An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease that devastates the lives of its victims, and challenges the family members and health care infrastructures that care for them. Clinically, attempts to understand AD have focused on trying to predict the presence of, and more recently demonstrate the presence of, its characteristic amyloid plaque and neurofibrillary tangle pathologies. Fundamental research has also traditionally focused on understanding the generation, content, and pathogenicity of plaques and tangles, but in addition to this there is now an emerging independent interest in other molecular phenomena including apolipoprotein E, lipid metabolism, neuroinflammation, and mitochondrial function. While studies emphasizing the role of these phenomena have provided valuable AD insights, it is interesting that at the molecular level these entities extensively intertwine and interact. In this review, we provide a brief overview of why apolipoprotein E, lipid metabolism, neuroinflammation, and mitochondrial research have become increasingly ascendant in the AD research field, and present the case for studying these phenomena from an integrated perspective.