Fig. 4: MCM definition and prediction of concurrent tau, amyloid, and structural brain changes in preclinical AD.
a Changes in a given biological factor (e.g., amyloid, tau deposition) at a specific brain region are modeled as a function of the local multifactorial synergistic interactions (e.g., how dysregulation of the cerebrovascular flow influences amyloid and tau depositions), the intra-brain alterations spreading through communicating cells, and external inputs (e.g., treatments). b This dynamic cause–effect model can be mathematically translated into a system of differential equations. Similar to previously proposed causal models of brain functioning12,68,69,70, in MCM, causality is intrinsic to its differential equations. Beyond traditional single-factor modeling approaches (commonly neuronal activity or misfolded proteins), MCM equations also describe: (i) how the present state of a given biological factor, in a given brain region, causes new fluctuations to itself or to other biological factors in the same or a different brain region, via multifactorial local interactions or by spreading through brain connections, and (ii) how the brain’s dynamic physical system could change due to the influence of external inputs (e.g., cognitive/sensory stimulus, therapeutic interventions, environmental influences). c MCM-simulated concurrent intra-brain changes in tau, amyloid, and gray matter (GM) density in a clinically healthy female participant with significant memory complaints (ADNI data, subject ID 024_S_5290). The resulting MCM simulation is based on the participant’s actual parameters (collected from 67 to 72 years). Then, for prediction purposes, we calculated an additional time window (from 73 to 76 years) of multifactorial data. Note the prominent increase in tau brain deposition in parallel to a substantial reduction in gray matter density in the brain. In a, FUNC refers to functional activity at rest (e.g., from fMRI); METB refers to glucose metabolism (e.g., from FDG-PET).
