Alois Alzheimer primarily defined Alzheimer’s disease (AD) in 1906(Dong et al., 2012) as a challenging brain disorder that displays chronic irreversible, progressive neurodegenerative features (Korolev, 2014; Sawikr et al., 2017). AD is characterized by brain atrophy and loss of cortical neurons, particularly pyramidal cells, and is responsible for cognitive dysfunction and the temporal lobe, including the hippocampus and entorhinal cortex, and synaptic loss (Korolev, 2014). It causes a significant disruption of natural brain structure and function, which is diagnosed by a gradually progressive deterioration of memory, intellectual disabilities, and cognitive deteriorated performance that trigger dementia, the decline in memory or loss of memory, deficiency in language/thinking/judgment skills, the discordance of visual and motor abilities, cognitive decline and leads to psychiatric and behavioral symptoms, which eventually brings death (Korolev, 2014; Sawikr et al., 2017; Cisternas and Inestrosa, 2017; Falsafi et al., 2014; Riise et al., 2015; Vanessa de Jesus et al., 2009).

AD is the most predominant form of dementia among older people (about 60%–70% of diagnosed cases) (Korolev, 2014; Sawikr et al., 2017; Cortini et al., 2019), and its prevalence among individuals around 60 years is 1 to 3 percent, 70 and 80 years is 3 to 13 percent and older than 85 years is more than 25 to 35 percent (Sawikr et al., 2017). It is estimated that by 2050, the number of Alzheimer's patients will reach 85 million (Zhang et al., 2019a). The exact mechanisms of AD etiology remain unknown, resulting in limitations in the therapeutic aspect of current drugs (Cisternas and Inestrosa, 2017; Wang et al., 2019a), making it one of the greatest challenges in the world with the emotional and financial burden on societies(Sharma et al., 2019; Chonpathompikunlert et al., 2010).

AD is a multifactorial disorder with various risk factors, including age, biological factors such as genetic alteration, inflammatory and immune responses, elevated blood glucose levels, type 2 diabetes, cerebral stroke, head trauma, hormonal alteration, oxidative stress, drugs toxicity, cardiovascular diseases, hyperlipidemia, hypertension and environmental factors such as low education level, poor social, mental and physical performance (Dong et al., 2012; Vanessa de Jesus et al., 2009; Zhang et al., 2019a; Sharma et al., 2019; Zhao et al., 2019a).

AD is divided into two genetically forms: familial (early-onset, (fAD)) and sporadic (Late-onset, (sAD)) (Wang et al., 2019a). Rare abnormalities commonly inherit the fAD form in three major genes, have a small proportion (5%–10%), and affect individuals under 65-year age (Korolev, 2014; Cortini et al., 2019; Wang et al., 2019a). Subjects with Down’s syndrome have a higher risk of early-onset AD. Autosomal mutation in presenilin-1 (PS-1) and 2, located on chromosomes 1 and 14, and in the amyloid precursor protein gene located on chromosome 2 are seen in fAD form (Cortini et al., 2019; Elnaggar et al., 2015).

sAD is major form of AD (90%–95%) with genetic and nongenetic risk factors. The existence of epsilon four allele for apolipoprotein E gene, located on chromosome 19 is one of the genetic risk factors. sAD is common in people with 65 and older ages, one of the risk factors of sporadic form is presence of epsilon four allele of the apolipoprotein E gene that located on chromosome 19 (Korolev, 2014; Cortini et al., 2019; Wang et al., 2019a).

Most recognized theories in AD pathology are tau, amyloid β (Aβ) and cholinergic hypotheses (Zhao et al., 2019a).

The major neuropathological hallmark in AD is an aggregation of extracellular senile plaques and deposition of non-soluble Aβ1–42 peptide, derived from cleavage of transmembrane amyloid precursor protein in the amyloidogenic pathway by β and γ secretases, that lead to neurodegeneration by disturbance in synaptic functions and induce apoptosis; aggregation of intracellular neurofibrillary tangles, accumulation of intracellular microtubule-associated protein tau which are hyperphosphorylated by several kinases such as glycogen synthase kinase 3β (GSK-3β), cyclin-dependent kinase 5(CDK5) and casein kinase 1(CK1). Hyperphosphorylation of tau results in the degeneration of neurons by disturbing the cell skeleton and axonal transport mechanisms (Dong et al., 2012; Riise et al., 2015; Vanessa de Jesus et al., 2009; Manolopoulos et al., 2010; Chonpathompikunlert et al., 2011).

Approximately 2% of the human genome can code proteins, whereas most of the human genome is not expressed (Yang et al., 2018a). Lots of non-coding RNAs have been discovered, like ribosomal RNA, microRNA (miRNA), transfer RNA, small nuclear RNA, and also long non-coding RNA (lncRNA) (Yang et al., 2018a). LncRNAs are a subclass of RNAs with little or no protein-coding potential, defined as transcripts longer than 200 nucleotides, transcribed by RNA polymerase II, have 5' capped and 3' polyadenylated tails, and are spliced like mRNAs (Yang et al., 2018a; Zarkou et al., 2018; Li et al., 2017a; Wang et al., 2019b). They can interact with DNA, RNA, and proteins to regulate the expression of target genes (Yang et al., 2018a). Growing evidence suggests that lncRNAs are involved in a wide variety of cellular processes, including cell cycle, cell proliferation, transcriptional responses, splicing, mRNA demolition, cells development and differentiation, gene imprinting, epigenetic regulation, genome rearrangement, cell apoptosis, and so on (Cortini et al., 2019; Zarkou et al., 2018; Li et al., 2017a; Wang et al., 2019b; Luo et al., 2019). In addition, the dysregulation of lncRNAs function and expression modulates the pathogenesis of numerous diseases such as cancer, neurodegenerative, cardiovascular, and metabolic disorders (Cortini et al., 2019; Zarkou et al., 2018) Regarding AD, many lncRNAs are involved in processes like neurotrophin depletion, mitochondrial dysfunction, synaptic failure, Aβ production/accumulation, and neuroinflammation (Cortini et al., 2019).

LncRNAs can affect many signaling pathways, particularly the Wnt/β-catenin pathway, one of the most conserved pathways, that participate in various biological processes such as embryogenesis, and tissue homeostasis and is involved in the expansion of the central nervous system containing synaptogenesis, plasticity and hippocampal neurogenesis (Zhang et al., 2019a; Yang et al., 2018a; Tiwari et al., 2015). LncRNAs are related to aging-associated impairments (Cortini et al., 2019), and thereby, their disturbance correlates with human neurodegenerative disorders like AD(Fig. 1) (Zhang et al., 2019a; Tiwari et al., 2015).

In this review, we discuss the lncRNAs’ underlying molecular mechanisms on the Wnt/β-catenin signaling pathway and their interactions with components of this pathway which are responsible for the formation and progression of AD. We hope this review will open new sights for diagnosing and treating AD.