with com- (28% vs 17% for research setting, P = .008), and APOE ε4 carriership plaints specific to attention/concentration (34% at age 70) compared to (37% vs 16% for APOE ε4 non-carriers, P < .001) were associated with persons without complaints specific to attention/concentration (14%, higher frequencies of amyloid positivity, whereas sex, education, and Figure 3C and Supplemental Figure 1C), and higher in persons with- symptoms of depression and anxiety were not (Figure 2, Supplemental out depressive symptoms (17% at age 70) compared to persons with Table 5, analysis 1 and analysis 2). None of the SCD-specific character- depressive symptoms (8%, Figure 3D and Supplemental Figure 1D). 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1837 F I G U R E 1 Heterogeneity in amyloid positivity between the included cohorts. Note: Prevalence of amyloid positivity is shown on the Y-axis and age is shown on the X-axis. Each line represents a different cohort. Characteristics of the different cohorts are described in Supplemental Table 1 Within a memory clinic setting, informant confirmation of complaints, The number of participants for which data were available for each memory complaints, attention/concentration complaints, and depres- combination of characteristics is shown in Supplemental Table 7. Fig- sive symptoms were not associated with amyloid positivity. ure 4 is a heat map showing the estimated frequency of amyloid posi- Furthermore, the influence of feelings of worse performance was tivity based on combinations of characteristics (associated confidence dependent on age (P = .005). In younger persons, feelings of worse per- intervals are displayed in Supplemental Table 8). The heat map visual- formance were associated with a lower frequency of amyloid positiv- izing the frequency of amyloid positivity by age, setting, APOE ε4 carri- ity (at age of 50: 4% with feelings of worse performance, vs 7% with- ership, and other SCD characteristics may assist interpretation of our out feelings of worse performance, P = .017), whereas in older per- findings. For example, in 70-year-olds, the frequency of amyloid pos- sons, feelings of worse performance were associated with a higher fre- itivity was lowest in APOE ε4 non-carriers in a research setting with- quency of amyloid positivity (at age 90: 68% with feelings of worse per- out informant confirmation of complaints (3%) and highest in APOE ε4 formance, vs 50% without feelings of worse performance, P = .021, Fig- carriers in a memory clinic setting with lower educational attainment ure 3F and Supplemental Figure 1F). No associations with amyloid pos- (54%). Although differences were relatively small compared with the itivity were found of sex, anxiety, and concerns about the complaints. effects of age, setting, and APOE ε4 carriership, the estimates differed 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1838 JANSSEN ET AL . F I G U R E 2 Amyloid positivity by age, setting, and APOE ε4 carriership. Note: Frequency of amyloid positivity for individuals with SCD is shown on the Y-axis, and age is shown on the X-axis. Each line represents a different combination of APOE ε4 carriership and setting. Number of participants included for each combination is shown in Supplemental Table 8 up to 31% for persons with versus without specific SCD characteristics 3.3.2 Influence of amyloid biomarker modality with similar age, setting, and APOE ε4 carriership. No difference was found in the in age-related frequency of amyloid positivity by biomarker modality. The frequency of amyloid positivity 3.3 Sensitivity analyses at age 70 was 26% (20% to 33% confidence interval) based on PET, and 28% (22% to 35% confidence interval, P = .556) based on CSF. Sam- 3.3.1 Heterogeneity when taking into account age, ple sizes did not allow examining the association of each characteristic setting, and APOE ε4 carriership with amyloid positivity based on PET or CSF separately. Supplemental Figure 2 demonstrates heterogeneity in amyloid- positivity frequencies between the included cohorts, when taking into 3.3.3 Discrepancy between self-reported and account age, setting, and APOE ε4 carriership. Variability in amyloid informant-reported complaints positivity between cohorts was larger in cohorts from a memory clinic setting than from a research setting (estimates at age 70 ranged from Discrepancy between self-reported memory complaints and informant 7% to 73% for APOE ε4 non-carriers in a memory clinic setting [11 confirmation of complaints occurred in 170 individuals (reported in cohorts] vs 2% to 19% for APOE ε4 non-carriers in a research setting 546 participants from nine cohorts), but was not associated with [6 cohorts]) and ranged from 23% to 91% for APOE ε4 carriers in a amyloid positivity in the model, including age, setting, and APOE memory clinic setting [11 cohorts] vs 6% to 45% for APOE ε4 carriers ε4 carriership (16% for discrepancy vs 15% for no discrepancy, in a research setting [6 cohorts]). P = .443). 