International Journal of

Molecular Sciences

Review
Comprehensive Overview of Alzheimer’s Disease: Etiological
Insights and Degradation Strategies
Manish Kumar Singh 1,2 , Yoonhwa Shin 1,2 , Songhyun Ju 1,2,3 , Sunhee Han 1,2,3 , Sung Soo Kim 1,2,3, *
and Insug Kang 1,2,3, *

1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University,
Seoul 02447, Republic of Korea; [email protected] (M.K.S.); [email protected] (Y.S.);
[email protected] (S.J.); [email protected] (S.H.)
2 Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
3 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
* Correspondence: [email protected] (S.S.K.); [email protected] (I.K.);
Tel.: +82-2-961-0524 (S.S.K.); +82-2-961-0922 (I.K.)

Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and affects
millions of individuals globally. AD is associated with cognitive decline and memory loss that
worsens with aging. A statistical report using U.S. data on AD estimates that approximately 6.9 million
individuals suffer from AD, a number projected to surge to 13.8 million by 2060. Thus, there is a
critical imperative to pinpoint and address AD and its hallmark tau protein aggregation early to
prevent and manage its debilitating effects. Amyloid-β and tau proteins are primarily associated
with the formation of plaques and neurofibril tangles in the brain. Current research efforts focus on
degrading amyloid-β and tau or inhibiting their synthesis, particularly targeting APP processing and
tau hyperphosphorylation, aiming to develop effective clinical interventions. However, navigating
this intricate landscape requires ongoing studies and clinical trials to develop treatments that truly
make a difference. Genome-wide association studies (GWASs) across various cohorts identified
40 loci and over 300 genes associated with AD. Despite this wealth of genetic data, much remains to
be understood about the functions of these genes and their role in the disease process, prompting
continued investigation. By delving deeper into these genetic associations, novel targets such as
Citation: Singh, M.K.; Shin, Y.; Ju, S.;
kinases, proteases, cytokines, and degradation pathways, offer new directions for drug discovery and
Han, S.; Kim, S.S.; Kang, I.
therapeutic intervention in AD. This review delves into the intricate biological pathways disrupted in
Comprehensive Overview of
AD and identifies how genetic variations within these pathways could serve as potential targets for
Alzheimer’s Disease: Etiological
Insights and Degradation Strategies.
drug discovery and treatment strategies. Through a comprehensive understanding of the molecular
Int. J. Mol. Sci. 2024, 25, 6901. https:// underpinnings of AD, researchers aim to pave the way for more effective therapies that can alleviate
doi.org/10.3390/ijms25136901 the burden of this devastating disease.

Academic Editors: Lilach Soreq and

Keywords: Alzheimer’s disease; amyloid-β; autophagy; GWAS; proteases; lysosome; tau
José Marco-Contelles

Received: 21 May 2024

Revised: 19 June 2024
Accepted: 21 June 2024 1. Introduction
Published: 24 June 2024
Alzheimer’s disease (AD) stands as the most prevalent form of dementia among the
elderly, with other types including frontotemporal dementia, Lewy body dementia, and
vascular dementia [1–4]. As AD progresses, it primarily impacts brain regions like the
Copyright: © 2024 by the authors.
hippocampus and prefrontal cortex and disrupts cognitive functions [1]. Studies have
Licensee MDPI, Basel, Switzerland. reported the extracellular accumulation of amyloid-β (Aβ)1–42 peptides and intracellular
This article is an open access article neurofibrillary tangles (NFTs) comprising Aβ oligomers and phosphorylated tau proteins.
distributed under the terms and The disease progression worsens brain functions and leads to synaptic loss and memory
conditions of the Creative Commons impairment [5]. In healthy individuals, tau proteins are typically phosphorylated at around
Attribution (CC BY) license (https:// 10 sites [5–7]. However, in AD patients, tau phosphorylation extends to 40–45 sites [6].
creativecommons.org/licenses/by/ Consequently, hyperphosphorylated tau loses its ability to bind to microtubules and is thus
4.0/). transported to different parts of neurons, such as soma, and dendrites spines, disrupting

Int. J. Mol. Sci. 2024, 25, 6901. https://doi.org/10.3390/ijms25136901 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2024, 25, 6901 2 of 28

