Reduced expression of fMRI subsequent memory effects 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, Richter, Schütze, Kizilirmak, Assmann, Knopf, et al., 2021) 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.