Importance听 Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations.

Objective听 To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states.

Evidence Review听 PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms 鈥渂iomarker鈥� OR 鈥渁myloid鈥� OR 鈥渢au鈥� OR 鈥渘eurodegeneration鈥� OR 鈥減reclinical鈥� OR 鈥淐SF鈥� OR 鈥淧ET鈥� OR 鈥減lasma鈥� AND 鈥淎lzheimer鈥檚 disease.鈥� The references of relevant articles were also searched.

Findings听 In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease.

Conclusions and Relevance听 The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

The recently revised Alzheimer Association (AA) criteria for Alzheimer disease (AD)¹ propose that AD be defined on biological evidence only. The diagnosis of AD can be provided to cognitively normal people with evidence of core 1 AD biomarkers encompassing cerebrospinal fluid (CSF) amyloid 尾 and tau ratios and plasma phosphorylated tau (p-tau) 217 validated against amyloid positron emission tomography (PET), even though these new criteria do not recommend testing for these biomarkers in cognitively normal individuals. This raises the question of the role and influence of biomarkers in the diagnostic workup.

In 2007, the International Working Group (IWG) revised the 1984 diagnostic criteria for AD and was the first to propose that the diagnosis of AD in patients with cognitive deficits could be anchored around the presence of biomarkers to support more accurate and earlier disease diagnosis.² Since then, brain amyloid PET has been shown to correlate with the presence and density of 尾-amyloid plaques in autopsy-derived brain tissue samples. CSF and plasma amyloid and p-tau biomarkers have been validated against amyloid PET. These validations justify the inclusion and reimbursement of biomarkers in diagnostic workups in different countries. However, the clinical value and utility of these biomarkers or tests differ depending on the context, eg, research or clinical settings, in which they are used.^3,4

The availability of these biomarkers has radically changed both observational and clinical trial research.⁵ They are regularly used to identify and confirm the presence of AD pathology with a strong emphasis on amyloid, to study the natural history of disease biology, to evaluate pharmacodynamic effects of treatment candidates, and to serve as surrogate clinical outcomes in clinical trials. At variance with postmortem investigation, which provides the final definitive but static information about lesions in the brain, these biomarkers allow dynamic in vivo monitoring of pathological changes and inform about their relationships to the onset and progression of symptoms.⁶ Each biomarker provides information about a type of pathological lesion or a process that has its own weight and contribution to the natural history of the disease. However, the so-called AD core 1 biomarkers are individually insufficient to account for the many mechanisms and interactions underlying the disease process. In turn, selected tau and amyloid biomarkers should be conceptualized as AD risk factors with different/specific weights and synergies across the disease continuum. The potential of many other biological markers is currently being actively investigated including markers of glial activation and neuroinflammation, such as GFAP and YKL-40; neurodegeneration, such as neurofilament light chain; and synaptic dysfunction and degeneration, such as neurogranin and SNAP-25.⁷

In the clinical setting, amyloid and tau biomarkers are used to support or refute a clinically suspected diagnosis. As acknowledged by neuropathologists in a National Institute of Aging conference consensus in 2012,⁸ Alzheimer neuropathologic changes are necessary but not sufficient for establishing the diagnosis of AD. They concluded, aligned with its historical definition, that AD is a clinicopathological entity that should be disentangled from Alzheimer pathological changes, which are frequently observed in postmortem brains of aged individuals who died without any cognitive or functional decline.⁹ Additionally, lesions of different pathological nature are frequently observed postmortem due to the high prevalence of comorbidities and to the synergy between pathologies¹⁰: combinations of 伪-synuclein aggregates (Lewy bodies), insoluble aggregates of TAR DNA-binding protein 43 (TDP-43), non-AD tauopathies, and vascular pathologies commonly exist alongside with amyloidopathy and AD tauopathy. These are more the norm than the exception in pathological studies¹¹ on sporadic cases.