the synaptic connections among them. Molecular and genetic studies in AD patients
have identified three primary genetic mutations associated with Early-Onset Alzheimer’s
Disease (EOAD), linked with genes encoding amyloid precursor protein (APP), presenilin
1 (PSEN1), and presenilin 2 (PSEN2) [8]. However, the APOEε4 allele is considered the
predominant genetic risk factor for AD, notably in sporadic AD cases referred to as Late-
Onset Alzheimer’s Disease (LOAD). Additionally, variations in CD33 splicing play a
significant role in altering and influencing this genetic predisposition [9,10]. Several tests
used for diagnosing AD clinically include brain imaging techniques such as positron
emission tomography (PET), cerebrospinal fluid (CSF)-based biomarkers like Aβ1–42,
p-Tau, and neurogranin-a synaptic protein, as well as blood test-based biomarkers such
as proinflammatory cytokines including IL-6, ICAM-1, and VCAM-1 [11]. Furthermore,
genome-wide association studies (GWASs) conducted across diverse populations have
implicated rare non-synonymous variants like TREM2, PLCG2, and ABI3 in LOAD [12].
Additionally, inflammatory pathways and various neuroinflammation-modulated signaling
pathways play significant roles in exacerbating Aβ toxicity and AD pathology. Thus,
understanding these genetic and molecular intricacies is vital for developing targeted
therapies aimed at mitigating the devastating effects of AD on cognitive function and
quality of life [13].
Existing evidence has revealed that various enzymes are dysregulated in AD, which is
involved in the cleavage of amyloid precursor protein (APP) and tau hyperphosphoryla-
tion, resulting in increased levels of amyloid-β and tau fibrils in neurons and, ultimately,
neurodegeneration. This process includes numerous endosomal–lysosomal proteases, such
as cathepsins, calpains, caspases, and matrix metalloproteinases (MMPs), which exhibit
a crucial role in tau cleavage and contribute to AD pathology [14]. Consequently, several
small molecule inhibitors targeting these proteases and kinases are currently under clinical
trials for treatment, aiming to inhibit the aggregation of amyloid-β and tau fibrils in AD
patients. Here, we comprehensively elucidate the important genetic factors and degra-
dation pathways implicated in the prevention of AD. Our object is to shed light on the
genetic risk factors, both high and low, and signaling pathways involved in Aβ cytotoxicity.
Additionally, we examine key degradation pathways, including the Receptor for Advance
Glycation End Product (RAGE), Endoplasmic Reticulum-Associated Degradation (ERAD),
and autophagy, which play crucial roles in the clearance of toxic Aβ plaques and NFTs
from the brain. We aim to highlight the genetic risk factors and neuronal markers that
warrant further investigation as potential early biomarkers and therapeutic targets that can
be utilized in the development of therapeutics and strategies to manage the progression of
AD effectively.

2. Methods
This review outlines potential strategies based on GWAS data in AD. We reviewed an
enormous amount of the literature on GWASs derived from transcriptomic, expression QTL
(eQTL), methylation QTL (mQTL), and methylome data. Identifying potential candidate
SNPs as risk factors for disease etiology was challenging because the significance threshold
(p-value < 0.05) was difficult to meet. Understanding the causal genetic variants and genes
influencing AD risk on susceptible loci remains limited, with only a few genes extensively
studied in AD patients. Despite a GWAS with a large population size identifying a locus
covering 3% of AD cases, attributing heritability to these loci is still ambiguous.
It was difficult to provide detailed information about each genetic locus, the af-
fected genes, and subsequent proteins associated with AD. This review encompassed
data from the last two and a half decades, sourced from the AD forum and the World
Health Organization (WHO). These data were collected through extensive searches of
online databases from January 2021 onwards such as https://www.alzforum.org, https:
//forum.alzheimers.org.uk, and https://www.who.int/data for gathering literature. For
research articles, Medline https://www.nlm.nih.gov/medline, https://clarivate.com/
webofscience-medline, PubMed https://pubmed.ncbi.nlm.nih.gov, and Google Scholar
Int. J. Mol. Sci. 2024, 25, 6901 3 of 28

https://scholar.google.com databases were used to find the most relevant and recent pub-
lications. The most important and recent research articles from each relevant author in
AD and tauopathy were included. The collected research allowed the inclusion of detailed
information related to GWASs across various populations, focusing on the most relevant
genes and data related to mechanisms affecting Aβ production and clearance of Aβ. Data
not directly linked with AD but rather other forms of dementia were excluded. This review
primarily focuses on the disease etiology based on GWASs and degradation pathways for
early biomarkers and therapeutic perspectives. A detailed discussion of each section with
significant mechanisms is provided, and references are cited for all encoded statements in
this review.

