Among the 1381 common genes of AD and T2DM, 361 genes overlapped with the memory-associated genes in the DisGeNet database (
Table S1). Using the information on protein interactions in the STRING database, Markov clustering of the interaction network was performed using the default parameters, and 93 clusters with different numbers of genes, ranging from 1 to 13, were obtained.
Table S4 lists these clusters and their associated proteins. The cluster numbers were determined according to the average local clustering coefficient of the network-based clustering method. Therefore, the first cluster (Cluster 1) had the highest average local clustering coefficient, indicating tighter connections between the proteins within the cluster compared to the other clusters.
3.1. Cluster 1 (CL1)
CL1 included 13 genes (
Figure 1). PI3K and PDGF-related genes were frequent in this cluster.
PI3K is a well-known enzyme involved in various cellular functions, including apoptosis, glucose uptake, and neuroprotection [
6]. Many PI3K family members (PI3K subtypes) function in the Akt and mTOR pathway [
6,
7]. In AD, the PI3K pathway is inhibited by Aβ, which has been linked to increased apoptosis of neurons [
8]. Moreover, the PI3K/Akt signaling pathway is involved in tau phosphorylation, dysregulated insulin signaling, suppression of autophagy through the activation of mTOR, and altered responses to oxidative stress in patients with AD [
8,
9]. PI3K plays a role in glucose uptake by muscle and adipose cells [
10], and abnormal PI3K signaling causes insulin resistance in animal models [
11]. The PI3K-related pathways, including Akt and mTOR, are associated with neuronal development and brain memory function [
12,
13,
14]. PI3K subtypes PIK3CA, PIK3CB, PIK3CD, PIK3CG, and PIK3R1 were all included in CL1.
PIK3CA was a hub gene in CL1; it is predicted to be involved in the immune-related phenomena of AD development [
15]. In an AD zebrafish model, 20S-protopanaxatriol (PPT) facilitates neurogenesis of neural stem cells (NSCs) and reduces NSC apoptosis and cell cycle arrest by Aβ (which might hinder PIK3CA and PPT binding) [
16]. Bioinformatics analysis of molecular docking and identification of network modules revealed that PIK3CA was one of the target genes for Byu dMar 25 (BM25), a molecule known to have therapeutic potential in AD [
17]. When frog skin peptide, which is a stimulant of insulin release, was administered to a T2DM mouse model, the expression of Pik3ca (the mouse ortholog) increased in skeletal muscles [
18,
19]. PIK3CB has been associated with insulin resistance and hepatic glucose production according to promoter variants [
20,
21,
22]. The expression of PIK3CB is downregulated in patients with AD and linked to the apoptosis and axon guidance pathways [
23]. PIK3CB is also genetically associated with mild cognitive impairment (MCI) showing abnormalities in temporal lesions that modulate memory function [
24].
PIK3CD mRNA in peripheral leukocytes is upregulated in patients with gestational diabetes, whereas it is downregulated in patients with T2DM treated with sitagliptin [
25,
26]. Similar to PIK3CB, PIK3CD is also genetically associated with MCI [
24]. PIK3R1 is well known for its relationship with T2DM and insulin resistance [
27,
28]. Mutations in
PIK3R1 cause SHORT (short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay) syndrome and accompanying T2DM [
29,
30,
31]. Moreover, the analysis of exome sequencing data from over 10,000 subjects in the Alzheimer’s Disease Sequencing Project showed evidence of a functional variant of
PIK3R1 [
32]. Coexpression network analysis has revealed that
PIK3R1 is one of the core immune genes involved in AD and that it is associated with Aβ and tau protein pathology [
33].
CL1 included two PDGF-related proteins, PDGFB and PDGFRB. PDGF is associated with vascular complications in T2DM [
34] and cell death caused by Alzheimer-associated neuronal thread protein [
35]. PDGFB and PDGFRB also involves in vascular complications of T2DM [
36,
37]. In AD, PDGFRB activation has a mitogenic effect that is blocked by Aβ, preventing the neuroprotective effects of PDGF-BB [
38]. Mutations in these two genes cause brain calcifications [
39,
40], which can be observed in patients with AD [
41].
3.2. Cluster 2 (CL2)
In CL2,
P53 acted as a hub gene by showing the strongest connectivity (
Figure 1). P53 has a neuroprotective effect by repressing BACE1 and thus the Aβ production cascade. Interestingly, Aβ may also repress
P53 expression in AD [
42]. Moreover, MCI is affected by conformational changes in P53 [
16,
43]. It is well known that cancer and AD have an inverse correlation in incidence, and the underlying molecular mechanisms seem to involve
P53 and related genes [
44,
45]. Phosphorylated forms, genetic variations, and unfolded P53 have been proposed as biomarkers for AD [
44,
46,
47]. P53-related novel mechanisms, including mitochondrial dysfunction and overexpression of CDK5 in AD and other neurodegenerative diseases, have also been proposed as biomarkers [
46,
48]. In previous studies, genetic variants of
P53 have also been associated with T2DM [
49,
50,
51]. Therefore,
P53 has been identified as one of the hub genes involved in the pathogenesis of AD and T2DM [
52]. Notably, P53 also regulates pancreatic cell survival and glucose homeostasis [
53].