The inherent logic of the new AA criteria leads to the conclusion that the development of emerging biomarkers of copathologies, eg, 伪-synuclein, TDP-43, and others in the future, could result in the diagnosis of 2, 3, or more different neurodegenerative diseases in a cognitively normal person, as a norm.¹¹ Although multiple diagnoses are common in older adult patients, it took decades of studies to demonstrate the superiority of the comorbidity-based vs the additive single-disease approach, now accepted as a valid clinical construct.¹² Therefore, we argue that biomarkers alone should remain markers of pathological processes and not markers of a specific disease.⁸ Furthermore, the contribution of biomarkers in the clinical setting depends on the context of use³ and, importantly, should differ between the assessment of individuals with and without cognitive impairment.⁴

The combination of common (amnestic syndrome of the hippocampal type, logopenic aphasia, posterior cortical atrophy) or uncommon (corticobasal syndrome, behavioral and dysexecutive variants) clinical phenotypes and the positivity of pathophysiological amyloid and tau biomarkers establishes the diagnosis of AD.⁴ This association defines the clinical-biological entity of the disease, proposed by the IWG,⁴ in line with the clinical-pathological description by Alois Alzheimer^13,14 and the neuropathological consensus.⁸ This scenario also enables a clinical-biological diagnosis at an early prodromal stage, ie, once mild but definite symptoms are in place. The concept of AD as a clinical-biological entity has played a vital role in the US Food and Drug Administration鈥檚 approval of antiamyloid monoclonal in prodromal AD.^15-17 The clinical implications and associated diagnostic narrative of the IWG and AA criteria are similar in the case of such patients with cognitive impairment and positive biomarkers but very different in cognitively normal individuals.¹⁸

Many cognitively normal people, with or without cognitive complaints, seek expert advice for their memory concerns, subjective perception of cognitive decline, positive family history of AD, or simply the wish to know their risk of AD. These persons can present with normal objective memory and cognitive performance and ask for evidence-based and clinically meaningful answers. Here, it is again necessary to distinguish between research and clinical settings.

In the research setting, there is major interest in developing effective drugs or other interventions at the earliest point in time possible in persons with an increased risk of progression to AD dementia. Functional recovery as a treatment outcome is highly unlikely once the degeneration in neural networks has reached a threshold of severity. We are in support of all research efforts in the field to move toward the goal of decreasing the incidence of cognitive impairment in cognitively normal persons at risk. As brain 尾-amyloidosis is an acknowledged risk factor for the onset of clinical symptoms, we endorse the view that clearing amyloid burden may possibly reduce the risk of future cognitive impairment鈥攗nder certain conditions鈥攁nalogous to treating vascular risk factors to prevent myocardial infarction or stroke. The vascular analogy has been endorsed by the international Dominantly Inherited Alzheimer Network, which has used the hypercholesterolemia/heart disease analogy to interpret their results on biomarker changes in autosomal dominant AD.¹⁹

In the clinical setting, extending the diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of diagnostic criteria that have a purely biological definition of the disease. The argument invoked by the AA workgroup is the analogy with cancer, where less severe stages, such as in situ gastric or breast cancer, allow the earliest possible diagnosis and the most favorable outcomes.²⁰ In these cancer scenarios, an asymptomatic incubation period is followed by gradual and steady growth resulting in the occurrence of the clinical symptoms over a fairly predictable time course. This scenario is fitting for the autosomal dominant form of AD, where fully penetrant monogenic variations in the APP, PSEN-1, and PSEN-2 genes identify persons who will almost invariably develop symptoms during their normal lifespan and to Down syndrome where the abnormal production of 尾-amyloid is responsible for the almost universal development of AD dementia.²¹