3. Alzheimer’s Disease Etiology

3.1. Amyloid-β Production, Tau Hyperphosphorylation, and Molecular Biomarkers
Amyloid-β (Aβ) is a peptide fragment of amyloid precursor protein (APP) that under-
goes enzymatic processing by two enzymes, β-secretase and γ-secretase. β-secretase is a
transmembrane aspartate protease, also termed β-site APP-cleaving enzyme-1 (BACE1) [15].
Similarly, γ-secretase is also an aspartate protease composed of four subunits including
presenilin (PSEN), Nicastrin (NCSTN), anterior pharynx defective 1 (APH1), and presenilin
enhancer-2 gene (PSEN-2) [16]. The cleavage of APP by β-secretase (BACE1) generates a
membrane fragment called C99 and, followed by α-secretase action, generates shorter solu-
ble Aβ1–15 and Aβ1–16 peptides at the ectodomain (Figure 1) [17]. Conversely, cleavage
at the C-terminal intramembranous site by γ-secretase generates insoluble Aβ peptides,
leading to the formation of Aβ plaques in the extracellular space and cytoplasm. Several
studies on the inhibition of these proteases have implicated reduced Aβ peptides in vivo
AD models. In LOAD, the levels of Aβ1–42 and tau hyperphosphorylation are increased
significantly. Tau, a microtubule-associated protein tau (MAPT), stabilizes neuronal struc-
ture and integrity by binding to tubulin molecules [18]. Several kinases such as glucose
synthase kinase-3 (GSK-3), cyclin-dependent protein kinase-5 (cdk5), protein kinase A
(PKA), calcium calmodulin-dependent protein kinase-II (caMKII), tau tubulin kinase, a
dual serine/threonine, and tyrosine kinase, expressed in human brains and multiple tissues
such as the spinal cord and testis. These kinases modulate the phosphorylation status of
tau in LOAD patients [19,20].
Mutational studies using GWAS data analysis identified APOE-ε4 as a predominant
risk factor, which is strongly associated with typical late-onset AD, albeit with low pen-
etrance. APOE exhibits three isoforms, i.e., ε2, ε3, and ε4, wherein APOEε4 increases
AD risk in a dose-dependent manner. Conversely, ApoE-ε2 provides protection against
the disease risk conferred by the APOEε4 allele [21]. APOE2 is the least common allele
variant in AD and is linked to elevated levels of tau and phosphorylated tau in APOE2-TR
mice overexpressing human TauP301L -APOE2. Single Recognition Particle 14 (SRP14), a
ribonucleoprotein complex targeting secretory proteins to the endoplasmic reticulum is
upregulated in APOE2 carriers compared with non-carriers, highlighting its critical role
in tau pathology and Aβ deposition in AD in vivo [22]. Rare variants in APOE3 with
mutations in the lipid-binding or lipoprotein receptor-binding regions decrease the risk
of AD to a comparable extent as APOE2 [1]. Notably, the APOE-ε3 V236E Jacksonville
variant (APOE3-Jac) reduces fibrillar Aβ plaques, whereas the APOE3 R136S Christchurch
(APOE3ch) reduces cognitive decline in patients with an autosomal AD mutation [23].
Conversely, APOE2 carriers exhibit delayed Aβ deposition, later clinical onset, and in-
creased longevity compared with non-APOE2 carriers [22]. Genetic evidence indicates
that individuals carrying the APOE-ε4 allele exhibit higher Aβ deposition compared with
APOE ε3/ε4 allele carriers [24]. Mutations in the PSEN1 and APOE genes can lead to the
increased formation of Aβ1–42 and the production of aggregated oligomers [25]. APOE
gene mutations, particularly APOEε4 and APOE2, play roles in Aβ metabolism and lipid
transport within the brain [26].
Int. J. Mol. Sci. 2024, 25, 6901 4 of 28

Figure 1. This image illustrates the processing of amyloid precursor protein (APP) and the subsequent
formation of amyloid plaques (A) as well as tau hyperphosphorylation and the formation of neurofib-
rillary tangles (B). (A). Processing of APP involves two pathways including the non-amyloidogenic
and amyloidogenic pathways. In the non-amyloidogenic pathway, α-secretase cleaves APP, while in
the amyloidogenic pathway, β-secretase and γ-secretase are involved in the cleavage process, leading
to the release of Aβ into the extracellular space. The initial cleavage of APP by proteases releases the
APP intracellular domain (AICD) into the intracellular space. (B). The tau protein normally binds to
microtubules, stabilizing their structure. However, hyperphosphorylation of tau leads to the release of
tau filaments and destabilization of the microtubule structure. This results in the formation of various
tau aggregates, including dimers, oligomers, paired helical filaments (PHFs), and neurofibrillary
tangles (NFTs). Adapted from Ref [17].

The APOE-ε4 gene significantly affects the splicing of CD33, while APOE2 gene
variants are associated with the regulation of HMOX-1 expression and possess antioxidant
properties relevant to AD [27]. APOE2 carriers show increased levels of SLAM family
member 8 (SLAMF8), a CD2 family member, implicated in modulating reactive oxygen
species and inflammation in the brain, as well as influencing macrophage function and
supporting the growth of neoplastic mast cells via SHP-2 [28]. Recent findings have
demonstrated that APOEε4 loss-of-function is associated with a high risk of AD. However
genetic analysis has revealed that ε4 drives AD risk via a gain in abnormal function rather
than a loss of function in AD pathogenesis. Supporting this hypothesis, studies have found
that APOEε4 increases tauopathy and neurodegeneration by promoting lipid accumulation
and impairing cholesterol metabolism in a tauopathy model [24,29]. The precise role of
APOE in AD pathogenesis remains elusive, and further studies are warranted to investigate
this potential mechanism in large populations carrying APOE mutations.
Tauopathies manifest as progressive cognitive and motor impairment, encompassing
conditions such as progressive supranuclear palsy, corticobasal degeneration, chronic trau-
matic encephalopathy, and certain forms of frontotemporal dementia. Genetic evidence
from model organisms like mice suggests that tau plays a pivotal role in age-related neu-
rodegeneration. However, fewer studies have demonstrated tau protein’s involvement in
progressive synaptic dysfunction and neuronal loss, likely stemming from various cellu-
lar derangements including oxidative and immune-mediated injury, altered proteostasis,
aberrant transcription, and post-translational modifications [18]. Tau, primarily localized
Int. J. Mol. Sci. 2024, 25, 6901 5 of 28

