Diagnostic criteria for apathy in neurocognitive disorders.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed.
METHODS: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019.
RESULTS: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. DISCUSSION: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

BACKGROUND

The Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) term neurocognitive disorders (NCD) includes dementias (major NCD), such as Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal lobar degeneration (FTD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD), and mild NCD such as mild cognitive impairment (MCI). While NCD are characterized by a decline in one or more cognitive domains they are frequently accompanied by neuropsychiatric symptoms (NPS) such as apathy. Apathy is broadly understood to refer to a lack of interest, enthusiasm, or concern (Oxford Dictionary).

Apathy symptoms are highly prevalent across NCD despite being defined a variety of ways. In those with MCI, apathy symptoms have been detected in up to 51% of patients. In vascular MCI (vMCI), apathy symptoms were reported in 17% to 88% of patients, with higher prevalence in those with more severe cognitive impairment. In a meta‐analysis of AD patients, apathy was the most common NPS, present in 49% of the pooled sample. Apathy has been shown to increase with AD severity, with 19% of patients reporting symptoms in mild AD, and 88% in moderate–severe AD. In a multicenter clinical trial of mild‐to‐moderate VaD, 65% of patients exhibited apathy symptoms, with the prevalence ranging from 53% in those with mild impairment to 92% in those with severe impairment. Apathy symptoms are common in those with FTD, occurring in approximately 57% of those with the language‐variety FTD, and up to 100% in moderate‐to‐severe FTD. , In DLB, apathy symptoms have been reported in 48% of patients with mild impairment and up to 100% in patients with severe impairment.

Apathy symptoms have also been consistently associated with negative consequences. They increase the likelihood of progression from normal cognition to MCI, and from MCI to AD. , In those with amnestic MCI, the risk of progression to AD was almost seven‐fold higher in those with apathy symptoms compared to those without. Additionally, those with amnestic MCI and apathy symptoms had a faster progression to dementia compared to those without. In AD, apathy symptoms have been linked with more rapid cognitive decline, more impaired basic and instrumental activities of daily living, and greater caregiver burden. Apathy symptoms have also been associated with increased mortality in nursing home and community‐dwelling patients with AD. In VaD, apathy symptoms have been correlated with poorer basic and instrumental activities of daily living. In FTD, PD, and DLB, apathy symptoms were correlated with increased caregiver burden. , , Apathy in DLB has been identified as a significant determinant of lower quality of life, a predictor of faster cognitive decline, and shorter time until admission to nursing homes.

Problem statement

To date, apathy has commonly been defined using arbitrary cut‐offs on various scales meant to capture symptom burden rather than with specific diagnostic criteria. Diagnostic criteria would provide a consistent definition of apathy, which in turn could advance research, particularly that delineating the neurobiological correlates of apathy and identifying effective treatments for patients.

Definitions of apathy

Originally described in 1991, Marin defined apathy as a disorder of motivation with cognitive, sensory, motor, and affective subtypes. That definition was echoed by Cummings et al. in 1994 with the development of the Neuropsychiatric Inventory (NPI). In 2000, Stuss et al. defined apathy as a disorder of initiative, manifesting in lack of self‐initiated action, cause of which may be affective, behavioral, or cognitive in nature. That definition also included “social apathy,” considered a disorder of sense of self and social awareness. In 2002, through the development of the Apathy Inventory, Robert et al. conceptualized apathy as a disorder of motivation with emotional blunting, lack of initiative, and lack of interest. In 2006, Sockeel et al. developed the Lille Apathy Rating Scale with the idea that apathy was a disorder of intellectual curiosity, action initiation, emotion, and self‐awareness. That same year, Levy and Dubois focused on apathy as a disorder of voluntary and goal‐directed behaviors, with three theoretically envisaged subtypes of disrupted “signal” processing: emotional‐affective, cognitive, and auto‐activation. Similarly, in 2008, Starkstein and Leentjens viewed apathy as a disorder of motivation with diminished goal‐directed behavior and cognition. While past efforts overlapped, inconsistencies between the definitions and scales used have resulted in the lack of a clear definition of clinically significant apathy.