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1839 F I G U R E 3 Amyloid positivity by age within APOE ε4 carriers (A-D) according to different subgroups of setting and informant confirmation (3A), setting and memory complaints (3B), setting and attention/concentration complaints (3C), or setting and depression (3D); and amyloid positivity by age within a memory clinic setting according to different subgroups of APOE ε4 carriership and education (3E), or APOE ε4 and feelings of worse performance (3F). Note: (A–D) show interaction with setting, and (E and F) show interactions with APOE ε4 carriership or age. A was based on the model including age, setting, APOE ε4 carriership, and informant confirmation of complaints, and shows estimated amyloid positivity for APOE ε4 carriers only. (B) was based on the model, including age, setting, APOE ε4 carriership, and complaints specific to memory, and shows estimated amyloid positivity for APOE ε4 carriers only. (C) was based on the model, including age, setting, APOE ε4 carriership, and complaints specific to attention/concentration, and shows estimated amyloid positivity for APOE ε4 carriers only. (D) was based on the model including age, setting, APOE ε4 carriership, and depressive symptoms, and shows estimated amyloid positivity for APOE-ε4 carriers only. (E) was based on the model including age, setting, APOE ε4 carriership, and education, and shows estimated amyloid positivity for a memory clinic setting only. (F) was based on the model including age, setting, APOE ε4 carriership, and feelings of worse performance, and shows estimated amyloid positivity for a memory clinic setting only. Results shown in (A–D) show a similar pattern for APOE ε4 non-carriers, and results shown in (E and F) show a similar pattern for persons in a research setting (Supplemental Figure 1A-1F). Data for each combination of characteristics are shown in Supplemental Table 7 4 DISCUSSION We noted a large variability in the frequency of amyloid positivity between cohorts ranging from 10% to 76% when estimated at age 70. The present study examined the association of different AD risk fac- This indicates that SCD indeed is a heterogeneous concept and the con- tors and SCD-specific characteristics with amyloid positivity in a large cept itself does not seem to be a predictor of amyloid positivity. We sample of 1640 participants with SCD from 20 cohorts. We found that found that part of this heterogeneity can be attributed to age, setting, in individuals with SCD, only older age, a memory clinic setting, and and APOE ε4 carriership. Older age, a memory clinic setting, and APOE APOE ε4 carriership were univariately associated with amyloid positiv- ε4 carriership were associated with a higher frequency of amyloid pos- ity, and none of the SCD-specific characteristics. When adjusting for itivity, which is in line with previous studies.6,15 these three factors, lower education was associated with increased When adjusting for age, setting, and APOE ε4 carriership, we found amyloid positivity. The associations of the SCD-specific characteris- that higher education was associated with a lower frequency of amy- tics informant confirmation of complaints, memory complaints, atten- loid positivity, which is in accordance with a lower risk for AD-type tion/concentration complaints, and depressive symptoms with amy- dementia in persons with a higher educational attainment but conflicts loid positivity were dependent on setting and were found within a with the general explanation that education lowers the risk of devel- research setting only. The association of feelings of worse performance oping dementia by compensation of the effects of brain pathology.24,25 depended on age: there was a higher frequency of amyloid positivity at In our previous study,3 we reported an increased frequency of amy- older ages and a lower frequency at lower ages. loid positivity with higher education in persons with normal cognition, 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1840 JANSSEN ET AL . F I G U R E 4 Heat map showing the mean predicted amyloid positivity by age, setting, APOE ε4 carriership, and significant characteristics from analysis 3. Note: Green colors indicate lower frequencies of amyloid positivity, and red colors indicate higher frequencies of amyloid positivity. Table columns contain the main characteristics age, setting, and APOE ε4 carriership, and rows contain additional characteristics that were associated with lower or higher frequency of amyloid positivity. Results are displayed for age 60, 70, and 80. Some of the combinations of characteristics were not available for persons age60, 70, or 80 and a slightly younger or older age was selected in 9% of the combinations (range from 3 years younger to 1 year older). *P < .05 or **P < .001 for difference between row characteristic (lower education vs higher education, without vs with informant confirmation of complaints, without vs with complaints specific to memory, without vs with complaints specific to attention/concentration, without vs with feelings of worse performance, without vs with depressive symptoms, respectively). but we did not separately