in the axons of healthy neurons, relocates to the soma and dendrites under pathological
conditions [30]. Axons play a crucial role in maintaining neuronal function by facilitating
anterograde and retrograde transport of cargo [31]. The mechanisms underlying tau seed-
ing and spreading remain elusive, but some in vivo studies suggest the involvement of
either exocytosis through vesicles or inflammation. The relevance of these mechanisms in
AD pathogenesis remains unclear. Studies in transgenic mice have linked the tau-mediated
reduction of kinesin-1 light chain to impaired anterograde axonal trafficking [32]. In AD,
hyperphosphorylation of tau increases, leading to the formation of neurofibrillary tangles
(NFTs) [11]. Tau-induced neuronal damage initiates in the entorhinal cortex and progres-
sively spreads to the hippocampus and other cortical regions. Later, tau oligomers spread
to other areas of the brain such as the corpus callosum and the mediolateral axis [33,34].
Additionally, extracellular oligomeric tau has been implicated in memory impairment
and cognitive dysfunction in mice [35]. Mutations in MAPT genes are reported in fa-
milial frontotemporal dementia (FTD), characterized by prominent neurofibrillary tangle
deposition [18].
Several studies have highlighted the cerebrospinal fluid (CSF) tau level as an early
indicator of Aβ pathogenesis. However, plasma Aβ also changes in AD patients compared
with controls, and the difference between amyloid-positive and -negative individuals is a
relatively small-fold change [36]. Recent research, utilizing positron emission tomography
(PET) analysis on CSF samples from Alzheimer’s disease (AD) patients, identified three
distinct phosphorylated tau (p-tau) epitopes, including p-tau 181, p-tau 217, and p-tau 231,
evident across clinical, preclinical, and pre-amyloid phases of AD [37,38]. Among these,
p-tau 231 exhibited a significant increase, accumulating notably in brain regions associated
with the default mode network, such as the precuneus, posterior cingulate cortex, and
orbitofrontal cortex [39]. As a result, cerebrospinal fluid (CSF) and brain regions affected
early in AD progression, such as the cortex and hippocampus, indicate that CSF p-tau
levels and Aβ PET are pivotal markers for the early detection of AD [40]. A parallel study
revealed elevated p-tau 217 and p-tau 181 levels in aggregated Aβ, detectable preceding the
onset of aggregated tau pathology [41]. This finding was supported by another study where
p-tau 181 was elevated in the CSF of patients with amyloid pathology and Braak NFT ≥ III
detected by Aβ and Tau PET screening in early AD stages, confirming an escalating trend
with disease progression [42,43]. Notably, 18F-fluorodeoxyglucose (FDG) PET has been
employed to differentiate between typical and atypical AD based on distinctive frontal and
parietal atrophy and hypometabolism [44]. Moreover, the levels of p-tau forms such as
p-tau 205 and total tau surged with the emergence of LOAD symptoms [45]. Notably, Phan
and Cho developed aptamer-mediated biosensors tailored to specifically detect p-tau at
threonine 231, a crucial early p-tau isotope frequently utilized in the diagnosis of AD [46].
Additionally, Gonzalez-Ortiz et al. demonstrated that plasma brain-derived tau (BD-Tau)
with p-tau alongside Aβ42/Aβ40 as a blood-based based-biomarker for diagnosis of AD.
This approach enhances agreement with autopsy results or those derived from CSF or
neuroimaging biomarkers [47,48]. Other blood biomarkers for AD including GFAP and β-
synuclein are significantly observed in AD [49,50]. Various studies have demonstrated that
combined biomarkers provide better diagnostic accuracy for AD than individual measures
alone [51]. For instance, the combination of three plasma biomarkers such as APP669–711
with Aβ and p-tau217, plasma Aβ42/Aβ40, and plasma NFL showed improved diagnostic
performance when the APOE genotype was included [52–54]. Further studies that analyze
combined biomarkers, including plasma Aβ42/Aβ40 and other measurements, may confer
even more accurate diagnoses from blood samples, representing a valuable avenue for
future investigation.
Additionally, modifiers of p-tau levels, such as the α7 subtype of nicotinic acetyl-
choline receptors (α7nAChRs), were found to induce tau phosphorylation at specific sites
(Ser 199, Ser 396, and Thr 205) in the hippocampus of 12-month-old α7 knockout mice.
Interestingly, these mice exhibited increased levels of APP and Aβ without the formation
of senile plaques, suggesting a potential role for α7nAChRs within the tripartite interplay
Int. J. Mol. Sci. 2024, 25, 6901 6 of 28

involving α7nAChRs, Aβ, and tau [55]. Increased oxidative stress leads to elevated level
of GSK-3β and protein kinase, and phosphatase PP2A activates tau phosphorylation at
ser396, ser404, and thr231. In the AD hippocampus, the decreased expression of peptidyl
prolyl cis-transferase (PIN1) and increased p-tau level act as an additive factor in AD
pathogenesis [56]. This observation is reinforced by subsequent experiments using cortical
neuronal cells with H2 O2 , which results in the activation of GSK-3β and PIN1. Thus, kinase
inhibitors could be beneficial in ameliorating p-tau in AD. Some kinase inhibitors including
Tideglusib and lithium, are utilized to modulate GSK-3β activity, although clinical trials
are ongoing in AD and other types of dementia [57]. Therefore, further investigations are
warranted to gain deeper insights into the pathological and non-pathological conditions of
p-tau and NFT production in AD and related tauopathies.