BRCA1 plays a role in repairing DNAs under stress, including the stresses caused by ultraviolet light and reactive oxygen species, and failures of this mechanism in neurons may be related to AD [
54,
55]. Downregulation of
BRCA1 and other DNA repair genes has been observed in patients with clinically evident AD [
56].
BRCA1 depletion was shown to impair cognitive function in mice [
57]. In addition, abnormal accumulation of P53 occurs in AD and other tauopathies [
58,
59], and may be caused by hypomethylation of the promoter region of
P53 [
60]. BRCA1 is known to interact with acetyl coenzyme A (CoA) carboxylase α (ACCA), which results in lipogenesis [
61]. Hypermethylation of BRCA1 was observed in patients with T2DM [
62].
S100B is well known for its role in AD. S100B is involved in gliosis and inflammatory reactions, and suppresses the neurodegeneration of cholinergic neurons in mouse models of AD [
63,
64]. Besides, S100B is associated with memory and cognition. The inhibition of IL-1, for example, decreases S100B, leading to an alleviation of cognitive deficits and tau production [
65]. Neutralization of S100B in a rat sepsis model increased cognitive performance scores [
66], and pharmaceutical suppression of S100B reduced gliosis and neuronal loss [
67]. Besides, it has been shown that S100B and receptor for advanced glycation products (RAGE) affect learning and memory impairment by interacting with IL-1, IL-6, and TNF-α [
68]. Serum S100B levels positively correlate with cognitive performance tests in a healthy elderly population [
69]. In contrast, they also show a positive correlation with AD severity [
70]. S100B is also associated with the pathophysiology of T2DM. In a mouse model, S100B induced beta cell apoptosis [
71]. Serum S100B levels were elevated in patients with T2DM with peripheral neuropathy [
72], and S100B levels correlated with cognitive performance in patients with T2DM [
73]. In the coronary arterioles of a mouse model, S100B suppresses the vasodilatation effect of acetylcholine [
74].
DNMT1 is an enzyme that catalyzes the transfer of methyl groups to DNA CpG sites, and previous research in animal models has shown that aberrant DNMT1 expression is associated with memory impairment [
75,
76,
77,
78]. In a high methionine-induced AD rat model,
DNMT1 was downregulated and tyrosine receptor kinase-induced memory impairment was observed [
79,
80]. In humans, DNMT1 has been associated with both AD [
81,
82,
83,
84], and T2DM, and increased
DNMT1 expression has been observed in beta islet cells from patients with T2DM [
85]. IL-6, which is a major inflammatory mediator, induces insulin resistance and reduces DNMT1 protein levels in endothelial cells [
86]. In CL2, PARP1 was not directly connected to P53, but linked to it via DNMT1.
In diabetic mice, NF-kB inhibition improves vascular function and increases cleaved PARP1 [
87,
88]. The role of PARP1 in T2DM was discovered through the modulation of PARP1 by diverse inhibitors. PARP1-inhibition reduces cardiac ischemia and inflammation in diabetic rats [
89], and prolongs the lifespan of
Caenorhabditis elegans under hyperglycemic conditions —probably via TCF7L2— [
90]. PARP1 is associated with the vascular complications of T2DM, and has treatment potential for this condition [
91,
92,
93,
94]. Angiotensin II-treated heart muscles of diabetic mice showed elevated PARP1 activity, cardiac hypertrophy, and inflammation, which were reversed by PARP1 inhibition [
91]. Mendelian randomization identified a causal relationship between genetic variants of
PARP1 and obstructive coronary arterial disease in patients with T2DM [
92]. When bromocriptine is used for the treatment of prolactinomas, it controls glucose and lipid profiles in diabetic rats, leading to changes in
p-AKT, followed by changes in Nf1 and PARP1 [
93]. Cholesterol-induced lipotoxicity, which is related to beta cell dysfunction in obese patients with T2DM, has been shown to be controlled by the inhibition of PARP1 by GLP-1 administration [
94].
