The M1 muscarinic agonists AF102B (Cevimeline, EVOXACTM: prescribed in USA and 
Japan for Sjogren's Syndrome), AF150(S) and AF267B--1) are neurotrophic and 
synergistic with neurotrophins such as nerve growth factor and epidermal growth 
factor; 2) elevate the non-amyloidogenic amyloid precursor protein (alpha-APPs) 
in vitro and decrease beta-amyloid (A beta) levels in vitro and in vivo; and 3) 
inhibit A beta- and oxidative-stress-induced cell death and apoptosis in PC12 
cells transfected with the M1 muscarinic receptor. These effects can be combined 
with the beneficial effects of these compounds on some other major hallmarks of 
Alzheimer's disease (AD) (e.g. tau hyperphosphorylation and paired helical 
filaments [PHF]; and loss of cholinergic function conducive to cognitive 
impairments.) These drugs restored cognitive impairments in several animal 
models for AD, mimicking different aspects of AD, with a high safety margin 
(e.g. AF150[S] >1500 and AF267B >4500). Notably, these compounds show a high 
bioavailability and a remarkable preference for the brain vs. plasma following 
p.o. administration. In mice with small hippocampi, unlike rivastigmine and 
nicotine, AF150(S) and AF267B restored cognitive impairments also on escape 
latency in a Morris water maze paradigm in reversal learning. Furthermore, in 
aged and cognitively impaired microcebes (a natural animal model that mimics AD 
pathology and cognitive impairments), prolonged treatment with AF150(S) restored 
cognitive and behavioral impairments and decreased tau hyperphosphorylation, PHF 
and astrogliosis. Our M1 agonists, alone or in polypharmacy, may present a 
unique therapy in AD due to their beneficial effects on major hallmarks of AD.