examine associations of education with amy- underlying pathophysiology is apparently partly associated with set- loid positivity in persons with SCD. Furthermore, higher educational ting and may be related to medical help-seeking.30 attainment was more frequent in the group of persons without SCD Of interest, the presence of feelings of worse performance was asso- (64% >14 years) compared to our present sample of persons with SCD ciated with a higher frequency of amyloid positivity in older persons (45% >14 years), and none of the participants with normal cognition only. In younger persons, feelings of worse performance might be due were from a memory clinic setting. to functional cognitive disorders31 rather than underlying AD pathol- Some SCD-specific characteristics were associated with amyloid ogy. Similar results were described in reviews by Jonker et al.,32 who positivity only in a research setting. Memory complaints as opposed to found that in younger persons with memory complaints that these complaints in non-memory domains, attention/concentration-specific complaints generally refer to neuropsychiatric symptoms or personal- complaints, and informant confirmation of complaints were indica- ity factors, and Rabin et al.,33 who also found that underlying causes of tive of amyloid positivity in a research setting only. Although previ- complaints vary with age. ous studies that were conducted within a single research or clinical Overall, effect sizes of education, informant confirmation of setting reported associations of memory complaints8,20,26 and infor- complaints, memory complaints, attention/concentration complaints, mant confirmation of complaints20,27 with amyloid positivity, we did depressive symptoms, and feelings of worse performance were rela- not observe such associations in our analyses. Possibly the lack of tively small and of limited added value in explaining heterogeneity in discriminative value of these characteristics in a memory clinic set- amyloid positivity in persons with SCD next to age, setting, and APOE ting results from the fact that memory complaints and informant con- ε4 carriership, which showed the strongest effects in our analyses. firmation are common in this setting (Supplemental Table 7). More- Most associations of SCD-specific characteristics with amyloid posi- over, a previous single-center study did not find an association of tivity were only seen in a research setting, implicating potential value attention/concentration complaints with amyloid positivity, whereas within research settings. The lack of associations with amyloid positiv- we did observe an association.28 Because the single-center study cor- ity of these SCD-specific characteristics in clinical settings could mean rected for age, sex, education, and depressive symptoms, direct com- that they are of less value within clinical settings. parisons are difficult. Furthermore, we found that depressive symp- In the present study, we combined data collected within a large num- toms were associated with a lower frequency of amyloid positivity ber of cohorts in different settings to examine associations between within a research setting only. Affective disorders are commonly asso- AD risk factors and SCD characteristics and amyloid positivity. A lim- ciated with SCD,13 but affective symptoms have also been associated itation of our study is that most cohorts only collected data on a subset with incident AD-type dementia in at-risk individuals.29 The risk of of characteristics of the subjective complaints. This may be explained 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1841 by the fact that most cohorts started data collection before the intro- (ADNI) database (adni.loni.usc.edu). As such, the investigators duction of the SCD research criteria and that collection of these char- within the ADNI contributed to the design and implementa- acteristics has not been fully implemented in clinical and research prac- tion of ADNI and/or provided data, but they did not partici- tice. Therefore, a limitation inherent to our approach is that each analy- pate in analysis or writing of this report. A complete listing of sis included a different sample and that statistical power was relatively ADNI investigators can be found at: http://adni.loni.usc.edu/wp- small for a number of characteristics. A limitation inherent to combin- content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf ing data from multiple studies is the use of different assessment meth- The ADNI was launched in 2003 as a public-private partnership led ods to define each characteristic. Although all assessment methods are by Principal Investigator Michael W. Weiner, MD. The primary goal transparently shown in Supplemental Table 3, caution is warranted in of ADNI has been to test whether serial magnetic resonance imaging comparing studies. However, despite considerable heterogeneity, asso- (MRI), positron emission tomography (PET), other biological markers, ciations were found across the different cohorts. Examining the influ- and clinical and neuropsychological assessment