Previous diagnostic criteria

In 2008 the European Psychiatric Association (EPA) recognized the need for apathy diagnostic criteria specific to AD and other neurodegenerative diseases. The resulting criteria required that apathy be diagnosed based on a loss of or diminished motivation and the presence of at least one symptom in at least two of three domains of apathy (reduced goal‐directed behavior, goal‐directed cognitive activity, or emotions). Those criteria also stated that the symptoms must result in clinically significant impairment and not be explained by other possible causes, such as physical disabilities, change in level of consciousness, or the effect of a substance. In addition, the EPA criteria delineated apathy as a persistent state, with symptoms pertaining to both self‐initiated or “internal” actions as well as the patient's responsiveness to “external” stimuli. Since then, there have been considerable advances in apathy research. In recognition of that, in 2018 an international consensus group used a rigorous transdiagnostic approach to update the 2009 EPA diagnostic criteria and expand their focus beyond NCD while operationalizing the criteria and providing guidance on updated assessment tools. As a result, the term “motivation” was replaced by “goal‐directed behavior/activity”; “domains” were re‐labelled “dimensions”; the domains of behavior and initiative were combined; and a new dimension, social interaction, was introduced. However, those criteria focus more broadly on brain disorders rather than NCD.

RESEARCH IN CONTEXT

Systematic Review: The authors reviewed the literature using traditional (e.g., PubMed) sources. As apathy has increasingly been recognized as a standalone construct in Alzheimer's disease and related neurocognitive disorders (NCD), there was a need to update the diagnostic criteria for apathy with a specific focus on NCD. The relevant references are appropriately cited.

Interpretation: The consensus process resulted in a set of diagnostic criteria for apathy in NCD that has had input from experts from academia, industry, and regulatory bodies.

Future directions: Future directions include the operationalization of these criteria, validation in both research and clinical settings, and development of new or validation of existing assessment scales.

HIGHLIGHTS

International academia, industry and regulatory experts formed an Apathy Workgroup.

Consensus criteria for apathy diagnosis in neurocognitive disorders were developed.

Criteria form a framework for defining apathy for use in diagnosis and research.

The need for apathy diagnostic criteria in NCD

The International Society for CNS Clinical Trials and Methodology (ISCTM) and the EPA appreciated the need for updated diagnostic criteria for apathy in NCD. These would incorporate the emerging understanding of the neurobiology and neurocircuitry of apathy in NCD, and recognize that memory problems, a core feature of NCD, make self‐reporting unreliable as the disease progresses. Criteria also needed to be applicable to those living in long‐term care facilities with variable self‐sufficiency in activities of daily living, and potential limitations in access to activities and socialization. Therefore, existing criteria needed to be revised to incorporate the assessment of observable traits by an informant (clinician or caregiver). The need for revised criteria was also warranted due to potential confusion between apathy and other symptoms present in NCD, such as cognitive impairment, physical impairment, and depression. Finally, the growing interest in apathy as a target for interventions further emphasized the need for diagnostic clarification. The current paper describes the collaborative, international consensus process led by the ISCTM Apathy Work Group (AWG) to update the diagnostic criteria for apathy specifically in NCD.

METHODS: CONSENSUS‐BUILDING PROCESS

The ISCTM‐AWG consisted of experts from academia, industry, and regulatory bodies who recognized the need to better understand, identify, and manage apathy and to provide a basis for further apathy‐related research. The 2018 Revised Diagnostic Criteria were used as an initial framework. As the purpose of this undertaking was not to develop diagnostic criteria de novo, a five‐step modified Delphi methodology was followed: (1) literature review, (2) preliminary survey, (3) preliminary international meeting (to define criteria), (4) consensus survey, and (5) final international meeting (to finalize consensus criteria). The criteria were finalized in July 2019. Details of the consensus‐building process can be found in the Appendix.