3.2. GWAS and Genetic Risk Factors Associated with AD and Synaptic Plasticity
High-throughput genomic analysis such as genome-wide association studies (GWASs)
identified several genes linked with disease progression and implicated in synaptic dysfunc-
tion and memory impairment [58]. GWAS screening primarily aims to identify susceptible
genes and investigate their impact on AD pathology and early detection. These studies
provide a novel approach to identifying genetic variations associated with AD, with a sig-
nificance threshold (p-value ≤ 0.05) for single nucleotide polymorphisms (SNPs), indicating
a potential risk factor for AD [59]. GWASs are implicated in early biomarkers for various
diseases, including cancers and age-related disorders [60,61]. A recent study utilizing the
U.K. Biobank for AD familial data, known as GWAS-by-proxy, uncovered 12 genomic loci
associated with LOAD [12]. However, our understanding of the causal genetic variants and
genes influencing AD risk at these loci remains limited, with only a few genes extensively
studied in AD patients.
Despite a large population size exceeding more than 1.1 million individuals and
the identification of 38 independent genome-wide significant loci, only 3% of AD cases
can be attributed to heritability [62,63]. Notably, novel loci such as rs5011804 at 12p12.1
have shown significant associations with the levels of CDRSB, FAQ, FS fusiform, and
ADAS13 in various AD cognitive and neuroimaging analyses, underscoring the necessity
for multiple measurements such as neuroimaging data (MRI), fluid biomarkers (blood
and CSF), cognitive impairment/dementia, and familial data to establish SNP association
as an AD risk factor [64,65]. New AD risk loci have been identified through higher-
density genotype imputation, shedding light on candidate causal variants at both new and
established risk loci. A GWAS meta-analysis also revealed early-age risk factors in AD
brain and lymph node samples such as SORL1, PTK2B, SLC24A4, and ZCWPW1 associated
with AD. It is necessary to conduct thorough sequencing studies and in-depth post-GWAS
analyses to fully understand the candidate genes and functional variants associated with
AD susceptibility. These investigations are crucial in order to determine the functional
significance of the identified loci in the pathophysiology of AD [12,66,67]. Furthermore, a
robust association was observed between the NYAP1 SNP and PILRA/PILRB protein in the
brain, with implications for regulating acute inflammatory reactions in the AD brain [28,68].
Numerous other candidate genes identified in GWASs as AD risk factors are local-
ized on different loci, such as rs6705798 encoding EPS15-homology domain-containing
protein1/2 (EHBP1), implicated in Glut4 transportation and expressed in various tissues
including the brain. Another SNP, rs73045836, encoding secreted extracellular calcium-
binding protein 2 (SMOC2) and its isoform SMOC1, has been identified as a novel biomarker
for AD in CSF and brain tissues [26]. In addition to APOE4, other genes associated with
AD risk, such as CLU, PICALM, CD33, MS4A4, MS4A6A, TREM2, ABCA7, CD2AP, and
EPHA1, have been identified in GWASs using meta-analysis methods involving both AD
patients and non-AD populations (Table 1). Among these AD risk genes, the myeloid cell
surface antigen CD33, rs3865444, and rs3836656 are linked to microglia-mediated clearance,
potentially promoting the accumulation of senile plaques [69,70]. Clusterin (CLU), also
known as apolipoprotein J (ApoJ), is a significant risk gene associated with AD that resides
Int. J. Mol. Sci. 2024, 25, 6901 7 of 28

