## 1 Introduction  
Dementia is a progressive or chronic syndrome associated with reduced cognitive ability beyond the considerable consequence of normal aging. Approximately 50 brain diseases can cause dementia, of which Alzheimer's disease (AD) is perhaps the most frequent among elderly patients and is likely to account for 50-70% of all cases of dementia [1]. AD is a chronic, progressive, irreversible, neurodegenerative disorder that is seen in age-dependent dementia. Early illness shows short-term memory loss, mood swings, inability to learn new information, difficulty in finding words, difficulty in solving problems, and disorientation in time and space [2, 3, 4, 5, 6]. Patients in severe stages suffer from serious memory loss, hallucinations, disorientation, and lack of self-sufficiency [5; 7; 8]. AD eventually leads to ample incapability and death of patients within 3 to 9 years after diagnosis [9]. To date, AD is the sixth leading cause of death [10; 11]. Since 2014, approximately 36 million people worldwide have been affected by AD. This figure will significantly increase to approximately 75.6 million and 135.5 million by 2030 and 2050, respectively. Today, someone develops AD every 67 s in America. According to the center for disease control (CDC), there are now 5.3 million people who have AD in the United States (US), and by 2050, the total number of patients is expected to grow to 13.2 million [1; 12; 13]. In addition, the World Health Organization (WHO) estimates that 5% of men worldwide and 6% of women over 60 years of age are largely characterized by [PERSON]'s dementia [3; 10; 14; 15]. The key pathological features of AD include beta-amyloid (A\(\beta\)) plaques, hyperphosphorylated tau proteins, known as neurofibrillary tangles, and neuronal loss, followed by cerebrovascular amyloidosis, inflammation, and other major synaptic changes in the brain [5; 6]. AD is a genetically heterogeneous disorder with an early-onset familial form (FAD), which is autosomal dominant and a late-onset sporadic form (SAD) [16]. Mutation in the A\(\beta\) precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes are responsible for FAD, while SAD has a complex etiology including genetic, viral, environmental, and metabolic factors, among others. In this regard, apolipoprotein E is a polymorphic protein of three isoforms (APOE2, APOE3, and APOE4) in which APOE4 is the most solid genetic risk factor for SAD [4; 9; 16; 17; 18]. Globally, AD has become more and more prevalent among aging populations. In this respect, identification of treatment options will need a better understanding of the pathological mechanisms involved and different ideas for drug design and assessment [19]. Despite the enormous progress made in AD research over the last few decades, the actual cause and pathogenesis of AD are not fully understood, so that there are only a few effective drugs available that can slow the progress rate of the disease [5; 12]. Currently, available FDA-approved drugs for the treatment of AD are acetylcholinesterase inhibitors (AChEI) such as rivastigmine, donepezil, and galantamine, and N-methyl-D-aspartate (NMDA) antagonists including mementine. Moreover, just fewer than 20% of patients respond moderately to these drugs with an average better in 6 to 12 months. However, approved drugs cannot treat AD without high side effects. There is, therefore, a strong need to identify and evaluate more appropriate medications with fewer side effects. Within this context, numerous herbal molecules have proven effective to prevent and manage various neurodegenerative disorders [12]. Withaferin A (WA), a steroidal glycowithanolide lactone obtained from the Ayurvedic medicinal plant _Withania somifera_ has the potential to be a therapeutic agent for AD. WA is a major biologically active withanolides with a wide range of activities, such as anti-inflammatory, antitumor, anti-angiogenic, and antioxidant activities, and it also inhibits mitochondrial apoptosis [20; 21].