RESULTS

Results of the first three steps, (1) literature review, (2) preliminary survey, and (3) details from the preliminary international meeting to define criteria, are included in the Appendix. In summary, the literature review supported keeping the cognitive and behavioral domains separate for NCD, and not introducing a social withdrawal domain. Results from the preliminary survey indicated strong agreement that diagnostic criteria specific for apathy in NCD are important for research and clinical practice. Any issues raised in the preliminary survey were discussed further at the subsequent preliminary international meeting.

Consensus survey

The consensus survey had 143 respondents from 30 countries. Of those, 29% were members of ISCTM, 33% were members of the International Psychogeriatric Association (IPA), and 41% were members of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) NPS Professional Interest Area (PIA) group, with some respondents being members of multiple groups. The majority of respondents were physicians (62%), with 11% of respondents from industry, and 4% of respondents from regulatory bodies. Survey results are summarized in Table 1.

TABLE 1

Consensus survey results

	Percentage of respondents that agreed with the statement
1. Do you agree with Criterion A: “The patient meets criteria for mild or major neurocognitive disorder (e.g.: AD, FTD, DLB, vascular dementia, a pre‐dementia cognitive impairment syndrome such as mild cognitive impairment, prodromal AD, subjective cognitive impairment, or other cognitive disorder)”	85.9
2a. Do you agree that Criterion B1, formerly known as “behavior,” should be labeled as “loss of initiative”?	85.7
2b. Do you agree that Criterion B2, formerly known as “cognition,” should be labeled as “loss of interest”?	86.4
2c. Do you agree that Criterion B3, formerly known as “emotion,” should be labeled as “emotional blunting”?	94.4
2d. Do you agree that Criterion B4, “loss of social activity,” should be considered an independent domain?	59.4
3. Do you agree with Criterion C: “These symptoms cause clinically significant impairment in personal, social, occupational, and/or other important areas of functioning.”	88.1
4. Do you agree with Criterion D: “These symptoms are not exclusively explained by physical disabilities, motor disabilities, diminished level of consciousness, or the direct physiological effects of a substance?	87.3
5. Do you feel that these criteria apply to all neurocognitive disorders? ‐ Yes, definitely ‐ Yes, somewhat ‐ Yes, a little bit ‐ No ‐ Unsure	37.7 42.6 2.5 5.7 11.5
6. Do you feel that these criteria are useful for clinical purposes?	92.7
7. Do you feel that these criteria are useful for research purposes?	90.2

Abbreviations: AD, Alzheimer's disease; DLB, dementia with Lewy bodies; FTD, frontotemporal lobar degeneration.

Final international meeting

Consensus on the wording of the apathy diagnostic criteria for NCD was reached at the final meeting (Table 2). The initial wording was revised in the following ways:

TABLE 2

Consensus diagnostic criteria for apathy in neurocognitive disorders

For a diagnosis of apathy, the patient needs to meet criteria A, B, C, and D
Criterion A. Primary diagnoses	The patient meets criteria for a syndrome of cognitive impairment or dementia (as defined by either ICD or DSM‐5 criteria; e.g.: AD, vascular dementia, FTD, DLB, PDD, a pre‐dementia cognitive impairment syndrome such as MCI, prodromal AD, or other cognitive disorder).
Criterion B. Symptoms and duration	The patient exhibits at least one symptom in at least two of the following three dimensions (B1 to B3). These symptoms have been persistent or frequently recurrent for a minimum of 4 weeks and represent a change from the patient's usual behavior. These changes may be reported by the patient themselves or by observation of others.
	Dimension B1	Diminished initiative: Less spontaneous and/or active than usual self: Less likely to initiate usual activities such as hobbies, chores, self‐care, conversation, work‐related or social activities
	Dimension B2	Diminished interest: Less enthusiastic about usual activities: ‐ Less interested in, or less curious about events in their environment ‐ Less interested in activities and plans made by others ‐ Less interested in friends and family ‐ Reduced participation in activities even when stimulated ‐ Less persistence in maintaining or completing tasks or activities
	Dimension B3	Diminished emotional expression/responsiveness: ‐ Less spontaneous emotions ‐ Less affectionate compared to their usual self ‐ Expresses less emotion in response to positive or negative events ‐ Less concerned about the impact of their actions on other people ‐ Less empathy
Criterion C. Exclusionary criteria	These symptoms are not exclusively explained by psychiatric illnesses, intellectual disability, physical disabilities, motor disabilities, change in level of consciousness, or the direct physiological effects of a substance.
Criterion D. Severity	These symptoms cause clinically significant impairment in personal, social, occupational, and/or other important areas of functioning. This impairment must be a change from their usual behaviour.