The model cannot be transferred to cognitively normal individuals with sporadic Alzheimer pathologic changes, as their lifetime risk of becoming symptomatic is much lower. Indeed, the lifetime risk of AD dementia in a 65-year-old man who is amyloid-biomarker positive has been estimated at 21.9%, a mere 1.7 times higher than the risk of an individual of a similar age who is amyloid-biomarker negative.²² Other reports have confirmed these estimates, with a lack of significant clinical progression in the Alzheimer鈥檚 Disease Neuroimaging Initiative cohort in cognitively normal individuals with isolated abnormal amyloid biomarkers after an 8-year follow-up,²³ whereas in research cohorts, only 17% of these cognitively normal individuals with isolated abnormal amyloid biomarkers progressed to mild cognitive impairment over 6 years.²⁴ Therefore, the revised AA criteria, proposing that a diagnosis of AD can be reduced to the sole presence of one AD core 1 biomarker, may introduce major uncertainty and variability in the clinical prognosis of patients diagnosed with AD.¹ The risk of progression of those who have abnormal amyloid biomarkers is marginally increased, including in those with combined abnormal amyloid and tau biomarkers (ie, soluble AD tau biomarkers [T1 biomarkers according to the AA framework: hazard ratio鈥�=鈥�1.08-1.31],²⁵ and unstratified tau-PET positivity [35% of progression after 7 years of follow-up]).^25,26 However, the risk of progression to AD dementia significantly increases when the aggregated forms of tau spread out in neocortical areas.²⁴ This biomarker profile, together with other specific conditions (Box), suggests that the underpinning pathological processes are active and that the development of clinical symptoms in the near future may be virtually inevitable. We do foresee the evolution of the diagnostic construct that we have introduced previously of presymptomatic AD as applying well within the diagnostic lexicon. In its initial iteration, it was introduced within the IWG framework for monogenic fully penetrant AD gene variations. We foresee being able to add new biomarker profiles within this presymptomatic grouping. Currently, long-term evidence for clinical progression remains limited, and estimates are based on nonrepresentative convenience cohorts of relatively small group size.

Box Section Ref ID

To summarize, the IWG approach allows for the identification of 2 different categories of cognitively normal individuals with positive biomarkers with different specific management strategies (Box). First, individuals who are amyloid positive (A+) and A+ and T1 positive have an increased (but far from a convincing benchmark of certainty) risk of developing clinical AD within their expected lifetimes. These individuals should be labeled at risk, and their follow-up in longitudinal cohorts will identify the modulating factors increasing/decreasing the risk of dementia and the likely emergence of symptoms. The second is a group of individuals who are cognitively normal but are already on the path to clinical disease. We anticipate a realistic future where more and more of these individuals could be considered presymptomatic AD on the basis of models that incorporate a multiplicity of predictive biomarkers (Box).

The previously mentioned classification derives from a theoretical pathophysiological framework recently developed as a revision of the traditional amyloid cascade, the probabilistic amyloid cascade model.²⁹ This model postulates decreasing penetrance of the phenotype from autosomal dominant variations (almost complete penetrance) to APOE蔚4 carrier status (intermediate penetrance) and APOE蔚4 noncarrier status (lowest penetrance) due to the increasing effect of stochastic factors (non-APOE genes, environmental exposures, copathology). It further implies that brain amyloidosis in cognitively normal persons is a risk factor for cognitive impairment and dementia and that the risk is higher in APOE蔚4 carriers.

The model further implies that the risk of progression to cognitive impairment in the asymptomatic at-risk population can be estimated by considering both markers of Alzheimer pathology (amyloid and tau) and other pathologies, including TDP 43, vascular abnormalities, and Lewy bodies; resilience; lifetime and environmental factors; genetics; and other biomarker risk factors.^10,30 The model is consistent with the view that amyloid and tau biomarkers can be used in combination to diagnose AD in patients with cognitive impairment.³¹

The consideration of whether cognitively normal persons with positive biomarkers for Alzheimer pathology should be labeled as asymptomatic at risk or already affected by AD is not just semantics, because behind the different concepts and semantic differences lie different strategies of management of these persons (Table). There is a need to acquire detailed personalized risk knowledge and to be able to communicate this effectively in clinical practice.

