Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M-1 muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non-specific activation of M-2-M-5 muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M-1 receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M-1 receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M-1 receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects. (C) 2017 Elsevier Ltd. All rights reserved.