To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies. According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline. HIGHLIGHTS: The Amyloid Cascade Model does not readily account for various parameters associated with Alzheimer's disease (AD). A unified model correctly identifying the pathogenesis of AD is greatly needed to inform the development of successful therapeutics. Mitochondria play a key and central role in the maintenance of optimal neuronal and synaptic function, the core pathological feature of AD. Mitochondrial dysfunction may be the primary cause of AD, and is a promising target for new therapeutic strategies.