Received: 18 August 2020 Revised: 27 August 2020 Accepted: 2 September 2020 Published online: 9 November 2020 DOI: 10.1002/dad2.12115 SHORT REPORT Theoretical frameworks and approaches used within the Reserve, Resilience and Protective Factors professional interest area of the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment David Bartrés-Faz1,2 Eider Arenaza-Urquijo3 Michael Ewers4 Sylvie Belleville5 Gaël Chételat6 Nicolai Franzmeier4 Julie Gonneaud7 José María González de Echevarri3 Ozioma Okonkwo8 Stephanie Schultz8 Michael Valenzuela9 Yaakov Stern10 Prashanthi Vemuri11 1 Department of Medicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain 2 Guttmann Brain Health Institute, Institut Universitari de Neurorehabilitació Guttmann, Autonomous University of Barcelona, Badalona, Spain 3 Barcelonabeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain 4 Institute for Stroke and Dementia Research (ISD), University HospitalLMU Munich, Munich, Germany 5 Research Center, Institut Universitaire de Gériatrie de Montréal and Department of Psychology, Université de Montréal, Montreal, Canada 6 UNICAEN, INSERM, U1237, PhIND “Physiopathology and Imaging of Neurological Disorders,”, Normandie University, Paris, France 7 Douglas Mental Health Institute, McGill University, Montreal, Canada 8 Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA 9 School of Psychiatry, Medicine, University of New South Wales, Sydney, Australia 10 Cognitive Neuroscience Division, Department of Neurology, Columbia University, New York, New York, USA 11 Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA Correspondence Prof. David Bartrés-Faz, Department of Abstract Medicine, Faculty of Medicine and Health Sciences; Institute of Neurosciences; Univer- Introduction: Reserve, resilience, maintenance, and related concepts are intensely sity of Barcelona, c/Casanova, 143, 08036 debated in aging and Alzheimer’s disease research. Barcelona, Spain. Email: dbartres@ub.edu Methods: Through a short survey, we gathered information about theoretical concepts and methodologies used among research groups of the Reserve, Resilience, and Pro- David Bartrés-Faz and Eider Arenaza-Urquijo tective Factors Professional Interest Area of the Alzheimer’s Association International contributed equally to this work. Society to Advance Alzheimer’s Research and Treatment. Results: Overall 53 research groups responded. Reserve and resilience were the most frequently used conceptual frameworks. Education, occupation, leisure, and social activities were frequently used as measures, as were longitudinal designs. Neu- ropsychological assessments were almost universal, and usage of imaging biomarkers was frequent. In observational-epidemiological study designs, resilience and reserve together (vs reserve alone) were commonly used as theoretical frameworks. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association Alzheimer’s Dement. 2020;12:e12115. wileyonlinelibrary.com/journal/dad2 1 of 6 https://doi.org/10.1002/dad2.12115 2 of 6 BARTRÉS-FAZ ET AL . Discussion: We provide a first description of concepts and methodologies used among reserve and resilience researchers. This will inform initiatives aiming to reach consen- sus on terminology and applications to establish common definitions. KEYWORDS brain reserve, cognitive reserve, maintenance, methodologies, outcome measures, resilience, techniques 1 INTRODUCTION executive committee agreed to undertake this initiative as part of the PIA’s activity. Beginning with the recognition of the disconnect between pathology Survey data collection was completed between October 2018 and and cognition in aging and dementia,1 the field of reserve, resilience, April 2020. In September 2018, the Executive Committee reached a and protective factors has evolved tremendously. The first theoreti- consensus regarding relevant items and questions of the survey, which cal frameworks included concepts such as brain reserve capacity2 or were planned as non-mutually exclusive fixed responses, but also leav- cognitive reserve versus brain reserve,3 which have been instrumental ing some open fields (see Table 1 and supporting information). By Octo- in propelling the research into inter-individual differences that allow ber 2018, the survey was formatted into a web-based platform by the some people to cope better with aging and disease. In the cognitive Alzheimer’s Association ISTAART and sent out to all PIA members. The aging field, several models aiming to explain inter-individual differ- first wave of responses had a total of 30 identifiable research groups ences have also emerged.4,5 Through autopsy6 and biomarker-based working within the field complete the surveys. Between May and July investigations of Alzheimer’s disease (AD) patients, our understanding 2019, and in September 2019, after the first workshop on research def- of these processes has evolved across the years. initions of the Reserve & Resilience meeting held in Bethesda, Mary- The recent biological definition of AD, acknowledging a long pre- land, USA, further individual group responses were collected. A final clinical phase of the disease7 and the emergence of specific biomark- round was undertaken using the PIA social media channels (Linkdln ers (cerebrospinal fluid [CSF] and neuroimaging8,9 ) have allowed fur- [PIA group] and PIA hashtag #ReservePIA) during March and April ther study of individual differences regarding the factors and mech- 2020. anisms responsible for the stability of cognitive and clinical func- tion, despite evident neuropathology.10 These observations have led 3 RESULTS to novel terms and concepts including resistance and resilience to describe the pathology–cognition mismatch.11,12 The rapid turnover of The present survey reports responses of 53 clinical and research ideas and theoretical frameworks has led to recent consensus state- teams. In terms of geography, 23 groups represented eight different ments, aiming to integrate the definitions and the study of brain European countries, 21 were from the USA or Canada, 4 were from mechanisms underlying concrete concepts.4,13 Further, initiatives such South America, 3 from Australia, 1 from China, and 1 from India (Fig- as the National Institute on Aging (NIA)-supported Collaboratory on ure 1A). Research Definitions (https://reserveandresilience.com/) have been funded to support workshops as a platform to exchange ideas and 3.1 Theoretical model/concept framework and develop operational definitions. examples of research findings We aimed to describe the most common conceptual frameworks, terminologies, experimental designs, outcome variables, and specific Most groups (84.9%) indicated that the term “reserve” best defined techniques used among researchers working in this field. For this, we their current research activity. The concept of resilience was the sec- conducted a survey within the Reserve, Resilience and Protective Fac- ond most commonly addressed (66% of the teams) followed by the use tors professional interest area (PIA) of the Alzheimer’s Association of maintenance (50.9%) and neuroprotection (39.6%; Figure 1B). International Society to Advance Alzheimer’s Research and Treatment (ISTAART) and present the results as part of this work. 3.2 Determinants and mechanisms of reserve and 2 METHODS resilience During the Alzheimer’s Association International Conference (AAIC) We asked participants about potential determinants of cognitive 2018 held in Chicago (Illinois, USA), the Reserve, Resilience and reserve. Up to 86.8% of participants answered that they considered Protective Factors PIA discussed a proposal to collect information environmental determinants, but the majority of teams also consider about the theoretical backgrounds and methodological approaches genetic aspects (50.9%) and to a lesser extent investigated gene– commonly used by ISTAART members. At a subsequent meeting, the environment approaches (35.8%). The high frequency of considering BARTRÉS-FAZ ET AL . 3 of 6 TA B L E 1 Specific questions included in the survey environmental determinants of reserve appears to be aligned with key measures used to study reserve and resilience. Here, most reported Group identification (84.9%) that they termed the measures as “classical” from the CR Key members reserve theory (ie, independent or composite scores of education, Institution occupation, social, and leisure activities; Figure 1C). Theoretical framework With regard to the mechanisms underlying the general concept What is the theoretical model/concept framework that of reserve (ie, irrespective of the theoretical approaches selected), best defines your group’s research work? most groups focused their activity on the biological mechanisms Specific aspects of cognitive reserve (86.8%), which were often combined with psychological (67.9%), Determinants of Cognitive Reserve tick box: psychosocial (54.7%), or the consideration of all three kinds of □ Environmental mechanisms (37.7%). □ Genetic □ EXG 3.3 Research study designs and methodologies If not, please specify. . . □ Mechanisms of Reserve, tick box: Most groups claimed they were currently engaged in observational– epidemiologic investigations (75.5%), and in particular in longitudi- □ Biological nal studies (84.9%), and fewer were conducting experimental stud- □ Psychological ies (37.7%), brain series/autopsy investigations (26.4%), or random- □ Psychosocial ized clinical trials (22.6%). Only one group was conducting reserve and If not, please specify. . . resilience–related