Novel mathematical modeling approach finds Fortasyn Connect affects memory through reducing hippocampal atrophy in the LipiDiDiet trial

Abstract Background LipiDiDiet is a 6‐year, randomized, double‐blind, placebo‐controlled intervention in 311 individuals with prodromal Alzheimer’s disease (AD)/mild cognitive impairment receiving the specific multinutrient combination Fortasyn Connect (Souvenaid) or a calorie‐matched placebo control once daily. 1 AD is characterized by neurodegeneration including significant synapse loss, and the hippocampal formation is particularly vulnerable in the early stages of AD. Results over the first 2 and 3 years of intervention showed that Fortasyn Connect reduced hippocampal atrophy and slowed decline on clinical and other measures related to cognition, function, and disease progression. 2,3 Here, possible mechanistic pathways through which the intervention may affect the risk of disease progression are being explored post‐hoc. Method A new type of multivariate joint model was applied to the 3‐year LipiDiDiet clinical trial data in which the longitudinal outcomes MRI hippocampal volume (HCV) and neuropsychological test battery (NTB)‐memory are allowed to be associated with disease progression and dropout, and affect each other directly. Specifically, for each longitudinal outcome a linear mixed‐effects model is used to estimate its trajectory, where, for the second longitudinal outcome, the linear predictor of the first outcome is included as time‐varying covariate. Results are compared for both pathways (HCV and NTB‐memory and vice versa), and with results of existing multivariate joint models that have the form of so‐called parallel mediator models (i.e. longitudinal outcomes are merely allowed to be correlated but not to influence each other causally). Result Comparing the models, we observed a strong association between changes in NTB‐memory and disease progression and no direct treatment effect on NTB‐memory. Notably, there was a strong direct treatment effect for HCV changes, together with a direct effect of HCV on disease progression. Moreover, indirect effects of HCV changes on disease progression were mediated through NTB‐memory. Conclusion This new multivariate joint model is useful in modeling possible mechanistic pathways. Overall results from application to the 3‐year data suggest that the observed intervention effects of Fortasyn Connect are partly mediated through reduction of hippocampal atrophy both directly and indirectly via NTB‐memory, in addition to yet to be defined other/complementary pathways. 1 Funding includes EU‐JPND. 2 Lancet Neurol. 2017;16:965‐975. 3 Alz & Dementia. 2021;17:29‐40.