Abbreviations: AD, Alzheimer's disease; DLB, dementia with Lewy bodies; DSM, Diagnostic and Statistical Manual of Mental Disorders; FTD, frontotemporal lobar degeneration; ICD, International Classification of Diseases; MCI, mild cognitive impairment; PDD, Parkinson's disease dementia.

Criterion A (Primary diagnoses):

Amended from “mild or major neurocognitive disorder” to “a syndrome of cognitive impairment or dementia” as defined by either International Classification of Diseases (ICD) or DSM‐5 criteria. This was done as the group felt that the terms mild or major NCD were too specific to one discipline, and could cause confusion.

Amended by removing subjective cognitive impairment (SCI), and including mild vascular cognitive impairment, as the group felt that SCI was outside the intended scope of these criteria.

Criterion B (Symptoms and duration):

Amended to remove Domain B4 (Social Interaction) as it was felt that there was insufficient evidence to support it as a separate domain in patients with NCD at this time, and there was no consensus among survey respondents with regard to its inclusion. The examples of behaviors previously listed under B4 could also be encompassed by diminished interest, initiative, and emotional expression/responsiveness, and were therefore integrated into domains B1 (Diminished initiative), B2 (Diminished interest), and B3 (Diminished emotional expression/responsiveness). However, the workgroup agreed that should evidence arise in the future that demonstrates the need to separate social interactions, that decision would be reconsidered. The limited opportunity for social interaction in certain care settings or living situations of patients with NCD was also discussed.

Amended so that each domain started with the word “diminished” as it was felt that this consistency would make the criteria easier to apply.

Amended so that the term “domain” was replaced with “dimension,” for consistency with the 2018 diagnostic criteria for apathy across brain diseases.

Dimensions B1, B2, and B3 had more examples, as it was felt that the examples in the initial wording were not generalizable enough.

Dimensions B1 and B2 were renamed from “behavior” and “cognition” to “initiative” and “interest,” respectively.

Dimension B3 was renamed, changing from “emotional blunting” to “diminished emotional expression/ responsiveness.” It was suggested by the workgroup that “emotional blunting” did not encompass the full extent of the intended behavior, and that “diminished emotional expression/responsiveness” was most consistent with the intent of the dimension.

Criterion C (Exclusionary criteria)

Amended to emphasize the exclusion of patients with psychiatric illnesses and changes in level of consciousness.

Criterion D (Severity)

Amended to reiterate that these behaviors should constitute a change from the patient's usual behavior. The group felt that this was a potential point of confusion that required emphasis.

The order of Criterion C and Criterion D were reversed.

DISCUSSION

The ISCTM‐AWG expert panel collaborated extensively with relevant stakeholder groups to develop a set of consensus criteria for the diagnosis of apathy in NCD. The panel adopted a broad definition of the population under study by replacing the initial DSM‐5–specific terminology of mild or major NCD, with a syndrome of cognitive impairment or dementia as defined by either ICD or DSM‐5 criteria. For additional clarification, the final wording includes a list of sample disorders. SCI was excluded from this list as it was deemed to be outside the scope of these criteria. While a framework has been proposed for SCI, the definition of SCI is evolving and uncertainty remains as to the best definition to predict future decline. These criteria also excluded mild behavioral impairment (MBI) without cognitive impairment as that diagnosis was thought to be beyond the purview of these diagnostic criteria. In addition, apathy symptoms are already part of MBI, as one of MBI domains is decreased motivation/drive.