A rich literature is available on the safety of disclosure of amyloid status to cognitively normal people.^32,33 The disclosure narrative and the way results are communicated have a significant impact on patient experience and involve clarifying that amyloid status does not equal AD.^34,35

We cannot see any benefit in providing a diagnosis of AD to those who are cognitively normal with positive biomarkers in individuals with a high chance of never developing cognitive impairment in their lifetime. The resulting psychological and societal consequences of being diagnosed with AD and never developing symptoms can be consequential.^36,37 In addition, recent findings show that high-dose gantenerumab achieved similar amyloid PET clearance as approved aducanumab despite its lack of clinical effectiveness.^15,38 This demonstrates the potential liability of the clinical and biological dissociation of the AD definition regarding drug approval. This decision becomes particularly challenging when dealing with biomarker-positive cognitively normal individuals, as the clinical effects may be more delayed in this population. There is a greater inclination to depend on a surrogate biomarker to account for the delayed clinical effect when evaluating this group,³⁹ which adds to the uncertainty in determining treatment efficacy, especially if the biomarker is definitory, as proposed by the AA.

Last, the potential for diagnostic error should not be underestimated, considering realistic statistical parameters of the respective biomarkers in real-world clinical practice, eg, positive predictive value and negative predictive value, that are, by definition, influenced by the disease prevalence in a given context of use.³ In principle, a protein biomarker always delivers a probabilistic distinction of groups as opposed to genetic biomarkers, which may offer a deterministic separation of groups. As an example, cutoff points for AD biomarkers extrapolated from White North American and European population samples to more diverse populations have uncovered significant differences.⁴⁰ Hence, interpreting biomarkers in the clinical context is crucial, as also emphasized by the AA criteria. This underscores the inherent limitations of relying solely on a biological definition of AD in clinical practice.¹

The potential consequences are easily understandable for patients consulting for a benign memory complaint due to attention disorders or age-related changes and the biomarker positivity representing a false-positive diagnosis.⁴¹ These risks will be amplified when testing is done directly to the consumer as it is currently becoming available commercially and through online sources without physician or clinician involvement. Given the current availability of blood-based biomarkers for amyloid and tau, an explosion of cognitively normal persons who are labeled as having AD on a purely biological definition of the disease may be expected.⁴² As a result, increasing societal pressure for antitau or antiamyloid drugs to prevent cognitive decline is foreseeable, including treatment off-label in persons who are cognitively normal.

The AA鈥檚 criteria do not endorse having the use of biomarkers to identify AD in those who are cognitively normal. Unfortunately, there may be no realistic way to control access to these biomarkers or diagnosis or treatment when a biomarker-only diagnosis is made according to these criteria. Considering the concerns raised, we believe that it is necessary to provide a clearer message on this critical issue. We recommend that routine diagnostic testing should not be performed in cognitively normal individuals outside of research purposes at this time. In this population, biomarkers of amyloid pathology are not diagnostic markers but risk markers. Risk assessment differs from diagnostic assessment, which can be done in the context of nondiagnostic patient journeys.^31,42

Diagnostic criteria for AD can have far-reaching societal, political, organizational, and economic implications. We want to restrict the focus in this Special Communication to the scientific evidence and clinical impact on health care practice of these proposed revised criteria. Considering AD as a purely biological entity may be useful for research studies in cognitively normal individuals. However, the IWG鈥檚 approach of considering biomarker positivity in the absence of cognitive impairment as a risk condition rather than a disease, in most cases, increases the motivation for secondary prevention treatments. It also enhances the societal relevance of AD, similar to the impact of risk factors for cardiovascular diseases.^31,43 Instead, it will help better assess the risk-benefit ratio of drugs according to each context of use. Moreover, communicating a risk condition may stimulate these individuals to control their risk factors and change their lifestyle, as well as prompting public health policymakers to foster initiatives and programs for reducing dementia risk at the population level.