3.3. Cluster 3
CL3 had well-known AD-associated genes, whose relatedness to T2DM has been less reported (
Figure 1). Amyloid precursor protein (APP) is probably the most frequently studied molecule in AD research. Therefore, only APP studies related to memory or cognitive impairment were included in this review. For this purpose, a PubMed search was performed with using “APP gene and Alzheimer’s disease and brain memory” as keywords; the results included many studies on APP and their impact on memory function. JNK inhibition, for example, was shown to eliminate memory impairment and long-term potentiation deficits in a mouse model of AD in which APP phosphorylation was inhibited [
95]. CRTC1 is a CREB coactivator whose expression is suppressed by APP [
96]. When all-
trans-retinoic acid was administered to APP/PS1 transgenic mice, improved spatial learning and memory were observed, compared with those of the control group, together with downregulation of CDK5 (a major kinase for APP and tau phosphorylation) [
97]. According with a mouse model, low-density lipoprotein receptor-related protein 6 (LRP6) is involved in memory deficits via Wnt signaling, and the downregulation of this process is linked to the phosphorylation of APP and increased production of Aβ [
98]. Besides, APP haploinsufficiency prevents memory deficits in Familial British Dementia mouse models [
99], and PTEN-induced putative kinase 1 (PINK1) is associated with memory impairment induced by APP PP [
16]. Moreover, increased APP intracellular domain (AICD) production in hippocampal neurons disrupts spatial memory [
100]. Meanwhile, the role of APP in T2DM pathophysiology remains unclear, given that there is limited molecular evidence. However, it has been suggested that APP is the main regulator of insulin secretion in pancreatic islets [
101]. Moreover, BACE2 (β-site APP-cleaving enzyme 2), a protease that is related to AD, is associated with insulin secretion in pancreatic islet cells [
102].
APOE is a well-known AD biomarker. Moreover, the functional relationship between APOE and memory has been reported in many studies. When a proteomic analysis was applied to an AD mouse model, APOE was found to be differentially expressed in the hippocampus, which is related to memory function [
103]. APOE is a transcriptional regulator of APP [
104,
105,
106], and is involved in various biological pathways, such as the PGC-1alpha/sirtuin 3 axis, which alters mitochondrial function and, eventually, memory performance [
107]. Multi-omics data analysis has revealed APOE haplotype-specific molecular alterations in both at gene and protein expression levels [
108].
APOE4 genotype induces an increase in unsaturated fatty acids and accumulation of lipid droplets [
109], and single-cell sequencing of postmortem human samples identified that some signaling pathways of cholesterol metabolism were altered in APOE4 carriers, resulting in reduced myelination [
110]. The effects of APOE on brain function were confirmed using clinical data and imaging analyses. Using functional MRI analyses, APOE4 carriers performing moderate or severe working memory tasks showed less brain activation than non-APOE4 carriers [
111]; APOE4 carriers also showed worse CA1 apical neuropil atrophy and episodic memory function [
112]. APOE genotypes were found to be related to lower memory testing scores in patients with amnestic MCI and AD [
113], lower memory performance in the normal elderly population [
114], and reduced white matter connectivity [
115], and gray matter volume [
116]. APOE is associated with cardiovascular complications in patients with T2DM [
117,
118]. In particular, atherosclerosis and nephropathy are the most frequently reported complications associated with APOE genotypes [
119,
120,
121,
122,
123,
124]. Mechanistically, APOE has been associated with insulin resistance in the muscles of mouse models [
125], islet amyloidosis [
126], and adipocyte enlargement in atherosclerosis [
127].
Clusterin (CLU) is a core protein in CL3; it is concurrently linked to APP and APOE. Studies of
CLU gene variants and plasma protein levels have consistently revealed that CLU is associated with AD [
128,
129,
130,
131,
132,
133,
134,
135]. Molecular biology studies have identified the role of CLU in the pathophysiology of AD. In a CLU knockout mouse model, amyloid plaques were sparse in the cerebral parenchyma but prevalent in cerebral vessels, indicating that Aβ clearance had shifted to perivascular drainage [
136]. CLU affects the lysosome pathway and Aβ processing in stem cell-derived neurons [
137]. Additionally, overexpression of CLU in astrocytes ameliorates amyloid accumulation and gliosis [
138]. It has also been found that the C allele of CLU is expressed at higher levels than other allelic variants and that C allele expression leads to exacerbation of inflammation and to an eventual inhibition of oligodendrocyte progenitor cell proliferation and myelination [
139]. CLU is also associated with memory function. In a young population, working memory performance differed between CLU genotypes [
140], and methylation around SNPs rs9331888 and rs9331896 in the
CLU gene was associated with episodic verbal memory in patients with schizophrenia [
141]. In patients with AD, delayed word recall test scores significantly correlated with rs11136000, one of the
CLU gene SNPs [
142]. Interestingly, the reduced episodic memory function that is associated with some CLU genotypes is attenuated by physical activity [
143]. CLU protein levels increase in exercised mice, increasing memory performance and reducing brain inflammation [
144].