in the central nervous system. It is synthesized and released by both astrocytes and neu-
rons in the brain, where it plays a role in regulating lipid metabolism. In the Caucasian
population, CLU variants, such as rs93331888 and rs11136000, have been identified [71].
However, in the Asian population no significant associations have been observed, indicat-
ing a notable variation in the impact of CLU on AD. Recently, additional candidate loci
including BIN1, TREM2, SORL1, MS4A, SPI1, and TOMM40 have also been identified
via GWAS meta-analysis (Table 1). These genes demand continued attention and further
exploration in the forthcoming studies [70].
Moreover, non-synonymous gene variants are significantly associated with trait as-
sociations, with most human trait-associated variants affecting gene expression rather
than altering protein-coding sequences. These variants likely mediate their effects via
altered gene expression, which may vary depending on cell type [2]. Functional map-
ping of variants to genes, utilizing positional data and expression quantitative trait loci
(eQTL) information from brain and immune tissues/cells, unveiled 989 genes linked to
38 genomic risk loci. These genes predominantly pertain to inflammatory signaling and
are associated with immune cells such as microglia, astrocytes, and oligodendrocytes in
LOAD patients [60,63]. GWASs identify intergenic regions, wherein all protein-coding
genes within 500 kilobases (kb) of the sentinel variant linkage disequilibrium (LD) region
(r2 > 0.5) are implicated as potential AD risk factors.
Transcriptomic analyses and whole-genome sequencing of brain samples from AD
patients have revealed alterations in the expression of genes involved in various signaling
pathways. Several mutations and loci associated with AD have been identified through
GWASs and collaborations such as the International Genomics of Alzheimer’s Project
(IGAP). Over the past two decades, at least 38 loci and more than 300 gene mutations
have been linked to AD. Some of the frequently mutated genes in AD cases include
CD2AP, APOEε4, PTK2B, CASS4, EPHA1, Zyxin, PACSIN, CD33, and CYP3A (Table 1) [60].
Recent analyses combining eQTL and expression transcriptome-wide association studies
(eTWASs) have revealed that the downregulation of EGFR is significantly associated with
reduced risk of AD [72]. Conversely, colocalization of eQTL-GWAS and methylation QTL
(mQTL) signals has identified TSPAN14, derived from lymphoblastoid cell lines, as being
correlated with AD risk [72]. Additionally, pathway enrichment analysis using STRING
has identified immune and tumor necrosis factor (TNF)-mediated signaling pathways,
involving genes such as SHARPIN, RBCK1, and LUBAC, regulated by OTULIN, as having
strong associations with AD risk [72,73].
A study on the Mexican American population with mild cognitive impairment (MCI)
revealed various methylation regions between control and MCI patients along with genes
implicated in neuronal death, metabolic dysfunction, and inflammatory processes [74].
Numerous environmental factors are associated with epigenetic modification and can be in-
herited. For instance, exposure to organophosphate pesticides has been shown to promote
tau hyperphosphorylation and microtubule dysfunction [75,76]. The methylation of genes,
such as ABCA7, BIN1, SORL1, and SLC24A4, is significantly associated with the patho-
logical processing of the tau protein and Aβ peptide in the dorsolateral prefrontal cortex.
Additionally, histone acetyltransferase and histone deacetylase inhibitors elevate histone
acetylation, thereby exerting various positive effects on AD including preventing memory
impairment, cognitive dysfunction, less deposition of the Aβ peptide, and reduced tau
phosphorylation and formation of NFTs [77]. Therefore, identifying polymorphisms associ-
ated with multiple environmental factors through GWASs could facilitate the development
of effective diagnostic and therapeutic strategies.
Furthermore, GWAS data serve as a valuable tool for understanding how AD progres-
sion is connected to the development of other diseases. Post-GWAS functional genomic
analysis is required to prioritize genes that modulate disease susceptibility and identify
candidate causal genes for further functional validation in AD animal models [78]. For
instance, Lee and colleagues used blood samples from AD patient and found associations
between the expression of GPBP1, also known as Vasculin, in both vascular wall and plasma,
Int. J. Mol. Sci. 2024, 25, 6901 8 of 28

crucial for atherosclerosis, and SETDB2, a SET-domain-containing lysin methyltransferases

involved in lipid metabolism via the glucocorticoid-dependent pathway. These genes have
disease-related signatures both in AD and cardiovascular disease (CVD), facilitating the
implementation of personalized prevention strategies [79]. Further analysis showed that
the expression of GPBP1 and SETDB2 is correlated with the tau level in AD mice [80]. Bel-
lenguez et al. conducted a comprehensive search for potential causal genes across 40 novel
loci and found that 51% of the AD loci contain candidate causal genes related to myeloid
cell function [72]. Although these genes are involved in various biological processes, the
exact mechanism through which they contribute to the pathogenesis of AD remains elusive.

Table 1. Genetic risk factors associated with AD and synaptic dysfunctions.

Genes Localization Functions References

Three human APOE isoforms—ε2,
Apolipoprotein E Binds to Aβ to facilitate its uptake and
ε3, and ε4—secreted from microglia, [21,29,81–84]
(APOE) clearance by microglia
astrocytes, and other neurons
Various transmembrane proteins such as
A disintegrin and
Expressed in neuroepithelial APP, n-Cadherin, neurexin-1,
metalloprotease
regions and differentiating neuroligin-1, and Cx3CL1 are substrates [85,86]
domain-containing
gray matter of ADAM10.; involved in learning and
protein 10 (ADAM10)
memory, and synaptic plasticity
Localized in the luminal domain of Conducts apolipoprotein-mediated
ATP-binding cassette
BBB endothelial cells and expressed transport of cholesterol and HDL affects [87,88]
transporters (ABCA7)
in brain tissues Aβ clearance by phagocytosis
Member of g-protein-coupled
Beta1 adrenergic Important role in learning and memory
receptor expressed in the brain and [11,89]
receptor (β-1 AR) functions through TNFα signaling.
release adrenaline
Bridging integrator Neuronal cells including pre- and Involved in Aβ peptide generation and
[90–92]
1 (BIN1) post-synaptic compartments tau spreading
Involve in receptor-mediated endocytosis;
CD2-associated protein Present in endothelial cells [93]
regulate Aβ generation in neurons
Type-1 transmembrane
glycoprotein expressed on
Binds to C3b, a cofactor, and removes
Complement component erythrocytes, and all blood cell
Aβ1–42 from the brain as well as from [11,94]
Receptor 1 (CR1) types, CD4+ T cells follicular
the circulatory system
dendritic cells, and
glomerular podocytes
Catalyzes the splicing of transcription
Inositol-requiring Localized in the ER membrane, factor box binding protein (XBP1) mRNA;
[95,96]
protein I (IRE1) binds to misfolded proteins degrades mRNAs of ER through RIDD
under UPR
Involved in synaptic plasticity and
Expressed in astrocytes,
learning and memory; decreased
IL33 oligodendrocytes, and in neurons [97]
IL33/ST2 signaling contributes to
binds to ST2 in microglia
synaptic impairment
PirB signaling is important for
Leukocyte Highly expressed in pyramidal
maintaining synapse density and
immunoglobulin-like neurons in visual cortex [63,98]
plasticity; plays role in learning
receptor B2 (LILRB2) and hippocampus
and memory
Binds with phosphatidylinositol-binding
Abundantly expressed in the liver, clathrin assembly (PICALM) to clear Aβ
LDL receptor-related
neurons, astrocytes, and monomers, oligomers, and aggregates [99–103]
protein-1 (LRP1)
vasculatures in the brain from the brain across the blood–brain
barrier (BBB)
Int. J. Mol. Sci. 2024, 25, 6901 9 of 28