The conceptual approach proposed by the IWG is to maintain the essential clinical-pathological concept of AD.¹⁴ We separate asymptomatic at-risk individuals from those who already have the disease. Persons who are asymptomatic at risk deserve full research interest and engagement because current estimates of their cumulative risk of progression to cognitive impairment are undetermined and need to be defined according to their genetic and biomarker profile, factors of risk or prevention, lifestyle, and potential mechanism of resilience. Individual cumulative risk profiling will drive strategies for risk reduction, including treatments with acceptable risk-benefit-cost ratio. The need is urgent to better estimate the risk of progression in the asymptomatic at risk and the presymptomatic population at large from well-designed observational representative population-based studies with long follow-up and accurate measurements of baseline modifiable risk factors and biomarkers of Alzheimer pathology.^43,44 The study of groups for whom this information is lacking (eg, Black, Hispanic, and other ethnic minoritized groups and populations from low- and middle-income countries) is of utmost importance, as their dementia risk factors may differ.

There are task forces actively engaged in devising practical solutions for the asymptomatic at-risk and the presymptomatic persons. In particular, Brain Health Services for the Prevention of Dementia will offer: (1) evaluation of risk, (2) communication of risk, and (3) risk-reduction interventions targeting modifiable risk factors and disease modifiers when these will be shown effective.³¹ Over time, the scenario might further evolve when well-tolerated drug treatments are developed. In such cases, a lower threshold of risk could be proposed for a preventive treatment in asymptomatic at-risk individuals.

To conclude, IWG continues to advocate for AD as a clinical-biological entity. In a clinical setting, a diagnosis of AD is made in the presence of an established clinical phenotype with supportive pathophysiological biomarkers of AD pathology (CSF biomarkers, amyloid or tau PET, or plasma biomarkers such as p-tau 217 pending their approval in clinical practice). The AD diagnosis encompasses the prodromal AD (predementia) and AD dementia stages, as these are just stages of the same disease.

The IWG discourages the use of biomarker investigation in cognitively normal individuals with or without complaints (eg, in the group of individuals with subjective cognitive decline) to diagnose AD. Biomarker investigations in cognitively normal individuals can be done in the context of ad hoc nondiagnostic patient journeys aiming to evaluate the risk of future cognitive impairment, to communicate it, and to put in place risk-reduction interventions. Pilot experiences of such patient journeys are currently in the research phase and might move into the clinic after due validation. Studies of cognitively normal individuals with positive AD biomarkers are important for defining predictive algorithms and risk estimates of progression to clinical symptoms. A very limited number of these individuals will be considered presymptomatic because of a genetic autosomal dominant variant or because of a very high risk for imminent cognitive impairment due to a particular biomarker profile. All the other biomarker-positive individuals, who are much more numerous, should be considered as asymptomatic at risk.

Future research should study cognitively normal persons in 2 main directions: (1) observational longitudinal studies with long follow-up where lifestyle risk factors and biomarkers are simultaneously assessed to accurately estimate the independent weight of each on the incidence of cognitive impairment and dementia and (2) interventional clinical trials, to test the efficacy of drugs against Alzheimer pathology and other risk reduction strategies in reducing the incidence of cognitive impairment and assess the therapeutic risk-benefit profiles.

Accepted for Publication: August 27, 2024.

Published Online: November 1, 2024. doi:10.1001/jamaneurol.2024.3770

Corresponding Author: Bruno Dubois, MD, MSc, D茅partement de Neurologie, Groupe Hospitalier Piti茅-Salp锚tri猫re, AP-HP Sorbonne Universit茅, Institute of Memory and Alzheimer鈥檚 Disease, 47-83 Boulevard de l鈥橦么pital, 75651 Paris Cedex 13, France (bruno.dubois@aphp.fr).

Author Contributions: Dr Dubois had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Dubois, Villain, Schneider, Fox, Campbell, Galasko, Kivipelto, Jessen, Hanseeuw, Boada, Nordberg, Waldemar, Frederiksen, Planche, Bejanin, Ibanez, Cappa, Caramelli, Allegri, Blennow, Ritchie, Agronin, Delano-Wood, Thambisetty, Jones, Lavretsky, Schott, Gatchel, Newhouse, Feldman, Frisoni.