The dimensions “behavior” and cognition” were relabeled as “initiative” and “interest” due to confusion in the context of NCD. Specifically, as apathy in NCD is a behavior, there was confusion as to the meaning behind the “behavior” dimension. Additionally, since the criteria are specific to those with cognitive disorders, there was confusion as to whether the cognition dimension was an assessment of overall cognitive ability.

Social interaction was not included as an independent domain in the current diagnostic criteria, in contrast to the diagnostic criteria in brain disorders, as there was insufficient evidence from the literature to support social interaction as a distinct and identifiable domain. Instead, social interactions are considered under initiation of social interactions (dimension B1) and interest in social interactions (dimension B2). Social interactions are complex and it is unclear which aspects should be considered in a diagnosis of apathy. One could argue that according to the Research Domain Criteria (RDoC), the social process domain would include affiliation and attachment and that affiliation is a behavioral consequence of social motivation. However, it was felt that additional aspects of social interaction might be mediated by neurocircuitry that may or may not totally overlap with apathy in NCD.

Consistent with a basic diagnostic structure, these criteria specify that apathy must not be wholly explained by another current comorbid psychiatric, physical, or motor illness, or any change in level of consciousness or the direct physiological effects of a substance. This criterion, specific to patients with cognitive impairment or dementia, shares wording with the apathy diagnostic criteria across brain disorders. A major area of discussion when developing these criteria was the overlap between apathy and other NPS, such as depression, and anhedonia as they can co‐occur but are considered distinct. , , , Apathy is often difficult to distinguish from depression as both can have diminished interest, loss of pleasure in activities (anhedonia), and decreased energy. , As described above, the hallmark symptoms of apathy in NCD are diminished initiative, diminished interest, and diminished emotional expression/responsiveness. However, symptoms like sadness, hopelessness, guilt, tearfulness, and suicidal ideation (whether active or passive) are specific to depression and may not be present in those with apathy. Furthermore, though anhedonia can co‐occur with apathy and depression, it is not a requirement to have anhedonia to reach a diagnosis of apathy or depression. For these reasons, we specified that apathy symptoms are not exclusively explained by psychiatric illnesses (e.g., depression) among other exclusions.

Another area of discussion was the potential misidentification of apathy as cognitive and/or physical impairment in patients with NCD. For example, patients may not be able to demonstrate initiative (domain B1) due to increased cognitive impairment, or because of long‐standing low initiative. As such, wording of the criterion specified that the symptom must represent a change from the patient's usual behavior. Furthermore, as physical impairment increases with NCD severity, there was concern that patients may not have the opportunity to physically engage in their usual hobbies and activities. Consequently, a diagnosis of apathy could be missed, or a physical impairment could be misdiagnosed as apathy. For this reason, the wording of criterion B was carefully chosen to be applicable to those who may be wheelchair bound. It was also specified in criterion C that symptoms of apathy could not be explained by physical disabilities.

The final aspect of the diagnostic criteria is that apathy should be of a severity that causes significant impairment or disruption in functioning. Functional deficits are independently associated with apathy across NCD including AD, , MCI, , and dementia. The presence of functional impairments may be observed in diverse contexts including personal, social, occupational, or other areas. This broad definition of deficits in daily functioning was selected to capture heterogeneity in the expression and scope of impairments related to diminished initiative, interest, and emotional expression/responsiveness. This criterion underlines the importance of identifying observable capacity across various functional areas. A specification to this criterion was added emphasizing that functional impairments must be a change from the typical level of functioning to qualify as supporting an apathy diagnosis. This distinction was specifically inserted to identify apathy related to NCD rather than apathy being a pre‐existing behavioral or personality trait.

CONCLUSIONS

Despite recognition of apathy symptoms and their impact, and an increased understanding of the underlying neurobiology of apathy, , there is a lack of currently available, effective treatments for these symptoms in dementia. , The ISCTM Working Group on Apathy appreciated these issues and agreed that as a first step diagnostic clarification was needed.

