Diminished utility of fMRI subsequent memory models with increasing severity across the Alzheimer’s disease risk spectrum

In functional magnetic resonance imaging (fMRI) studies, episodic memory is commonly investigated with the subsequent memory paradigm in which brain activity is recorded during encoding and analyzed as a function of subsequent remembering and forgetting. Impaired episodic memory is common in individuals with or at risk for Alzheimer’s disease (AD), but only few studies have reported subsequent memory effects in AD or its risk states like mild cognitive impairment (MCI). One reason for this might be that subsequent memory responses may be blunted in AD or MCI and thus less likely to manifest in fMRI signal differences. Here, we used Bayesian model selection of single-subject fMRI general linear models (GLMs) for a visual novelty and memory encoding experiment to compare the model performance of categorical and parametric subsequent memory models as well as memory-invariant models in a clinical cohort (N = 468) comprising healthy controls (HC) as well as individuals with subjective cognitive decline (SCD), MCI, and AD, plus healthy relatives of AD patients (AD-rel). We could replicate the previously reported superiority of parametric subsequent memory models over categorical models ([Soch et al., 2021a][1]) in the HC and also in the SCD and AD-rel groups. However, memory-invariant models outperformed any model assuming subsequent memory effects in the MCI and AD groups. In the AD group, we additionally found substantially lower model preference for models assuming novelty compared to models not differentiating between novel and familiar stimuli. Our results suggest that voxel-wise memory-related fMRI activity patterns in AD and also MCI should be interpreted with caution and point to the need for additional or alternative approaches to investigate memory function. ### Competing Interest Statement F. Jessen has received consulting fees from Eli Lilly, Novartis, Roche, BioGene, MSD, Piramal, Janssen, and Lundbeck. E. Düzel is co-founder of neotiv GmbH. The remaining authors report no disclosures relevant to the manuscript. ### Funding Statement This work was supported by the German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen, DZNE; reference number BN012). The authors further received support from the Deutsche Forschungsgemeinschaft (CRC 1436, A05 and Z03) and from the European Union and the State of Saxony-Anhalt (Research Alliance “Autonomy in Old Age”). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The DELCODE study protocol was approved by the ethics committees of the medical faculties of all recruiting sites: Berlin (Charite, University Medicine), Bonn, Cologne, Göttingen, Magdeburg, Munich (Ludwig-Maximilians-University), Rostock, and Tübingen. The ethics approval process was coordinated by the ethics committee of the medical faculty of the University of Bonn (registration number 117/13). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from the DELCODE study are available via individual data sharing agreements with the DELCODE study board (for more information, see ). The code used for the Bayesian model selection of first-level fMRI data from the FADE paradigm has been published previously (Soch et al., 2021) and is available via GitHub (). [1]: #ref-50