Table 1. Cont.

Genes Localization Functions References

Hyperphosphorylated and induced
Microtubule-associated Expressed in neurons, maintain
formation of tau aggregates and [11]
protein tau (MAPT) microtubule structure in axons
NFTs in AD
Phosphatidylinositol-
Present in pre- and post-synaptic
binding clathrin
compartments and involve in Involved in synaptic dysfunction in AD [93]
assembly protein
regulating SV recycling
(PICALM)
Protein tyrosine kinase Highly expressed in Role in synaptic plasticity regulation
[104,105]
2β (PTK2B) the hippocampus and memory
Expressed in pyramidal neurons in A significant AD risk variant pA442A,
Phospholipase D (PLD3) [106]
the brain altered microglia and lysosomal function
Mostly PSEN1- and
Involved in induced cleavage of APP
Presenilin (PSEN) PSEN2-encoded proteins expressed [16]
results in Aβ peptide generation
in brain
Binds to eIF2α and Nrf2; potentially
Protein kinase RNA-like Localized in the ER membrane,
inhibits translation and restore [107,108]
ER kinase (PERK) binds to misfolded proteins
ER homeostasis
Protein sorting and trafficking within the
trans-Golgi network to the membrane
Membrane bound protein
Sortilin-related receptor and targets protein in the
containing VPS10 and the [109,110]
1 (SORL1) endosomal/lysosomal system, APP
YWTD/EGF domain
processing and trafficking, synapse
formation and synaptic functions
Triggering receptor
Expressed in the immune cells of Activates downstream signaling in
expressed on myeloid [58,111,112]
myeloid origin microglia
cell 2 (TREM2)

3.3. Signaling Pathways Associated with Aβ Production and Tau Phosphorylation

Metabolic dysfunction is a well-established symptom in AD, evidenced by glucose
hypometabolism detectable even before the onset of AD symptoms. Individuals with in-
sulin resistance, type 2 diabetes mellitus (T2D), hyperlipidemia, obesity, or other metabolic
diseases are at a high risk of developing AD with aging [113]. Impaired insulin signaling
has been linked to neuroinflammation and cognitive decline [114]. Insulin resistance is
observed in brain tissues affected by AD, particularly in the hippocampus and cerebral
cortex. In T2D, altered TNF-α/JNK signaling leads to insulin resistance in the hippocampus
and cortex [115]. Phosphorylation of downstream signaling molecules like AKT, PI3K,
and GSK-3β regulates the increase in Aβ production and tau phosphorylation in the brain.
Another important regulator of GSK-3β is the mTOR pathway, which regulates neuronal
growth, differentiation, and interconnectivity [9,34]. In AD models, mTOR activity was
found to reduce with aging; thus, altered mTOR signaling might affect AD pathogene-
sis [116,117]. In the brain, insulin-responsive glucose transporters, specifically GLUT4 and
GLUT8, are localized on the BBB and within neurons and glia. Chronic hyperinsulinemia
leads to the downregulation of insulin transporters at the BBB, consequently reducing the
amount of insulin that enters the brain [118]. Older adults with insulin resistance exhibited
patterns of reduced brain glucose levels similar to those observed in AD, affecting the
same brain regions. This supports the hypothesis that insulin resistance may ultimately
contribute to the pathogenesis of AD [119].
Furthermore, sodium–glucose co-transporter-2 inhibitors (SGLT2), such as dapagliflozin
and Canagliflozin, restore the mTOR pathway via nutrient-sensitive mechanism, result-
ing in activated glucose uptake and reduced blood glucose levels, potentially mitigating
excitotoxicity in the neurons. This could lead to a reduction in tau phosphorylation and
Int. J. Mol. Sci. 2024, 25, 6901 10 of 28

the accumulation of Aβ in AD models [120,121]. Additionally, caspases, Nrf2, and NF-κB

