Alzheimer’s Disease: An overview

• A prevalent form of Dementia characterized by cognitive and memory decline in aging individuals.

• Involves Amyloid beta (Aβ) plaques and neurofibrillary tangles.

• The cholinergic hypothesis suggests that reduced acetylcholine in the brain contributes to AD;

• Notably, 3 out of the 7 AD-approved drugs are Cholinesterase Inhibitors (ChEI).

BChE: The New Frontier

• BChE levels can increase by 40-90% in the AD brain.

• ​This increase predominantly occurs in the temporal cortex and hippocampus, areas most affected by AD.

• ​In pivotal brain areas such as the human hippocampus and amygdala, 10% of ChE-positive neurons contain BChE.

• ​High levels of BChE are found in neuronal plaques in AD.

• Both AChE and BChE amplify the activity of the toxic Beta-Amyloid peptide in tissue culture.

• BChE may be involved in the transformation of diffuse Beta-Amyloid into compact, neuritic plaques.

• There is evidence of a link between the K variant of BChE, ApoE4 and the incidence of some forms of AD.

• Selective BChE inhibitors can increase ACh levels in the rat cortex without affects on AChE.

• Selective BuChE inhibitors can improve learning in elderly rats.

Potential benefits of BChE inhibition

• Likely to improve outcomes in clinical therapy of AD, especially in later stages when BChE levels increase.

• Selective BChE inhibition is potentially advantageous because it may circumvent the classical cholinergic toxicity that is a common side effect of AChE inhibition.

• Potential applications extend beyond AD, including Parkinson’s disease (PD), dementia with Lewy bodies, and combating drug abuse, like heroin.