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Authors: Daly, Timothy | Houot, Marion | Barberousse, Anouk | Agid, Yves | Epelbaum, Stéphane

Article Type: Research Article

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. Show more

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

DOI: 10.3233/JAD-191321

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

Authors: Daly, Timothy | Houot, Marion | Barberousse, Anouk | Petit, Amélie | Epelbaum, Stéphane

Article Type: Research Article

Abstract: Background: Therapeutic research into Alzheimer’s disease (AD) has been dominated by the amyloid cascade hypothesis (ACH) since the 1990s. However, targeting amyloid in AD patients has not yet resulted in highly significant disease-modifying effects. Furthermore, other promising theories of AD etiology exist. Objective: We sought to directly investigate whether the ACH still dominates the opinions of researchers working on AD and explore the implications of this question for future directions of research. Methods: During 2019, we undertook an international survey promoted with the help of the Alzheimer’s Association with questions on theories and treatments of AD. Further efforts to promote …a similar study in 2021 did not recruit a significant number of participants. Results: 173 researchers took part in the 2019 survey, 22% of which held “pro-ACH” opinions, tended to have more publications, were more likely to be male, and over 60. Thus, pro-ACH may now be a minority opinion in the field but is nevertheless the hypothesis on which the most clinical trials are based, suggestive of a representation bias. Popular vote of all 173 participants suggested that lifestyle treatments and anti-tau drugs were a source of more therapeutic optimism than anti-amyloid treatments. Conclusion: We propose a more democratic research structure which increases the likelihood that promising theories are published and funded fairly, promotes a broader scientific view of AD, and reduces the larger community’s dependence on a fragile economic model. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia prevention, diversity in science, gender, lifestyle factors, lifestyle interventions, pharmaceutical industry, tau protein, women in science

DOI: 10.3233/ADR-210030

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 637-645, 2021

Authors: von Schnehen, Andres | Hobeika, Lise | Houot, Marion | Recher, Arnaud | Puisieux, François | Huvent-Grelle, Dominique | Samson, Séverine

Article Type: Research Article

Abstract: Background: Understanding the nature and extent of sensorimotor decline in aging individuals and those with neurocognitive disorders (NCD), such as Alzheimer’s disease, is essential for designing effective music-based interventions. Our understanding of rhythmic functions remains incomplete, particularly in how aging and NCD affect sensorimotor synchronization and adaptation to tempo changes. Objective: This study aimed to investigate how aging and NCD severity impact tapping to metronomes and music, with and without tempo changes. Methods: Patients from a memory clinic participated in a tapping task, synchronizing with metronomic and musical sequences, some of which contained sudden tempo changes. After exclusions, 51 patients …were included in the final analysis. Results: Participants’ Mini-Mental State Examination scores were associated with tapping consistency. Additionally, age negatively influenced consistency when synchronizing with a musical beat, whereas consistency remained stable across age when tapping with a metronome. Conclusions: The results indicate that the initial decline of attention and working memory with age may impact perception and synchronization to a musical beat, whereas progressive NCD-related cognitive decline results in more widespread sensorimotor decline, affecting tapping irrespective of audio type. These findings underline the importance of customizing rhythm-based interventions to the needs of older adults and individuals with NCD, taking into consideration their cognitive as well as their rhythmic aptitudes. Show more

Keywords: Aging, Alzheimer’s disease, auditory perception, dementia, music, neurodegenerative diseases

DOI: 10.3233/JAD-231433

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 945-959, 2024

Authors: Gagliardi, Geoffroy | Epelbaum, Stéphane | Houot, Marion | Bakardjian, Hovagim | Boukadida, Laurie | Revillon, Marie | Dubois, Bruno | Dalla Barba, Gianfranco | La Corte, Valentina | for the INSIGHT-preAD study group

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology is found in the brain years before symptoms are usually detected. An episodic memory (EM) decline is considered to be the specific cognitive sign indicating a transition from the preclinical to the prodromal stage of AD. However, there is still no consensus on the most sensitive tool to detect it. Objective: The goal of our study was to determine which EM measures, among three clinically used EM tests and one research EM test, would be optimal to use for detection of early decline in elderly cognitive complainers. Methods: 318 healthy elderly participants with subjective cognitive …complaint were followed for two years. We applied generalized linear mixed models to investigate the effect of baseline brain amyloid and metabolism on the longitudinal evolution of four EM tests. Results: Our findings show that participants performed significantly worse in two out of four EM tests (i.e., the Memory Binding Test and the Delayed Matched Sample test 48 items) as their level of brain amyloid load increased. However, we did not find an association between EM measures and brain metabolism. An interaction of the two biomarkers was associated with the number of intrusions in the Memory Binding Test over two years. Conclusion: As most clinical trials in AD are now including patients at its early clinical stage, the precise delineation of the transition phase between the preclinical and prodromal stages of the disease is of crucial importance. Our study indicates that challenging EM tests and intrusions are valuable tools to identify this critical transition. Show more

Keywords: Alzheimer’s disease, biomarkers, cognition, episodic memory, preclinical

DOI: 10.3233/JAD-180966

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 811-824, 2019

Authors: Guieysse, Thomas | Lamothe, Roxane | Houot, Marion | Razafimahatratra, Solofo | Medani, Takfarinas | Lejeune, François-Xavier | Dreyfus, Gérard | Klarsfeld, André | Pantazis, Dimitrios | Koechlin, Etienne | Andrade, Katia

Article Type: Research Article

Abstract: Background: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer’s disease (AD). Objectives: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support …for detecting anosognosia. Methods: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects’ estimation of their performances in a computerized experiment. Results: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. Conclusions: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis. Show more

Keywords: Alzheimer’s disease, anosognosia assessment, caregiver burden, error-monitoring, HABC-M, timely diagnosis

DOI: 10.3233/JAD-230552

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1723-1733, 2023

Authors: Foucard, Cendrine | Palisson, Juliette | Belin, Catherine | Bereaux, Chloé | Dumurgier, Julien | Paquet, Claire | Degos, Bertrand | Bouaziz-Amar, Elodie | Maillet, Didier | Houot, Marion | Garcin, Béatrice

Article Type: Research Article

Abstract: Background: The TNI-93 is a quick memory test designed for all patients regardless of their education level. A significant proportion of patients with Alzheimer’s disease (AD) are illiterate or poorly educated, and only a few memory tests are adapted for these patients. Objective: In this study we aimed at assessing the diagnostic value of the TNI-93 for diagnosis of patients with biologically confirmed amyloid status. Methods: We included all patients who had an analysis of AD cerebrospinal fluid biomarkers, a neuropsychological assessment including a TNI-93 and an anatomical brain imaging at Avicenne Hospital between January 2009 and November 2019. We …compared the TNI-93 scores in patients with amyloid abnormalities (A+) and patients without amyloid abnormalities (A-) according to the AT(N) diagnostic criteria. Results: 108 patients were included (mean age: 66.9±8.5 years old, mean education level: 8.9±5.2 years). Patients from the A + group (N= 80) were significantly more impaired than patients from the A- group (N= 28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p = 0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p ≤ 0.001), total recall (A+: 5.7±3.5; A-:7.8±2.8; p ≤ 0.001), and on number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p = 0.002). ROC curves revealed that the best scores to discriminate A + from A- patients were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74). Conclusion: The TNI-93’s immediate, free, and total recalls are valuable tools for the 39 diagnosis of AD. Show more

Keywords: Alzheimer’s disease, AT(N), cerebrospinal fluid biomarkers, illiteracy, memory test, neuropsychology

DOI: 10.3233/JAD-210546

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1461-1471, 2021