Promising Genetic Biomarkers of Preclinical Alzheimer's Disease: The Influence of APOE and TOMM40 on Brain Integrity

Figure 2

The mitochondrial disconnection model is an extension of the TOMM40-induced mitochondrial cascade in Alzheimer’s disease (adapted from [31, 117]). TOMM40 governs the Tom40 complex on the outer mitochondrial membrane, allowing the influx of amyloid beta (Aβ) into the organelle. TOMM40 influence occurs either independently or dependently of APOE. Nevertheless, TOMM40-induced influx of Aβ to the cell starts downstream apoptotic processes via Reactive Oxygen Species (ROS), inducing cell death. We hypothesize that this results in early functional and structural alterations within the Medial Temporal Lobe (MTL), primarily in the hippocampus (yellow). Subsequent disconnection of the MTL, via deterioration of White Matter pathways such as the cingulum (green), fornix (red), and uncinate fasciculus (blue) follow. Disconnection of the MTL may induce secondary functional and structural alteration in distal areas possibly as a result of primary mitochondrial-induced cell death. (Brain graphic: courtesy of Michel Thiebaut de Schotten from the Natbrainlab, King’s College, London, UK.).