research on animal models. The high prevalence of □ Clinical outcomes of Cognitive Reserve, tick box: groups engaged in longitudinal studies is probably reflective of the □ Cognitive status fact that most of them indicated that they considered cognitive decline □ Cognitive decline (96.2%) in their study designs with lower percentage of groups working □ Incidence of dementia on incidence of mild cognitive impairment (MCI; 45.3%) or dementia □ Incidence MCI (43.4%) as primary outcomes (Figure 1D). Concerning the main tech- niques used, most investigations include neuropsychological assess- Key measures ments (88.7%), and frequently consider imaging (75.5%) as well as CSF □ Classical Cognitive Reserve measures (education, markers (54.7%) data (Figure 1E). occupation, social, leisure) We finally investigated whether the two main frameworks, namely □ Residual approaches etc. reserve and resilience, were associated with distinct study designs, Methods employed clinical outcomes, main measures, and principal techniques. To inves- Study designs, tick box: tigate this, we compared the responses of those groups that had □ Observational-Epidemiologic indicated that their main conceptual model was reserve but did not □ Longitudinal include resilience (N = 12), to those groups that included resilience □ Experimental (N = 36; all but four including reserve too). Those groups that had □ Brain series selected resilience as a theoretical framework more frequently used □ RCT observational–epidemiological study designs (Figure 2A; Fisher’s exact test: 8.15, P < .005). They also appear to include more frequently a “bio- □ Animal models If not, please specify logical component” in their techniques (ie, CSF), key measures (ie, bio- Specific Techniques, tick box: logical) or study designs (ie, brain series), as well as mental health status □ Neuropsych as key measures (Figure 2A-D); however, formal testing did not reveal □ CSF and imaging biomarkers significant differences (not shown). □ Autopsy studies If not, please specify 4 DISCUSSION Top 3-5 findings and relevant references, also please feel free to provide a link to your website or Pubmed Here, we surveyed and present an overview of the concepts search for relevant publications and methodological approaches currently used by groups mainly Abbreviations: CSF, cerebrospinal fluid; MCI, mild cognitive impairment; pertaining to the Resilience and Protective Factors’ PIA of ISTAART. RCT, randomized controlled trial. This survey captured the breadth of the theoretical model/concept framework and determinants/approaches that are used in our 4 of 6 BARTRÉS-FAZ ET AL . F I G U R E 1 Graphical representation of responses obtained to the survey questions. A, World globe figure with the distribution of the N = 53 groups responding per continent/ main region. B, What is the theoretical model/concept framework that best defines your group’s research work? C, “Key measures” classical CR measures (education, occupation, social, leisure) residual approaches, etc. D, Clinical outcomes of Cognitive Reserve tick box: Cognitive status, Cognitive decline, Incidence of dementia, Incidence MCI (mild cognitive impairment). E, Specific Techniques tick box: Neuropsych CSF (cerebrospinal fluid) and Imaging Biomarkers, Autopsy Studies. If not, please specify. Values represent percent of responses. Within each item, responses were not mutually exclusive (ie, more than one answer per item was allowed) research area and also highlights the opportunity present in unifying quently associated with the use of “biological” or mental health aspects the language across research groups and methodologies. (personality, stress, psychoaffective states, Figure 2A, B, and D) should Present findings indicate that the term reserve is the most fre- be addressed in follow-up investigations. quently used in AD research. However, the concept of resilience is Most of our respondents focus on the study of environmental deter- also commonly incorporated. It should be noted that according to minants of reserve followed by genetic aspects and consider classical current conceptual definitions,3 resilience refers to a more general measures within neuropsychological and neuroimaging investigations. term that aggregates multiple reserve-related processes. In the over- Finally, we noted that a large percentage of respondents informed all sample, more than 20% of professionals use all four main concepts that they were engaged in longitudinal studies, which due to their (reserve, resilience, maintenance, neuroprotection) in their research. advantages over cross-sectional designs14 appears to be a prevalent A comparison between groups that used the term resilience versus approach. This may also be related to the fact that “cognitive decline” reserve (without resilience) showed similar use of methodologies, tech- was one of the main outcomes used by PIA members and that it is the niques, clinical outcomes, or general study designs, except for the fact design of choice to investigate protective mechanisms.3 that they tended to be more frequently engaged in observational– Biomarkers were widely used across all research groups reflecting epidemiological studies. Whether the resilience term is more fre- the emergence and increased use of in vivo measurements in AD. More BARTRÉS-FAZ ET AL . 