The gene set/PEA explored whether the DEGs are associated with certain biological processes or molecular functions. The results showed a giant network consisting of 74 nodes connected via 167 edges (Figure 4). The nodes and edges in the network represented genes and functional interactions, respectively. In the network, 58 genes were differentially expressed in AD, while 13 were linker genes. The clustering coefficient of the network was observed as 0.249 with network diameter 7 (Figure 3; Supplementary Table S3). The results suggest the proximity of differentially expressed genes and their coordinated functional association with the biological process [34]. It is interesting to note that DEGs observed in AD phenotype also share some characteristics of Huntington’s disease (HD).

The early pathologic symptoms involve behavioral/mental disease (apathy and sadness) and cognitive deficiencies (impaired judgment, confusion, and memory loss). Comparatively, HD patients usually undergo lesser cognitive performance than AD [35,36]. However, in the late-stage stage, patients with both pathologies face difficulties in eating and ambulation, leading to mortality [36]. The underlying mechanism may involve two signaling pathways, namely retrograde endocannabinoid and VEGF signaling (Table 1). Synaptic function is modulated by lipid messengers known as endocannabinoids, which could impact various neuronal functions and behaviors through stimulating cannabinoid receptors in the central nervous system [37]. Specifically, the endocannabinoids moderate paracrine and juxtacrine signaling between cells, and it has been reported that a retrograde endocannabinoid signal retards secretion of γ-aminobutyric acid (GABA) in the hippocampal CA1 areas by acting on presynaptic cannabinoid receptor-1 [38]. Further, the correlation between high focal amyloid-β accumulation and aberrant endocannabinoid signaling has been implicated in synaptic impairment, neuronal hyperexcitability, and excitotoxic neuronal damage in the AD pathology [39].

The VEGF contributes to various roles within the brain and fosters survival of neurons by stimulating neurotrophic, angiogenic, and cytoprotective activities [40]. However, during early stages of AD, a disrupted VEGF pathway governing crucial activities in synapse function has been evidenced due to toxic–soluble amyloid-beta oligomers. Mechanistically, VEGF inhibits the caspase-3-calcineurin pathway accountable for the loss of postsynaptic glutamate receptor owing to amyloid-beta oligomers [41]. This implies that re-instating VEGF activities on neurons might protect synaptic dysfunction in AD. Further, neuron-derived VEGF has been documented to participate not only in the development of cortical and hippocampal regions (likely through angiogenesis independently) but also act as a neurotrophic factor to stimulate neurons, possibly via activating VEGF receptors [42].

Although the pattern of cognitive abilities diagnosed in HD differs from AD [43,44], the dementia diagnosis criteria share some similarities in both diseases [44], which are initially characterized in the terms of specific loss of certain neuronal subtypes. These diseases are first defined by a specific loss of certain neuronal subtypes on a neuropathological level. In the early stage, medium spiny neurons in the striatum experience atrophy in HD, whereas large pyramidal neurons in the hippocampal CA1 zone, as well as neurons in the basal forebrain and the entorhinal cortex, are major regions of early AD [45,46,47]. Furthermore, substantial progress has been made to explicate shared neurodegenerative mechanisms for AD as well as HD. These mainly include synaptic dysfunction, neurotrophic factor-associated aberrations, apoptotic pathways, post-translational modifications, and protein aggregation and clearance. Neuronal apoptosis is common in AD and HD, which could be attributed to excitotoxicity mediated by N-methyl-D-aspartate (NMDA) a subtype of glutamate receptor) due to its high permeability to calcium [48]. Specifically, out of two subunits, i.e., NR2A and NR2B, comprising NMDA receptors, the hyperactivation of NR2B predominantly at extrasynaptic sites is common in both HD and AD.

The Aβ-induced dysfunction of the NMDA receptor is moderated by tyrosine kinase (Fyn) which phosphorylates NR2B [49] and facilitate its integration into the plasma membrane, leading to an increased magnitude of NR2B on the cell surface [50,51]. This further progresses to an inappropriate activation of enzymes (such as calpains and other Ca²⁺-regulated enzymes) and mitochondrial dysfunction, resulting in cellular apoptosis. Notably, non-neuronal contributions to excitotoxic activities also occur in the form of activated microglia, the common markers of inflammation in the pathology of AD and HD. This has been corroborated in animal studies demonstrating microglial production of quinolinic acid, a tryptophan degradation pathway metabolite and also a selective NMDA receptor agonist, which induce pathologic characteristics of HD and AD when administered into striatum and nucleus basalis of rodents, respectively [52].

Further, neurotrophins such as neural growth factor (NGF) and brain-derived neurotrophic factor (BDNF) also participate in pathologies of AD and HD [53]. The BDNF identifies TrkB receptors, whereas NGF binds to tyrosine protein kinase A (TrkA) receptors to activate downstream signaling pathways. Further, NGF as well as BDNF also bind to p75 neurotrophin receptor, which is pertinent to signaling after neuronal injury. Reports have also indicated that imperfections in intracellular trafficking may be an etiology for suppressed levels of BDNF in the HD or AD brains [54]. Specifically, decreased BDNF levels in AD and HD due to polymorphisms in the gene encoding BDNF occur, which is related to an elevated risk of AD and HD through binding of pro-BDNF to huntingtin-associated protein-1, an essential process for the intracellular trafficking of pro-BDNF [55].

The results showed deregulation of DYNLL1 and KLRN in AD (Table 1) [56], which is also associated with the HD phenotypes [57]. The eukaryotic light chain LC8 is highly conserved and has both dynein-dependent and dynein-independent activities. As a component of the dynein motor, LC8 is required for key cellular functions such as tubulin minus-end-mediated intracellular transport, chromatid separation during mitosis, and nuclear movement [58]. Furthermore, DYNLL1 has also been associated with axonemal transport required for neuronal development, function, and survival [59]. A study by Karunakaran et al. indicated that ciliary motility responsible for brain development, particularly neurogenesis and neuronal migration, could be regulated by axonemal dynein motors [60]. Multifunctional DYNLL1 is also needed for the proper development of both the adaptive and innate B-cell, responsible for lymphomagenesis [61]. In an important report, the kidney and brain protein (KIBRA), a cytoplasmic phosphoprotein associated with enhancing memory, has been reported to bind with DYNLL1 and is deregulated in the brains of AD patients [62]. Interestingly, DYNLL1 has also been found to be disrupted in HD [63]. In addition, KLRN is particularly expressed in the hippocampal region, contributing to the growth and maintenance of hippocampal pyramidal neuron dendrites and dendritic spines [64,65]. It is associated with HD in humans and may play a role in the HD-dependent Ras-related signal pathway [66]. KLRN interacts with several cytoplasmic proteins including peptidylglycine α-amidating monooxygenase and huntingtin-associated protein 1, and suppresses inducible nitric oxide synthase (iNOS) [67,68]. Notably, KLRN has been reported to be under-expressed in AD hippocampus [56]. Although the genes DYNLL1 and KLRN are not directly related with disease phenotypes, their association indicates a common genetic basis for the pathogenesis of AD and HD. The retrograde endocannabinoid and VEGF signaling pathways were also found to carry deregulated genes in AD phenotypes; however, their association with the disease pathogenesis was not significant.