can be combined to ence of assessment method (clinical interview vs scale) for the differ- measure the progression of mild cognitive impairment (MCI) and early ent SCD characteristics was not possible due to the used definitions Alzheimer’s disease (AD). for SCD characteristics: most studies defined the presence of specific Data collection and sharing for this project was funded by the ADNI characteristics based on one item from a questionnaire or based on a (National Institutes of Health Grant U01 AG024904) and DOD ADNI specific question within a structured interview. Furthermore, sample (Department of Defense award number W81XWH-12-2-0012). ADNI sizes did not allow analyses stratified by modality, and potential influ- is funded by the National Institute on Aging, the National Institute ence of amyloid modality on the associations reported in the present of Biomedical Imaging and Bioengineering, and through generous study cannot be excluded. However, no main effect of modality was contributions from the following: AbbVie, Alzheimer’s Association; found in univariate analyses. Finally, the cross-sectional nature of the Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, present study does not allow assessment of stability of the SCD char- Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; acteristics over time. Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroIm- mun; F. Hoffmann-La Roche Ltd and its affiliated company Genen- tech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer 5 CONCLUSIONS AND IMPLICATIONS Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Our findings show that next to age, setting, and APOE ε4 carrier- Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; ship, other characteristics in the context of SCD related to amyloid Neurotrack Technologies; Novartis Pharmaceuticals Corporation; pathology are education, informant confirmation of complaints, mem- Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Com- ory complaints, attention/concentration complaints, feelings of worse pany; and Transition Therapeutics. The Canadian Institutes of Health performance, and depression, but mostly within a research setting only. Research is providing funds to support ADNI clinical sites in Canada. Our findings show that enrichment characteristics for preclinical AD Private sector contributions are facilitated by the Foundation for the proposed in the SCD research criteria13 indeed are associated with National Institutes of Health (www.fnih.org). The grantee organization amyloid pathology, but these associations often depend on age and set- is the Northern California Institute for Research and Education, and ting. Our study also suggests that education is an additional character- the study is coordinated by the Alzheimer’s Therapeutic Research istic important to consider in studies on SCD. Inclusion of practical, low- Institute at the University of Southern California. ADNI data are cost AD risk factors, and SCD-specific characteristics aids in the iden- disseminated by the Laboratory for Neuro Imaging at the University of tification of individuals that will likely benefit from disease-modifying Southern California. A proportion of data used in preparation of this treatment. However, the effect sizes of the SCD-specific characteris- article were obtained from the Pre-symptomatic Evaluation of Novel tics were relatively small and of limited added value next to age, APOE or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD) ε4 carriership, and across settings. Because it has been suggested pre- program (htpp://douglas.research.mcgill.ca/stop-ad-centre), data viously that consistency over time of SCD characteristics is associated release 5.0 (November 30, 2017). As such, the investigators of the with a greater risk of future decline,14,34 the longitudinal relationship PREVENT-AD program contributed to the design and implementation between SCD characteristics with amyloid and other AD biomarkers, of PREVENT-AD and/or provided data but did not participate in as well as associations with clinical progression are important areas analysis or writing of this report. A complete listing of PREVENT- for future research. Future research might also examine this longitu- AD Research Group can be find in the PREVENT-AD database: dinal relationship in individuals with evidence of both amyloidosis and http://preventad.loris.ca/acknowledgements/acknowledgements.php? tauopathy, since these individuals might be at increased risk of clinical date = [2020 = 04-01]. progression. The present study was supported by European Medical Informa- tion Framework (EMIF)-AD. The EMIF-AD project has received sup- ACKNOWLEDGEMENTS port from the Innovative Medicines Initiative Joint Undertaking under *A proportion of the data used in preparation of this article was EMIF grant agreement no. 115372, resources of which are com- obtained from the Alzheimer’s Disease Neuroimaging Initiative posed of financial contribution from the European Union’s Seventh 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1842 JANSSEN ET AL . Framework Program (FP7/2007-2013) and EFPIA companies’ in kind University of Perugia, Department of Medicine and Surgery. - From contribution. 