Acquisition, analysis, or interpretation of data: Villain, Schneider, Boada, Barkhof, Froelich, Padovani, Rowe, Nitrini, Slachevsky, de Souza, Bozoki, Widera, Bombois, Levy, Georges, Swantek.

Drafting of the manuscript: Dubois, Villain, Schneider, Jessen, Boada, Frederiksen, Ibanez, Cappa, Ritchie, Thambisetty, Lavretsky, Schott, Newhouse, Feldman, Frisoni.

Critical review of the manuscript for important intellectual content: Villain, Schneider, Fox, Campbell, Galasko, Kivipelto, Jessen, Hanseeuw, Boada, Barkhof, Nordberg, Froelich, Waldemar, Frederiksen, Padovani, Planche, Rowe, Bejanin, Caramelli, Nitrini, Allegri, Slachevsky, de Souza, Bozoki, Widera, Blennow, Ritchie, Agronin, Delano-Wood, Bombois, Levy, Thambisetty, Georges, Jones, Lavretsky, Gatchel, Swantek, Feldman, Frisoni.

Administrative, technical, or material support: Villain, Campbell, Kivipelto, Ibanez, de Souza, Ritchie, Feldman.

Supervision: Dubois, Villain, Jessen, Boada, Frederiksen, Padovani, Cappa, Nitrini, Allegri.