5 of 6 F I G U R E 2 Visual comparison of responses between the groups that included reserve as a main theoretical framework but excluded resilience (N = 12) versus those including this latter term in their definitions (N = 36). Survey questions: (A) Study designs tick box: Observational-Epidemiologic, Longitudinal, Experimental, Brain series, RCT, Animal models, If not, please specify; (B) “Key measures” Classical Cognitive Reserve measures (education, occupation, social, leisure) Residual Approaches etc.; (C) Clinical outcomes of Cognitive Reserve tick box: Cognitive status, Cognitive decline, Incidence of dementia, Incidence MCI (mild cognitive impairment); and (D) Specific Techniques tick box: Neuropsych CSF (cerebrospinal fluid) and Imaging Biomarkers, Autopsy Studies, If not, please specify. Values represent percent of responses. Within each item, responses were not mutually exclusive (ie, more than one answer per item was allowed) than 50% of groups used CSF-based markers and >75% used “imaging (ISTAART), through the Reserve, Resilience and Protective Factors biomarkers.” This latter term was not further specified in the survey, professional interest area (PIA). The views and opinions expressed although some groups designated that they were using “PET [positron by authors in this publication represent those of the authors and emission tomography]-based biomarkers,” to be in accordance with do not necessarily reflect those of the PIA membership, ISTAART, or the relevance of molecular imaging markers in the discipline.15,16 Alto- the Alzheimer’s Association. The Reserve, Resilience and Protective gether and provided the high prevalence of groups stating that they use Factors PIA executive board members are grateful to Jodi Titiner, “neuroimaging” information, either as key measures or specific tech- ISTAART Member Service Specialist, for her constant support and niques, a future detailed survey should include more fine-graded ques- technical guidance in designing the web-based survey platform. The tions about the particular PET tracers or magnetic resonance imaging authors are grateful to all research groups and investigators that pro- (MRI) sequences they use in their research. Finally, other professionals vided their responses and agreed to be included in the supplemen- specifically stated they were using blood-based information, which also tary table (names and affiliations appear as provided): Emily Rogalski, likely reflects the advent of these biomarkers in the AD research field17 Changiz Geula, Marsel Mesulam (Northwestern University); Anje Sol- and which should also be assessed in more detail in further versions of dan (Johns Hopkins University School of Medicine); Corinne Pettigrew the survey. (Johns Hopkins); Paulo Caramelli, Leonardo Cruz de Souza, Elisa de In summary, this report represents a first survey of the terms and Paula França Resende (Universidade Federal de Minas Gerais [UFMG], methodologies used by the Reserve, Resilience and Protective Factors Belo Horizonte, Brazil); Nikolaos Scarmeas (National and Kapodis- PIA. Repeating this type of questionnaire in the future may be useful to trian University of Athens); Rik Ossenkoppele and Anita van Loenhoud measure how the focus of professionals’ work within the area, as well as (VU University Medical Center); Henne Holstege (Amsterdam UMC); the use of emerging technologies, evolve in response to the progressive Renata Kochhann (Pontifical Catholic University of Rio Grande do Sul incorporation of new consensus on theoretical and empirical research – Brazil); Dharma Singh Khalsa (Alzheimer’s Reseaarch and Preven- within the field. tion Foundation); Corinne Fischer (St. Michaels Hospital); Tarek Rajji (University of Toronto and Centre for Addiction and Mental Health ACKNOWLEDGMENTS [CAMH]); Miranka Wirth (Charité - Universitätsmedizin Berlin); Joe This manuscript was facilitated by the Alzheimer’s Association Inter- Verghese, Roee Holtzer, Helena Blumen, Emmeline Ayers (Albert Ein- national Society to Advance Alzheimer’s Research and Treatment stein College of Medicine); Marcio Soto (Universidad Católica San 6 of 6 BARTRÉS-FAZ ET AL . 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