2019: MIRIADE funded under Marie Skłodowska-Curie actions by the The Fundació ACE Healthy Brain Initaitive (FACEHBI) study was European Union’s Horizon 2020 research and innovation programme. supported by funds from Fundació ACE Institut Català de Neurocièn- Payments were made to University of Perugia. From 2019: bPRIDE cies Aplicades, Grifols, Life Molecular Imaging, Araclon Biotech, Alkah- project funded by the European Joint Programming on Neurodegen- est, Laboratorio de análisis Echevarne and IrsiCaixa. erative Diseases (JPND, European Union’s Horizon 2020 research and Research of Alzheimer Centre Amsterdam is part of the neurode- innovation programme). Payments were made to University of Perugia; generation research program of Amsterdam Neuroscience. Alzheimer is member of the Editorial Board of the following journals (unpaid): • Centre Amsterdam is supported by Stichting Alzheimer Nederland and Neurology • Movement Disorders • Biomolecules • Scientific Reports • Stichting VUmc fonds. The SCIENCe project is supported by research Frontiers in Aging Neuroscience • Cells • Journal of Alzheimer Disease grants from Gieskes-Strijbis fonds and stichting Dioraphte. Wiesje van • Biomarker Insights • Journal of Integrative Neuroscience Lucilla Par- der Flier holds the Pasman chair. netti is member of the following societies (unpaid): - Since 2019: Mem- The Sant Pau Memory Unit has received funding from Centro de ber of the Fresco Network for Parkinson’s disease. - Since 2020: Mem- Investigación Biomédica en Red sobre Enfermedades Neurodegenera- ber of the Research Council of Norway, Member of the Icelandic Centre tivas (CIBERNED); Instituto de Salud Carlos III; jointly funded by Fondo for Research, Coordinator of a Center of Excellence of the Parkinson Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera Foundation; and received Lumipulse kits from Fujirebio and ELISA kits de hacer Europa”; Generalitat de Catalunya; Fundació "La Marató TV3” from Euroimmun (2021) Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Tormod Fladby reports receiving research support for the present Española para el Fomento de la Investigación de la Esclerosis Lateral manuscript from European Union (EU)/Joint Programming on Neu- Amiotrófica (FUNDELA); Global Brain Health Institute; Fundació Cata- rodegenerative Diseases (JPND) and The Norwegian Research lana Síndrome de Down; and Fundació Víctor Grífols i Lucas. Council; receiving consulting fees from Biogen and Novo Nordisk; The Imagerie Multimodale de la maladie d’Alzheimer a un stade having several planned, issued, and pending patents regarding innate Precoce (IMAP) study (G Chételat, Caen) was supported by the Pro- immune amyloid beta clearance and regulation of inflammation; gramme Hospitalier de Recherche Clinique (PHRCN 2011-A01493- participating on Data Safety Monitoring Board or Advisory Board 38 and PHRCN 2012 12-006-0347), the Agence Nationale de of Biogen, Novo, and Nordisk; and is leader of the board of Nansen la Recherche (ANR LONGVIE 2007), Fondation Plan Alzheimer Neuroscience (unpaid). (Alzheimer Plan 2008–2012), Association France Alzheimer et mal- José Luis Molinuevo is currently a full-time employee of Lund- adies apparentées AAP 2013, the Région Basse Normandie and the beck and earlier has served as a consultant or at advisory boards for Institut National de la Santé et de la Recherche Médicale (INSERM). the following for-profit companies, or has given lectures in symposia A proportion of data used in preparation of this article were sponsored by the following for-profit companies: Roche Diagnostics, obtained from the LeARN study and prepared by Ron Handels. The Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green LeARN study was performed within the framework of CTMM, the Cen- Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neuro- ter for Translational Molecular Medicine, a Dutch public-private part- sciences, NovoNordisk, Zambón, Cytox, and Nutricia. nership; project LeARN (grant 02 N-101). Sylvia Villeneuve reports receiving research support from Canadian The Amyloid Biomarker Study was supported by Biogen, which pro- Institutes of Health Research (CIHR). vided financial support for the conduct of the research. Biogen was not Jakub Hort reports research support from Czech Ministry of Health involved in the collection, analysis, and interpretation of data, or in the and honoraria for lectures by Schwabe and Lundbeck, as well as travel writing of the report or the decision to submit the article for publica- grant from Czech grant agency and participating in a Data Safety Mon- tion. itoring Board or Advisory Board from Axon company and having stock options in Alzheon company. CONFLICT OF INTEREST Stéphane Epelbaum reports research support from Fondation Willemijn Jansen reports receiving research support from Biogen. Recherche Alzheimer and consulting fees from Biogen and Roche, hon- Olin Janssen reports receiving research support from Biogen. oraria