Mayank Handa a , Sanjay Tiwari a , Awesh K. Yadav a , Waleed H. Almalki b , Saad Alghamdi c , Khalid S. Alharbi d , Rahul Shukla a, ⇑ , Sarwar Beg e, ⇑ a Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, UP, India b Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia c Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia d Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia e Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India Alzheimer’s disease (AD) is an irreversible dementia state with characteristic clinical manifestations, including declining cognitive skills and loss of memory, which particularly affects the older population. Despite significant efforts in the field of nano-based drug delivery, there have been few successes achieved in the design of a rational drug therapy. Nanoemulsions (NEs) have potential for the delivery of AD therapeutics owing to their capability for brain drug delivery. Still, there is a long way to go before such therapeutics become a reality in the clinic. In this review, we highlight the preclinical assessment of NEs for AD and discuss the regulatory constraints to their clinical acceptance. Keywords: Nanoemulsion; Intranasal; Oral; Alzheimer’s disease; Mucociliary clearance Introduction The WHO Global Burden of Disease report states that neurological disorders are the second-leading cause of death globally, 1 with stroke, migraine, AD, and other forms of dementia having the highest number of new reported cases and deaths. 2,3 AD is an irreversible dementia state with characteristic clinical manifesta- tions of declined cognitive skills and loss of memory that partic- ularly affects older patients. 2 Although there are several hypotheses have postulated the role of various molecular path- ways underlying AD, the main cause appears to be the obstruc- tion of molecules and nutrition within the brain resulting from the presence of amyloid b (Ab) plaques and tau protein. 4 The lack of a potential therapeutic system is a major challenge in the clin- ical management of the disease. AD can only be managed, rather than cured, with currently available therapeutics and also by providing care-giving facilities to patients. In the USA, the estimated cost for care-giving facili- ties for patients with AD was US$290 billion in 2019, which could increase to US$1.1 trillion by 2050. 5,6 The delivery of ther- apeutics to the brain remains a challenge because of entry restricted by the blood–brain barrier (BBB), 7,8 with the delivery into the brain of many potential neurotherapeutic agents with promising efficacy in AD impacted by both the BBB and blood- cerebrospinal fluid barrier (BCSFB). 9–11 Thus, many researchers have formulated or introduced new drug delivery systems (DDS) that can effectively transport drugs into the central ner- vous system (CNS). 12 Nanotechnology has paved the way for the advanced treat- ment of AD because of its ability to improve the brain targeting of drugs. 13,14 Nanoscale drug delivery systems comprises solid lipid nanoparticles (SLNs), polymeric nanoparticles (NPs), nanos- tructured lipid carriers (NLCs), nanoemulsions (NEs), liquid crys- tals, among others. These nanoscaled systems can be delivered intranasally, transdermally, and intravenously routes to maxi- mize the entry of drugs into the brain. In this review, we focus Therapeutic potential of nanoemulsions as feasible wagons for targeting Alzheimer’s disease ⇑ Corresponding authors. Shukla, R. (rahulshuklapharm@gmail.com), Shukla, R. (rahul.shukla@niperraebareli.edu.in), Beg, S. (sarwar.beg@gmail.com), Beg, S. (sarwar. Drug Discovery Today d Volume xxx, Number xx d xxxx 2021 REVIEWS POST-SCREEN (GREY) 1359-6446/Ó 2021 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2021.07.020 www.drugdiscoverytoday.com 1 Please cite this article in press as: M. Handa et al., Drug Discovery Today (2021), https://doi.org/10.1016/j.drudis.2021.07.020