Defining Alzheimer’s disease: stipulations and the ethics of diagnostic change

Michalon R(1)(2), Planche V(3)(4), Lemoine M(5), Keuck L(6)(7), Villain N(8)(9).

Author information:
(1)CESP, Villejuif, Île-de-France, France.
(2)Centre Alexandre Koyré, Histoire des Sciences et des Techniques,
Aubervilliers, Île-de-France, France.
(3)University of Bordeaux, CNRS UMR 5293, Institut des Maladies
Neurodégénératives, Bordeaux, France.
(4)Centre Mémoire Ressources Recherches, Service de Neurologie des Maladies
Neurodégénératives, Pôle de Neurosciences Cliniques, CHU de Bordeaux, Bordeaux,
France.
(5)University of Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France.
(6)Department of History and Medical School OWL, Bielefeld University, History
and Philosophy of Medicine Group, Bielefeld, Germany.
(7)Institute for Studies of Science, Bielefeld University, Bielefeld, Germany.
(8)Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau-ICM, Paris,
France .
(9)Department of Neurology, Institute of Memory and Alzheimer’s Disease, AP-HP
Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France.

Recent revisions of Alzheimer’s Disease (AD) definitions by two leading research
groups—the Alzheimer’s Association and the International Working Group—reflect
divergent approaches: the former promotes a strictly biological definition,
while the latter promotes a clinicalbiological construct. We contend that this
emerging controversy is not merely semantic, but scientifically, clinically, and
politically significant. Drawing on philosophical tools and situating the
current debate within a broader historical context from the reconceptualization
of AD in the 1970s onwards, we explore how definitions can serve as
transformative instruments, acting as strategic bets that reshape scientific
fields and clinical practices. Ultimately, we draw from the AD case study to
argue for a critical reflection on the risks and promises of such definitional
acts. We also propose a renewed attention to the ‘ethics of stipulating’ in the
field of contemporary biomedical sciences. Introduction In response to advances
in diagnostics and therapeutics, two major research groups specialising in
Alzheimer’s disease (AD) have recently revised their definition and diagnostic
criteria for the condition. While they concur on certain aspects—most notably,
the centrality of amyloid and tau pathologies—the two groups have proposed
different types of definition. The Alzheimer’s Association (AA) group asserts
the following fundamental principle: “AD is defined by its unique
neuropathologic findings; therefore, detection of AD neuropathologic change by
biomarkers is equivalent to diagnosing the disease” 1(p.5145). This definition
regards specific biological changes as the unique defining feature rather than a
joint characteristic, together with specific symptoms, of a disease. In this
framework, asymptomatic individuals can be diagnosed with ‘preclinical AD’.
Conversely, the International Working Group (IWG) advocates a
‘clinical–biological construct’,2 wherein AD is diagnosed only in individuals
exhibiting characteristic pathophysiological features and corresponding
phenotypic expression (or a very high risk thereof). The IWG framework
distinguishes two categories of asymptomatic individuals: those at low lifetime
risk of developing clinical–biological AD, labelled ‘asymptomatic at risk for
AD’, and those with a very high probability of clinical–biological AD,
classified as ‘presymptomatic AD’. What could be considered as an incipient
controversy is emerging, as the IWG believes that the AA is proposing a new
definition of AD, which is not aligned with its historical clinical–pathological
concept. Some commentators have dismissed the divergence between the AA and IWG
frameworks as ‘semantic differences’, framing the debate as a matter of
effective ‘communication with patients and families’.3 However, while the
controversy might be scrutinised as a matter of semantics, its grounds as well
as its implications extend far beyond health professionals to patient
communication. This article first establishes key conceptual tools for
understanding definitional propositions and their place in AD’s scientific
history before concluding with an analysis of the strategic choices regarding
the current controversy on the redefinition of AD. It ends with a few
propositions regarding the ethics of disease definitions drawn from the case
study at hand. Conceptual analysis and scientific change: a potted philosophical
approach Understanding the conceptual dimensions of this debate requires
engaging with two central topics of philosophy of science: one concerned with
conceptual analysis, that is, the analysis of the relation between words and
their referents, and the other with scientific change, namely, how scientific
knowledge unfolds. Descriptive versus stipulative definitions A definition is a
statement intended to regulate the use of a term. In scientific and medical
contexts, the rationale guiding the construction of such statements typically
follows two distinct strategies.4 The first is retrospective and present
oriented: it seeks clarification by aligning a term’s definition with its actual
usage, usually as informed by empirical findings about the entity in question.
In its ideal form, this approach yields what is known as a descriptive
definition. The second strategy is prospective and future oriented. It mobilises
the transformative power of definitions to foster new forms of knowledge, to
enhance practical engagement and to improve both individual and population
health outcomes. Rather than describing how a term is used, it prescribes how it
ought to be used. In its ideal form, this approach results in a stipulative
definition. The rationality underlying stipulative definitions brings them close
to certain forms of betting—such as wagering on stocks—where uncertainty is
acknowledged as partly irreducible but nevertheless minimised, calculated and
rationalised. They can also be portrayed as hypotheses guiding action.
Stipulations are invariably animated by a positive vision of the future. Yet
they also carry risks: of misdirecting research communities, squandering time
and resources, delaying beneficial interventions or encouraging premature or
inappropriate practices. Stipulations are thus inherently speculative, amounting
to calculated risks that their proponents judge worth taking. Table 1 outlines
the key features that distinguish the descriptive and stipulative dimensions of
definitions.

DOI: 10.1136/jnnp-2025-337832
PMID: 41702711

Conflict of interest statement: Competing interests: RM, ML and LK have no
competing interests to declare. Independent of this work, VP was, during the
past 3 years, a local unpaid investigator or subinvestigator for clinical trials
granted by Novo Nordisk, Biogen, Janssen, Alector, Roche and BMS. VP served as a
consultant for Motac Neuroscience (animal studies). Independent of this work, NV
received research support from Fondation Bettencourt-Schueller, Fondation
Servier, Union Nationale pour les Intérêts de la Médecine, Fondation Claude
Pompidou, Fondation Alzheimer, Banque Publique d’Investissement, Lion’s Club
Alzheimer and Fondation pour la Recherche sur l’Alzheimer; travel grant from the
Movement Disorders Society, Merz-Pharma, UCB Pharma and GE Healthcare SAS; is an
unpaid local principal investigator or subinvestigator in NCT05531526 (AR1001,
AriBio), NCT06079190 (AL101, GSK), NCT04241068 and NCT05310071 (aducanumab,
Biogen), NCT05399888 (BIIB080, Biogen), NCT03352557 (gosuranemab, Biogen),
NCT04592341 (gantenerumab, Roche), NCT03887455 (lecanemab, Eisai), NCT03828747
and NCT03289143 (semorinemab, Roche), NCT04619420 (JNJ-63733657, Janssen—Johnson
& Johnson), NCT06544616 (JNJ-64042056, Janssen—Johnson & Johnson), NCT04374136
(AL001, Alector), NCT04592874 (AL002, Alector), NCT04867616 (bepranemab, UCB
Pharma), NCT04777396 and NCT04777409 (semaglutide, Novo Nordisk), NCT05469360
(NIO752, Novartis), NCT06647498 (remternetug, Washington University School of
Medicine); is the unpaid French national coordinator in NCT05564169 (VHB937,
Novartis); has given unpaid lectures in symposia organised by Eisai and the
Servier Foundation; has been an unpaid expert for Janssen—Johnson & Johnson,
Eli-Lilly, Novartis.

Auteurs Bordeaux Neurocampus