for presentation from Eisai, and travel support from Edimark. Stephanie Vos reports receiving a personal grant from ZonMw, Alberto Lleó reports research support from Instituto de Car- and research support from Alzheimer Nederland and Stichting Rinsum los III: Fondo de Investigación Sanitario (PI17:01896; PI20/01330; Ponssen. AC19:00103); payment to the institution Instituto de Carlos III: Merce Boada reports receiving research support from Grifols and CIBERNED (COEN); payment to the institution, patent royalties (per- the Instituto de Salud Carlos III (ISCIII) grant; receiving consulting fees; sonal and institutional payments); personal consulting fees from Bio- and participating on Data Safety Monitoring Board or Advisory Board gen, Nutricia, Roche, and Fujirebio-Europe; personal fees from Bio- from Biogen, Roche, Merck, Zambon, Cortexyme. gen and Nutricia for lectures or educational programs; and patent Lucilla Parnetti reports receiving funds for clinical trials from WO2019175379 A1 Markers of synaptopathy in neurodegenerative INDENA S.P.A., Biogen, EISAI Co., Ltd.; payments were made to disease issued. 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1843 Sebastiaan Engelborghs reports participating in Data Safety Moni- Agustin Ruíz receives research support from the Innovative toring Boards or Advisory Boards of Biogen, Eisai, Icometrix, Novartis, Medicines Initiative 2 Joint Undertaking, which receives support from Pfizer, and Roche. the European Union’s Horizon 2020 research and innovation pro- Wiesje M van der Flier reports receiving research funding from gramme (ADAPTED Grant No. 115975). AR’s research is also sup- ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVas- ported by Instituto de Salud Carlos III (ISCIII) grants PI16/01861 cular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences and PI19/01301. Acción Estratégica en Salud, integrated in the Span- & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equi- ish National R+D+I Plan and funded by ISCIII-Subdirección Gen- librio, Pasman stichting, Biogen MA Inc, Boehringer Ingelheim, Life- eral de Evaluación and the Fondo Europeo de Desarrollo Regional MI, AVID, Roche BV, Fujifilm, and Combinostics. WF holds the Pas- (FEDER-“Una manera de Hacer Europa) and JPco-fuND-2 “Multina- man chair. WF has performed contract research for Biogen MA Inc and tional research projects on Personalised Medicine for Neurodegerative Boehringer Ingelheim. WF has been an invited speaker at Boehringer Diseases” PREADAPT project, and reports consulting fees from Land- Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Med- steiner Genmed, Grifols, Araclon biotech and lecture fees from Ara- scape). All funding is paid to her institution; and she is consultant to clon Biotech; has EU Patent EP21382305.7; and participated on Data Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc, and is Safety Monitoring Board or Advisory Board of Grifols SA and Land- associate editor at Alzheimer’s, Research & Therapy. steiner Genmed. Susan Landau reports receiving support for the present manuscript Marta Marquié receives research support from the Instituto de from NIH U19 AG024904 (PI: Weiner), funds to the institution (UC Salud Carlos III (ISCIII) grant PI19/00335 Acción Estratégica en Salud, Berkeley); honorarium for speaking at Hillblom Symposium UC San integrated in the Spanish National R+D+I Plan and financed by ISCIII- Francisco 2019; travel fees paid for attending meetings and confer- Subdirección General de Evaluación and the Fondo Europeo de Desar- ences as member of Scientific Program Committee for the Alzheimer’s rollo Regional (FEDER-“Una manera de Hacer Europa). Association International Conference 2017-2019; and participating in PI17/01474 Acción Estratégica en Salud, integrated in the Spanish Advisory Board for KeifeRx. National R+D+I Plan and financed by ISCIII-Subdirección General de Julius Popp reports receiving support from Synapsis Foundation Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- Alzheimer Swiss (to institution; Swiss National Research foundation (to Una manera de hacer Europa), and reports consulting fees from Grifols, institution); Om Pharma Switzerland (to institution), and receiving con- Araclon, Biogen, Roche. Lilly, Schwabe, Cortexyme, Merck and Nutricia. sulting fees from Om pharma Switzerland (to institution). Henning Boecker received 2 x Promotionsstipendium, University Anders Walling reports receiving payment for expert testimony Clinic Bonn, payments were made to institution, and receiving travel from Lundbeck lecture. support from 2019: Sino-German Center for research promotion, co- Philip Scheltens reports receiving research support from ZonMW funded by both DFG and National Science Foundation of China (NSFC) and Alzheimer Nederland and has received consultancy fees (paid to - payments were made to institution (travel reimbursement). the institution) from AC Immune, Alkermes, Alnylam, Alzheon, Anavex, Oliver Peters reports receiving institutional grants from Astra Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Check- Zeneca, Novartis, Biogen, Genentech, Roche, Eisai, and