Conflict of Interest Disclosures: Dr Villain reported receiving grants from Union Nationale pour les Int茅r锚ts de la M茅decine (UNIM), Fondation Claude Pompidou, Fondation Alzheimer, Banque Publique d鈥橧nvestissement, and Fondation pour la Recherche sur l鈥橝lzheimer; serving unpaid as local principal investigator or subinvestigator in NCT04241068 and NCT05310071 (aducanumab, Biogen), NCT05399888 (BIIB080, Biogen), NCT03352557 (gosuranemab, Biogen), NCT05463731 (remternetug, Eli-Lilly), NCT04592341 (gantenerumab, Roche), NCT03887455 (lecanemab, Eisai), NCT03828747 and NCT03289143 (semorinemab, Roche), NCT04619420 (JNJ-63733657, Janssen 鈥� Johnson & Johnson), NCT04374136 (AL001, Alector), NCT04592874 (AL002, Alector), NCT04867616 (bepranemab, UCB Pharma), NCT04777396 and NCT04777409 (semaglutide, Novo Nordisk), NCT05469360 (NIO752, Novartis); serving unpaid as national coordinator for NCT05564169 (masitinib, ABScience), NCT (AD04, ADvantage Therapeutics GmbH); performing unpaid lectures in symposia organized by Eisai and the Servier Foundation; and serving unpaid as an expert for Janssen鈥揓ohnson & Johnson. Dr Schneider reports receiving from The Della Martin Foundation Endowment and grants from the National Institutes of Health (NIH) P30 AG066530 Alzheimer's Disease Research Center, NIH R01 AG053267 DIAN-TU: Next Generation Prevention Trial, Eisai Inc DIAN-TU: tau antibody trial, NIH R01 AG051346 Novel Cognitive and Functional Measure for Alzheimer鈥檚 Disease Prevention Trials, NIH U24 AG057437 Alzheimer鈥檚 Clinical Trials Consortium, NIH R01 AG074983 A尾 DNA vaccine AV-1959D, NIH R01 AG054434 Delivery of Essential Fatty Acids to the Brain in Alzheimer鈥檚 disease, and from Eli Lilly & Co; in addition Dr Schneider has participated in donanemab clinical trials outside the submitted work. Dr Fox reports receiving consultant fees from Eisai, Lilly, Roche, Siemens, and Biogen paid to UCL, not taken personally, Biogen outside the submitted work. Dr Campbell reported receiving personal fees from Blue Agilis Inc outside the submitted work. Dr Galasko reports receiving personal fees from Eisai, GE Healthcare, and Fujirebio during the conduct of the study. Dr Kivipelto reported receiving grants from Innovative Health Initiative, Alzheimer's Disease Data Initiative, KI-Janssen Strategic Collaboration, Alzheimer's Drug Discovery Foundation, and Gates Ventures outside the submitted work. Dr Hanseeuw reported receiving grants from FNRS-WelBio and consulting fees from Biogen/Eisai and Roche paid to institution outside the submitted work. Dr Boada reported receiving consulting fees from Grifols, Araclon Biotech, Roche, Biogen, Lilly, Merck, Zambon, and Novo Nordisk; holding advisory board memberships with Grifols, Roche, Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma; and receiving lecture fees from Roche, Biogen, Grifols, Nutricia, Araclon Biotech, Servier, and Novo Nordisk outside the submitted work. Dr Barkhof reported receiving personal fees from Merck Steering Committee and Biogen Steering Committee; grants from Roche MS project; data safety monitoring board fees from Prothena and Eisai; and consultant fees from Combinostics outside the submitted work. Dr Froelich reported receiving grants from HORIZON-RIA (RECAGE # 779237, 2D-BioPAD # 101120706, EQUICARES # 101156500), the HECTOR II Foundation (FRAILBRAIN), and Network on Ageing Research Heidelberg University; investigator fees from Axon Neuroscience, Noselab, Anavex, Boehringer Ingelheim, Eisai, Hummingbird, and Novo Nordisk, all paid to my institution; personal fees from Biogen, BioVie, Eisai, Eli Lilly, Grifols, Janssen Cilag, Neurimmune, Noselab, Novo Nordisk, Roche, TauRX, Dr Schwabe, Avanir/Otsuka, PharmatrophiX, Charit茅 Berlin, Neuroscios, and Vivoryon; serving as executive board member of the European Alzheimer Disease Consortium and as advisory board member for the Baden-Wuerttemberg Alzheimer Society. Dr Planche reported receiving grants from Fondation PSP France, Fondation Recherche Alzheimer; personal fees from Motac Neurosciences; and serving as unpaid investigator or subinvestigator for clinical trials granted by Novo Nordisk, Biogen, TauRx Pharmaceuticals, Janssen, and Alector during the past 3 years. Dr Rowe reported receiving nonfinancial support from Cerveau Technologies outside the submitted work and payment to produce amyloid and tau PET radiopharmaceuticals for clinical trials. Dr Bejanin reported receiving grants from Instituto de Salud Carlos III (ISCIII) through the projects PI22/00307 and CP20/00038 and cofunded by the European Union, Alzheimer鈥檚 Association (AARG-22-923680), and Ajuntament de Barcelona, en colaboracion con la Fundaci贸 La Caixa outside the submitted work. Dr Ibanez reported receiving grants from ANID/FONDECYT Regular (1210195 and 1210176 and 1220995); ANID/FONDAP/15150012; ANID/PIA/ANILLOS ACT210096; ANID/FONDAP 15150012; and the Multi-Partner Consortium To Expand Dementia