Amyloid-β in Alzheimer’s Disease: A Study of Citation Practices of the Amyloid Cascade Hypothesis Between 1992 and 2019

Article type: Research Article

Authors: Daly, Timothy^{a; *} | Houot, Marion^{b; c} | Barberousse, Anouk^a | Agid, Yves^b | Epelbaum, Stéphane^{b; c}

Affiliations: [a] Philosophy Department, Sorbonne Université, Paris, France | [b] Institut du Cerveau et de la Moelle épinière, ICM, Inserm, U 1127, CNRS, UMR 7225, Sorbonne Université, Inria, Aramis project-team, Inria-APHP collaboration, Paris, France | [c] AP-HP, Hôpital de la Pitié Salpêtrière, Institute of Memory and Alzheimer’s Disease (IM2A), Centre of Excellence of Neurodegenerative Disease (CoEN), National Reference Centre for Rare and Early Dementias, Department of Neurology, Paris, France

Correspondence: [*] Correspondence to: Timothy Daly, Philosophy Department, Sorbonne Université, 1 Rue Victor Cousin, 75005 Paris, France. Tel.: +33 6 37 41 23 14; E-mail: [email protected].

Abstract: The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer’s disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-β (Aβ) in AD pathophysiology, and with the community apparently divided about the ACH’s validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, “HH92”) and classified the polarity of their HH92 citation according to Greenberg (2009)’s citation taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH’s central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aβ’s pathogenicity in AD.

Keywords: Alzheimer’s disease, amyloid cascade hypothesis, amyloid-β, belief, bibliometrics, citations, confirmation, Karl Popper, reproducibility, scientific bias

DOI: 10.3233/JAD-191321

Journal: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1309-1317, 2020