Fujifilm; and point, GemVax, Genentech, Green Valley, Novartis, Novo Nordisk, Peo- received Consulting fees from Biogen, Roche, Eisai, Abbvie, and Grif- pleBio, Renew LLC, and Roche. He is PI of studies with AC Immune, fols, and received payment or honoraria for lectures from Schwabe, CogRx, FUJI-film/Toyama, IONIS, UCB, and Vivoryon. He is a part-time MSD. employee of Life Sciences Partners Amsterdam. He serves on the board Lorena Rami reports research Grant from Spanish government to of Brain Research Center and New Amsterdam Pharma, and partici- IDIBAPS (PI Lorena Rami) grant no. PI19/00745. pated on the Data Safety Monitoring Board of Genentech. Alexa Pichet Binette reports Human Amyloid Imaging conference: Peter J. Snyder is a consultant to AlzeCure Pharma (Sweden). payment made to me Alzheimer’s Association: payments made directly Chris Rowe reports Cerveau Technologies grant paid to institution to waive conference fees. Biogen grant paid to institution, Abbvie grant paid to institution, con- Judes Poirier reports support provided by the Fonds de la sulting fees from Cerveau Technologies, educational materials prepa- Recherche en Santé du Québec and the JL Levesque Foundation and ration payments from Biogen, participating in Cerveau Technologies has served at the scientific advisory board of the CIHR and Alzheimer Scientific Advisory Board, and receiving salary payment from Aus- Foundation of France. tralian Dementia Network. Jiri Cerman reports receiving research support from Charles Uni- Gaël Chételat has received research support from the Euro- versity, and consulting fees from Biogen, as well as participating on pean Union’s Horizon 2020 research and innovation program (grant Data Safety Monitory Board or Advisory Board of Biogen. agreement No. 667696), Inserm, Fondation d’entreprise MMA des Bruno Dubois received consulting fees from Biogen and research Entrepreneurs du Futur, Fondation Alzheimer, Programme Hospital- grants for his institution from Roche and Fondation Merck-Avenir and ier de Recherche Clinique, Région Normandie, Association France received Equipment SIMOA paid by Lions Alzheimer. Alzheimer et maladies apparentées, and Fondation Vaincre Alzheimer Daniele Altomare received research support from Institute of (all to Inserm); and personal fees from Fondation d’entreprise MMA des Health Carlos III (ISCIII), Spain research grants PI18/00435 and Entrepreneurs du Futur. No stock options, patents, or royalties. INT19/00016 to DA Department of Health Generalitat de Catalunya 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1844 JANSSEN ET AL . PERIS research program SLT006/17/125 to DA; consulting fees for travel funding from Eisai, Functional Neuromodulation, Axovant, Eli his participation in advisory boards from Fujirebio-Europe and Roche Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Diagnostics; speaker honoraria from Fujirebio-Europe, Roche Diagnos- Genomics; consultancy fees from Qynapse, Jung Diagnostics, Cytox tics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Phar- Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon maceuticals S.A.; and support for attending meetings from Nutricia. Genomics, and Functional Neuromodulation; and participated in sci- Juan Fortea reports funding from Fondo de Investigaciones Sani- entific advisory boards of Functional Neuromodulation, Axovant, Eisai, tario (FIS), Instituto de Salud Carlos III, to my institution; National Insti- Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfan- tutes of Health, to institution; Fundació La Marató de TV3, to my insti- del, Oryzon Genomics, and Roche Diagnostics. He is co-inventor in tution; Generalitat de Catalunya, to institution; Fundació Catalana Sín- the following patents as a scientific expert and has received no royal- drome de Down, to institution; and -Fundació Víctor Grífols i Lucas; ties: In Vitro Multiparameter Determination Method for The Diagno- and has served as a consultant for Novartis and Lundbeck, has received sis and Early Diagnosis of Neurodegenerative Disorders Patent Num- honoraria for lectures from Roche, NovoNordisk, Esteve, and Biogen; ber: 8916388; In Vitro Procedure for Diagnosis and Early Diagno- has a patent WO2019175379 A1 Markers of synaptopathy in neu- sis of Neurodegenerative Diseases Patent Number: 8298784; Neu- rodegenerative disease issued; and has served at advisory boards for rodegenerative Markers for Psychiatric Conditions Publication Num- AC Immune, Zambon, and Lundbeck, as well as institution received sup- ber: 20120196300; In Vitro Multiparameter Determination Method port from AC Immune to acquire Quanterix NfL Kits. for The Diagnosis and Early Diagnosis of Neurodegenerative Disor- Marie Eckerström reports receiving consulting fees from ders Publication Number: 20100062463; In Vitro Method for The Medavante-prophase, payment for on-demand independent reviewer Diagnosis and Early Diagnosis of Neurodegenerative Disorders Pub- assignments, and payment for lectures from Department of Psychol- lication Number: 20100035286; In Vitro