Neurotoxic Saboteurs: Straws that Break the Hippo's (Hippocampus) Back Drive Cognitive Impairment and Alzheimer's Disease

Late onset Alzheimer's disease (AD) is the most common cause of progressive cognitive dysfunction and dementia. Despite considerable progress in elucidating the molecular pathology of this disease, we are not yet close to unraveling its etiopathogenesis. The hippocampus is at the epicenter of cognition being associated with learning and memory. A battery of neurotoxic modifiers has been delineated that may unleash deleterious heterogeneous pathologic impacts. Synergistically they target hippocampus causing its neuronal degeneration, gray matter volume atrophy, and progressive cognitive decline. The neurotoxic factors include aging, stress, depression, hypoxia/hypoxemia, hypertension, diabetes, obesity, alcohol abuse, smoking, malnutrition, and polypharmacy-to name a few. Addressing upstream pathologies due to these multiple and heterogeneous neurotoxic modifiers vis-a-vis hippocampal dysfunction is of paramount importance. The downstream-generated inflammatory cytokines, mitochondrial dysfunction, oxidative stress, hypoperfusion, excitotoxicity, amyloid beta, and neurofibrillary tangles may then trigger and sustain neurocognitive pathology. The failure of clinical trials in AD is due in part to this complex multifactorial neurotoxic-pathophysiological labyrinth. The key is to employ appropriate preventive and treatment strategies prior to significant hippocampus damage and its dysfunction. Prevention/reversal of the diverse neurotoxic impacts, delineated here, should be an integral part of therapeutic armamentarium, in order to ameliorate hippocampus dysfunction and to enhance memory in aging, mild cognitive impairment, and AD. Throughout, the paper highlights both the challenges presented by the ever present neurotoxic onslaught, and the opportunities to overcome them. Hence, arresting AD pathogenesis is achievable through early intervention. A targeted approach may ameliorate neurocognitive pathology and attenuate memory deterioration.