Finding biomarkers constitutes a crucial step for early detection of Alzheimer's disease (AD). Brain imaging techniques have revealed structural alterations in the brain that may be phenotypic in preclinical AD. The most prominent polymorphism that has been associated with AD and related neural changes is the Apolipoprotein E (APOE) ε4. The translocase of outer mitochondrial membrane 40 (TOMM40), which is in linkage disequilibrium with APOE, has received increasing attention as a promising gene in AD. TOMM40 also impacts brain areas vulnerable in AD, by downstream apoptotic processes that forego extracellular amyloid beta aggregation. The present paper aims to extend on the mitochondrial influence in AD pathogenesis and we propose a TOMM40-induced disconnection of the medial temporal lobe. Finally, we discuss the possibility of mitochondrial dysfunction being the earliest pathophysiological event in AD, which indeed is supported by recent findings. 1. Introduction Alzheimer’s Disease (AD) is one of the leading causes of dementia today and it poses an immense societal challenge as the prevalence is expected to continue to rise [1]. This makes it imperative to identify early preclinical changes in AD with high accuracy, in order for intervention strategies to yield effective outcome and to allow affected individuals to partake in an active treatment plan [2–5]. AD is characterized by early pathological changes in the brain, including senile plaques, neurofibrillary tangles, synapse, and neuronal loss. Neurofibrillary tangle formation may initiate in subcortical nuclei such as the dorsal raphe and locus coeruleus, prior to spreading to transentorhinal regions [6, 7]. Findings also support that pathological changes in AD commence in the medial temporal lobe (MTL) [8–10], primarily in the entorhinal cortex (ERC) and hippocampus (HC) [11–13], which undergo initial gray matter (GM) loss. Recently, attention has also been directed towards the impact of pathological mechanisms on white matter (WM), as up to 50% of AD cases present with global WM deterioration in neuropathological examinations [14, 15]. The temporal succession of GM and WM changes in preclinical AD remains to be determined; so far there is support for both primary and secondary WM changes within the MTL [16, 17]. MCI is regarded as a prodromal state of AD, where individuals present with subjective memory complaints and/or objective memory impairment, but are still intact in daily life and do not meet current AD diagnostic criteria [2, 18, 19]. Amnestic type MCI (aMCI), where memory impairment is
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