It is important to recognize the limitations of diagnostic criteria for apathy, and any other NPS. NPS, such as apathy, occur in close conjunction with other neuropsychiatric and cognitive symptoms, and are therefore difficult to assess in isolation. Updated criteria may not address all issues regarding the identification, assessment, and treatment of apathy and this would be an oversimplification of the complexity of the apathy construct. Nevertheless, criteria will help consistently define a population of patients suffering from a clinically significant syndrome, even in the presence of differing underlying diseases.

Clinical trials of drugs targeting apathy are being pursued, and drug interventions based on knowledge of apathy neurocircuitry show promising results. , The stepwise process undertaken to create these diagnostic criteria for apathy involved multiple stakeholders, and benefited greatly by the involvement of individuals from the Food and Drug Administration (FDA) and European Medicines Agency (EMA). It is anticipated that applying a standard definition of apathy would ensure that all patients in clinical trials meet an agreed‐upon definition of apathy, and that stakeholders will be given a portion of “the roadmap” necessary to facilitate development of treatments for apathy.

Future directions by the ISCTM‐AWG include developing a scale that will address the three dimensions of apathy clearly, and detect clinically significant apathy in patients with NCD. This scale will include relevant examples and definitions to ensure the criteria are being applied appropriately. Validation of the consensus criteria is also a necessary next step to confirm its clinical and research utility. This will be achieved through future research using these criteria and comparing it to the diagnostic criteria across brain disorders. Findings from those studies will also provide valuable information relevant to clinical diagnosis, service provision, and apathy research, and will provide information on possible updates to the criteria to help users in the identification and treatment of apathy in NCD.

