Decrypting the Possible Mechanistic Role of Fenofibrate in Alzheimer's Disease and Type 2 Diabetes: The Truth and Mystery.

Alzheimer's disease (AD) is a neurodegenerative disease caused by the progressive deposition of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFTs). Of note, metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D) are associated with the development of brain IR and associated neurodegeneration. In addition, AD neuropathology and linked cognitive impairment accelerate the development of peripheral IR and the progression of T2D. Therefore, there is a bidirectional relationship between T2D and AD. It has been demonstrated that AD and T2D induce dysregulation of peroxisome proliferator-activated receptor alpha (PPAR-α) leading to the central and peripheral metabolic disturbances. Hence, dysregulated PPAR-α could be a shared mechanism in both AD and T2D, and restoration of PPAR-α signalling by PPAR-α agonist fenofibrate (FN) may alleviate T2D and AD. Therefore, this review aims to shed light on the potential involvement of PPAR-α in T2D and AD, and how FN could be effective in the management of AD. FN seems to be effective in both AD and T2D by dual neuroprotective and antidiabetic effects that can mitigate AD neuropathology and T2D-related complications by modulating various cellular processes and inflammatory signalling pathways. In conclusion, FN could be a possible candidate in the management of AD and T2D by modulating different signalling pathways involved in the pathogenesis of these conditions.