The amyloid-beta (Aβ) and tau proteins have been the two leading targets thought to be the causative agents leading to Alzheimer’s disease (AD)Amyloid beta (Aβ),   the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. APP is processed into Aβ peptides by the actions of two proteolytic proteins, β-secreatse and γ-secretase. β-secretase, also known as β-site APP cleaving enzyme (BACE), is an aspartyl protease that initiates Aβ peptide production. While β-secretase1 is the predominant form in neural tissue, β-secretase2 isoforms are present in lower levels and therefore inhibitors of both forms could be investigated as therapeutic targets. β-secretase1 in particular has been found to have increased activity in Alzheimer’s patients, as well as those with mild cognitive impairment that went on to develop AD. 
These enzymes are up-regulated in response to cellular stress such as oxidative stress, ischemia, and energy depletion. β-secretase1 is in lipid raft domains of the cell membrane and requires glycosaminoglycans for effective cleavage.β-secretase1 cleaves APP to release a soluble extracellular fragment and a membrane-bound fragment, C99. C99 is then cleaved by γ-secretase at several potential transmembrane locations, yielding a variety of Aβ peptides ranging from 39 to 43 amino acids in length. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. 

References

1.Sage C. Arbor, et al. Yale J Biol Med. 2016 Mar; 89(1): 5–21.