CONFLICTS OF INTEREST

Dr. Miller is a full‐time employee of Signant Health. Dr. Robert reports grants from French Alzheimer's Association, French research ministry ANR, European H20 20 programs, French National Solidarity council, University Côte d'azur Idex; and consulting fees from Lundbeck and Servier outside the submitted work. Dr. Ereshefsky receives support from APEX Innovative Services, which conducts research for most pharma, and performing site for NIDA, and through Follow the Molecule LLC receives consulting compensation from Biogen, Bioxcel, Neurocrine, Taisho, Atlas Investments, Athira, Intracellular, Cerevel, and Karuna. Dr. Adler has no relevant disclosures. Dr. Bateman reports no conflicts of interest or disclosures. Dr. Cummings has provided consultation to Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, BioXcel, Cassava, Cerecin, Cerevel, Cortexyme, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven, Third Rock, and United Neuroscience pharmaceutical and assessment companies. Dr. Cummings has stock options in ADAMAS, AnnovisBio, MedAvante, and BiOasis. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. Dr Cummings is supported by Keep Memory Alive (KMA), NIGMS grant P20GM109025, NINDS grant U01NS093334, and NIA grant R01AG053798. Dr. DeKosky chairs the medical advisory boards for Acumen and Cognition Therapeutics the DSMB for Biogen, is the editor for Up To Date, and is the Associate Editor for Neurotherapeutics. Dr. Fischer receives grant funding from Brain Canada, Patient Centred Outcomes Research Trust‐Fund, St. Michaels Hospital Foundation, Hoffman LaRoche, and Vielight Inc, all outside the submitted work. Dr. Husain reports grants from the Wellcome Trust, NIHR Biomedical Research Centre Oxford, European Union; and consulting fees from Otsuka, outside the submitted work. Dr. Ismail has received research support from the Alzheimer Society of Calgary, Brain Canada, Canadian Consortium on Neurodegeneration in Aging, Canadian Institutes of Health Research, and consulting fees from Janssen, Lundbeck, and Otsuka, all outside the submitted work. Dr. Jaeger is the owner of CognitionMetrics, LLC, which over the past two years has held consulting contracts with Acadia, Aptinix, Biogen, Eisai, Harmony, INmune Bio, Iproteos, Ironwood, Jazz Pharma, Janssen, LuMind, Lundbeck, Otsuka, Ovid, Perception, and Syndesi. Dr. Lerner receives grant support from National Institute on Aging, ADDF, Global Alzheimer's Platform foundation, and the Elizabeth Severance Prentiss Foundation. Ms. Li reports no conflicts of interest. Dr. Lyketsos has received grant funding from NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo‐Smith‐Kline, Eisai, Pfizer, Astra‐Zeneca, Lilly, Ortho‐McNeil, Bristol‐Myers, Novartis, National Football League, Elan, Functional Neuromodulation, Bright Focus Foundation; has been a consultant or advisor to Astra‐Zeneca, Glaxo‐Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, AbbVie, Janssen, Orion, Otsuka, Servier, Astellas, Roche, Karuna, SVB Leerink, Maplight, Axsome; and has received honoraria or travel support from Pfizer, Forest, Glaxo‐Smith Kline, and Health Monitor. Dr. Manera has no conflicts of interests to disclose. Dr. Mintzer has received research support from the National Institute on Aging, Alzheimer's Disease Cooperative Study (ADCS), Alzheimer's Disease Trials Research Institute (ATRI), Alzheimer's Clinical Trials Consortium (ACTC), Eisai Pharmaceuticals, AgeneBio, TauRx, ACADIA, Novartis, and Biogen as well as consulting fees from Otsuka, ACADIA, and Avanir. Dr. Moebius receives consulting compensation from Exciva and Athira through moebius‐consult LLC, all outside the submitted work. Dr. Mortby is supported by the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship (#1102028). Dr. Muelien is a full‐time employee of H. Lundbeck SAS. Dr. Pollentier is a full‐time employee of Boehringer Ingelheim International GmbH. Dr. Porsteinsson reports personal fees from Acadia Pharmaceuticals, Avanir, Cadent Therapeutics, Functional Neuromodulation, Syneos, and BioXcel; and grants to his institution from Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, and Novartis. Dr. Rasmussen is an independent consultant to psi‐napse, is an advisor to the NHS (Academic Health Science Network Kent, Surrey, Sussex, Surrey Heartlands ICS), and receives funding for consultancy/advisory board/speaker's bureau from Acadia, Alz Soc, Andera Partners, Biogen, ConSynance, Merck, Nuricia, and Roche. Dr. Rosenberg has received research support from the National Institute on Aging, Alzheimer's Association, Lilly, Functional Neuromodulation (FNMI), Lilly, Alzheimer's Disease Cooperative Study (ADCS), Alzheimer's Disease Trials Research Institute (ATRI), Alzheimer's Clinical Trials Consortium (ACTC), as well as consulting fees from GLG, Leerink, Otsuka, Avanir, ITI, IQVIA, Food and Drug Administration, Cerevel, Bioxcel, and Sunovion, all outside the submitted work. Dr. Ruthirakuhan has received funding through a Canadian Institute of Heath Research postdoctoral fellowship. Dr. Sano reports no conflicts of interest. Ms. Zucchero Sarracini report no conflicts of interest. Dr. Lanctôt reports grants from Alzheimer's Association, Alzheimer Society of Canada, Alzheimer's Drug Discovery Foundation, Canadian Institutes of Health Research, National Institute on Aging; and consulting fees from Abide, BioXcel, Cerevel, Exciva, Highmark Interactive, ICG Pharma, Kondor Pharma, and Otsuka, outside the submitted work.

TABLE A1

Preliminary survey results

Question	% answering “important,” “very important,” or “extremely important”
For research purposes, how important are the diagnostic criteria for the following targets?
‐ To improve understanding of the phenomenology	100.0
‐ To improve the understanding of the neuroanatomical and biological correlates	100.0
‐ To help clinicians in the choice of the pharmacologic treatments	96.4
‐ To improve the population selection criteria in pharmacological clinical trials	100.0
‐ To improve the population selection criteria in non‐pharmacological clinical trials	92.9
For clinical purposes, how important are the diagnostic criteria for the following targets?
‐ To improve prevention strategies	75.0
‐ To improve diagnostic and assessment strategies	100.0
‐ To help clinicians in the choice of pharmacologic treatments	96.4
‐ To help clinicians in the choice of non‐pharmacologic treatments	92.9
‐ To help family caregivers to understand the pathology and put in place care strategies	85.7
‐ To help professional caregivers to understand the pathology and put in place care strategies	96.4