Procedure for Diagnosis ogy, University of Gothenburg. and Early Diagnosis of Neurodegenerative Diseases Publication Num- Louisa Thompson reports receiving grant AACSF-20-685786 ber: 20090263822; In Vitro Method for The Diagnosis of Neurode- Alzheimer’s Association 5/01/2020 – 4/31/2023 payments made to generative Diseases Patent Number: 7547553; CSF Diagnostic in Brown University, and payment or honoraria for lectures from Sage Vitro Method for Diagnosis of Dementias and Neuroinflammatory Bionetworks payments. Diseases Publication Number: 20080206797; In Vitro Method for Victor Villemagne reports receiving consulting fees and payment or The Diagnosis of Neurodegenerative Diseases Publication Number: honoraria for lectures from IXICO Hospicom ACE Alzheimer’s Center. 20080199966; Neurodegenerative Markers for Psychiatric Condi- Rachel Buckley reports research support from NIH-NIA K99/R00 tions Publication Number: 20080131921. This work has been per- Pathway to Independence award Alzheimer’s Association Research formed during his previous position at Sorbonne University, Paris, Fellowship and Alzheimer’s Association International Conference France. At Sorbonne University he was supported by the AXA Research travel fellowship (2019). Fund, the “Fondation partenariale Sorbonne Université” and the “Fonda- Samantha Burnham reports receiving research support from tion pour la Recherche sur Alzheimer,” Paris, France. grants NHMRC GNT1161706, NHMRC GNT1156891, NHMRC Betty M. Tijms is inventor on patent on biological subtypes in AD, GNT1191535, NHMRC GNT2001320, and NHMRC MRFF117 1338. No. PCT/NL2020/050216 (owner stichting VUmc). Marion Delarue reports wages for my work in Chetelat’s lab Frans Verhey reports receiving research support from Profile, EMR (U1237-PhIND) at Caen paid by INSERM or University of Caen Nor- Interreg DISTINCT H2020 All to our institution. mandy (since July 2017); wages for my work in LPCN-EA7452 at Uni- Frank Jessen reports receiving research support for the present versity of Caen Normandy paid by University from IReSP fundings manuscript from German Center for Neurodegenerative Disorders (from January 2021); Punctual Sessions at IFRES (from 2015), paid by (DZNE); personal fees for lectures from Lilly and Roche; and personal "Association Pierre Noal." fees for participating on Data Safety Monitoring Boards or Advisory Inez Ramakers reports research support from Janssen Pharmaceu- Boards of Abbvie, AC Immune, Biogen, Böhringer, Danone, Eisai, GE ticals > to institution and EIT Health > to institution. Healthcare, Green Valley, hummingbird, Janssen, MSDOM Pharma, Hilkka Soininen reports grants from the Academy of Finland, Euro- Roche, and Vifer; Executive committee German Psychiatric Associa- pean Union, and Danone which were paid to institution; as well as tion (DGPPN) Vice chair European Alzheimer’s Disease Consortium personal consultation fee from Novo Nordisk; personal payment for (EADC). membership of a Data Safety Monitoring Board, of ACImmune. Se also Pieter Jelle Visser reports receiving research support from ZonMW reports having been the head of the board of Muistiliitto, which is the (Redefining AD), from ZonMW (Netherlands Consortium of Dementia Finnish Alzheimer Association from 2018-2020 for which no payment Cohorts (NCDC), from Innovative Medicine Initiatives (IMI) (Amypad), was received. from IMI (RADAR-AD), and from Biogen (Amyloid biomarker study Harald Hampel is an employee of Eisai Inc. and serves as Senior group). All payment were made to institution. He also reports receiv- Associate Editor for the journal Alzheimer’s & Dementia and does not ing payment for Workshop grant writing organized by Synapsis; patent receive any fees or honoraria since May 2019. Before May 2019 he PCT/NL2020/050216, and is Senior editor Alzheimer Research and had received lecture fees from Servier, Biogen, and Roche; research Therapy and Biomed Central (BMC) Geriatrics and a Member of the grants from Pfizer, Avid, and MSD Avenir (paid to the institution); Executive board of European Alzheimer’s Disease Cohorts (EADC). 15525279, 2022, 10, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12512 by Readcube (Labtiva Inc.), Wiley Online Library on [06/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JANSSEN ET AL . 1845 Tomasz Gabryelewicz, Marcel Olde Rikkert, Elena Chipi, Steffen clinic: differential affective and imaging correlates. Alzheimers Dement. Wolfsgruber, Michael Heneka, Jonas Jarholm, Adrià Tort-Merino, 2017;13:550-560. 19. Slot RER, Verfaillie SCJ, Overbeek JM, et al. Subjective Cogni- Pedro Rosa-Neto, Jiri Cerman, Marc Teichmann, M. Belén Sánchez- tive Impairment Cohort (SCIENCe): study design and first results. Saudinós, Jarith Ebenau, Cornelia Pocnet, Yvonne Freund-Levi, Åsa K. Alzheimers Res Ther. 2018;10:76. Wallin, Magda Tsolaki, Luiza Spiru, and Rik Ossenkoppele have nothing 20. Miebach L, Wolfsgruber S, Polcher A, et al. Which features of subjec- to disclose. tive cognitive decline are related to amyloid pathology? Findings from the DELCODE study. 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