Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia. A major neuropathological hallmark of AD is the deposition of amyloid-β protein (Aβ) in the form of neuritic plaques. Aβ is formed by the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ -secretase. It was recently suggested that TMP21 is a novel member of the γ-secretase complex which negatively regulates APP cleavage at the γ-site, but does not affect cleavage of APP or Notch at the -site . In vitro knockdown of TMP21 increases Aβ production and AD patients have less TMP21 expressed in their brains, suggesting that a deficiency in TMP21 may exacerbate AD pathology. TMP21 is most commonly known for its role in vesicle trafficking. Here we present the most recent research on TMP21 in relation to AD, including TMP21's roles in the modulation of γ-secretase activity and protein trafficking.