Research In Latin America (ReDLat, supported by Fogarty International Center [FIC] and National Institutes of Health, National Institutes of Aging [R01 AG057234, R01 AG075775, R01 AG021051, CARDS-NIH], Alzheimer鈥檚 Association [SG-20-725707], Rainwater Charitable foundation 鈥� Tau Consortium, the Bluefield Project to Cure Frontotemporal Dementia, and Global Brain Health Institute) outside the submitted work. Dr Caramelli reported receiving advisory board/speaker fees from Ach茅, Nutricia, Eurofarma, Knight Therapeutics, Novo Nordisk, and Roche outside the submitted work. Dr Slachevsky reported receiving grants from ANID (FONDECYT #1231839), ANID (FONDAP 15150012), and the Multi-Partner-Consortium to expand dementia research in Latin-America, which is supported by National Institutes of Health, National Institutes of Aging (R01 AG057234; R01AG075775, R01AG21051, and CARDS-NIH), Alzheimer鈥檚 Association (SG-20-725707), Fogarty International Center and Rainwater Charitable Foundation鈥檚 Tau Consortium, the Bluefield Project to Cure Frontotemporal Dementia, and the Global Brain Health Institute (GBHI) during the conduct of the study. Dr de Souza reported receiving grants from Funda莽茫o de Amparo 脿 Pesquisa de Minas Gerais (FAPEMIG) and Conselho Nacional de Pesquisa Cient铆fica (CNPq) and personal fees from Biogen, Lilly, Abbott, Knight, and Novo Nordisk outside the submitted work. Dr. Blennow reports serving as a consultant and at advisory boards for AbbVie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, Sanofi and Siemens Healthineers; serving at data monitoring committees for Julius Clinical and Novartis; giving lectures, producing educational materials, and participating in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the submitted work. Dr Ritchie reported being CEO, founder, and majority shareholder of Scottish Brain Sciences that holds contracts with Lilly, Roche Diagnostics, Merck, Signant Health, Biogen, and Janssen Cilag outside the submitted work. Dr Agronin reported serving as clinical study investigator for Eli Lilly, Eisai, Biogen, Neurim, Alzheon, Karuna, Suven, Bristol Myers Squibb, and Life Molecular Imaging Team outside the submitted work. Dr Bombois reported serving as investigator for Janssen, Johnson & Johnson, Alector, UCB, GSK, Novo Nordisk, Novartis, Eisai, Biogen, Roche, GE-Healthcare, and Eli Lilly outside the submitted work. Dr Levy reported receiving grants to his institute from Institut du Cerveau, Janssen (NCT04619420), Transposon (NCT04993755), and AP-HP PHRC (NCT03481933) during the conduct of the study. Dr Georges reported being executive director of Alzheimer Europe, which receives grants and support for its activities from the European Union鈥檚 Citizens, Equality, Rights, and Values (CERV) and Horizon Europe programs, from the Luxembourg National Research Fund (FNR), as well as from private and public organizations and companies, including AbbVie, Alector, Alzheon, BioArctic, Biogen, Bristol Myers Squibb, Eisai, Essity, GE Healthcare, Grifols, Janssen, Lilly, Merck Sharp & Dohme, Nutricia, Prothena, Roche, and TauRx (all funding is paid to his institution). Dr Jones reported receiving grants from NIH, Bluefield Foundation, and Race Against Dementia outside the submitted work. Dr Lavretsky reported receiving royalties for published books with Oxford University Press and Hopkins University Press. Dr Schott reported receiving grants from Alzheimer鈥檚 Association, Alzheimer鈥檚 Research UK, Medical Research Council, the NIHR; consulting fees from Eli Lilly; and serving as chief medical officer for Alzheimer鈥檚 Research UK. Dr Gatchel reported receiving grants from NIH/National Institute on Aging (NIA), salary support from MEDVAMC, and one-time consultant fees from Eisai outside the submitted work. Dr Newhouse reported receiving grants from NIA, Eisai, Novo Nordisk, and ACImmune outside the submitted work. Dr Feldman reported receiving grants from (all grant funding went directly to UC San Diego): Annovis (QR Pharma), Vivoryon (ProBioDrug), AC Immune, Biohaven Pharmaceuticals, and LuMind Foundation; a Novo Nordisk, Axon Neuroscience, Arrowhead Pharmaceuticals, Roche/Genentech Pharmaceuticals, Tau Consortium, Janssen Research & Development and LuMind Foundation service agreement with UC San Diego for consulting activities and/or travel support and/or data safety monitoring board activities; philanthropic support from Epstein Family Alzheimer's Research Collaboration for Alzheimer therapeutic research; conference travel expenses from Royal Society of Canada paid to UC San Diego; and having a patent for US patent No. PCT/US2007/07008 with personal royalties received. No other disclosures were reported.

Meeting Presentation: This paper was presented at the 17th Clinical Trials on Alzheimer鈥檚 Disease conference; November 1, 2024; Madrid, Spain.

Additional Information: Coauthor Francisco Lopera, MD, died September 10, 2024.