indirectly influence this pathway. Moreover, CREB signaling is also implicated in AD
pathology. CREB phosphorylation is altered in AD patients because of altered GSK3-β
activity and PKA signaling [122]. CREB regulates neurotrophins, such as brain-derived neu-
rotrophic factor (BDNF) and nerve growth factor (NGF), which are essential for cognitive
processes [122]. There are reports that showed increased amyloid-β levels downregulate
CREB signaling and reduce BDNF/NGF expression, leading to synaptic loss and cognitive
dysfunction [123,124].
Other pathways, including oxidative stress, mitochondrial OXPHOS, lipid metabolism,
and autophagy failure, are also involved in AD pathology (Figure 2) [125,126]. Elevated
ROS levels in the brain contribute to neuronal damage. The increased ROS result in ele-
vated peroxidized (O2− ) lipid and free radicals generated by mitochondrial dysfunction or
metabolites in the brain remains unclear and requires more investigation. Studies on mice
neuronal glia co-cultures indicate increased lipid droplets (LDs) in astrocytes depending on
APOE gene expression in AD [127]. A GWAS identified that NDUFAF6 rs6982393, encoding
an ADH-ubiquinone oxidoreductase important for mitochondrial assembly I, was linked
to increased Aβ toxicity. Another gene variant rs11667768 is linked with phospholipase
D3 (PLD3). PLD3 knockout mice showed an increase in lipid droplets in the brain and,
subsequently, an increase in Aβ deposition [128]. GPR55, a G-protein-couple receptor
implicated in glucose and energy homeostasis, and the RhoA/ROCK pathway were re-
ported in Aβ1–42 in the hippocampus and frontal cortex in AD transgenic mice. In vivo
pharmacological inhibition of GPR55 and RhoA/ROCK demonstrated neuroprotective
effects, reducing apoptosis and oxidative stress induced by elevated Aβ levels in the mouse
brain (Figure 2) [129,130].

Figure 2. This image depicts various biological processes affected by AD. It illustrates increased
amyloid-β plaques, tau hyperphosphorylation, elevated ROS levels, and impaired amyloid-β clear-
ance pathways, along with metabolic abnormalities. Reduced degradation, heightened lipid oxidation
and metabolite accumulation, mitochondrial dysfunction, and the aging process contribute to the
progression of AD. Vascular impairments and defects in the exosome pathway heighten the risk
of amyloid-β accumulation, while calcium release and metal dyshomeostasis exacerbate cognitive
impairment and neuronal cell death.

GWASs focus on investigating potential risk factors associated with AD using clinical
samples, leading to an increase in the number of loci and identification of new risk factors,
SNPs, and mutations significantly associated with AD. However, these GWAS-identified
Int. J. Mol. Sci. 2024, 25, 6901 11 of 28

genes are related to numerous pathways, necessitating systematic characterization to es-

tablish links among APP metabolism, tau function, and genetic risk factors for effective
drug targeting and therapy. The TNF-α signaling pathway has been found to be highly
associated with AD risk factors [131]. The inhibition of TNF-α signaling has shown a signif-
icant reduction in AD and tau pathology in vivo, including memory impairment, synaptic
plasticity, and synapse loss in the brain [73,132]. CD42, a cell division cycle 42 protein and
a Rho GTPase, has been identified as an important gene for AD progression in clinical
hippocampus samples, with a p-value of 7.8 × 10−6 in DEG pathway enrichment analysis.
CD44 is localized in both neuronal and glia cells and plays a role in neuroinflammation. A
loss-of-function mutation in CD44 significantly exacerbates neurotoxicity associated with
Aβ, thereby exacerbating cognition dysfunctions, NFT formation, and amyloid plaque ac-
cumulation [133,134]. RPH3A, a small G-protein involved in exocytosis of neurotransmitter
release and synaptic vesicle traffic, is downregulated in vivo in AD mice [135]. Integrin β-5
(ITGB5), also known as CD18, is correlated with diabetic neuropathy and has been found
to be associated with AD progression [136]. However, the underlying mechanisms need to
be evaluated and confirmed in AD clinical samples.

3.4. Inflammatory Pathways Aid in Alzheimer’s Disease Progression

Inflammation stands as a primary acute response in various neurodegeneration dis-
eases. In AD, the accumulation of amyloid plaques and NFTs within the neurons triggers
the inflammatory signaling pathway. This activation leads to the release of either pro-
inflammatory cytokines or anti-inflammatory cytokines within the brain tissues, particu-
larly in microglia and astrocytes [131]. These cells engage in crosstalk, releasing different
inflammatory cytokines and chemokines at the site of inflammation to aid in the clearance
of Aβ plaques and aggregated proteins [131]. In AD, the accumulation of Aβ and tau
fibrils in the brain and blood vessels compromise the function and integrity of the blood–
brain barrier (BBB). This triggers the release of pro-inflammatory cytokines and activates
myeloid cell-dependent neutrophil infiltration that results in the upregulation of adhesion
molecules (e.g., VEGF) on brain endothelial cells [137]. Subsequently, neutrophils release
neutrophil extracellular traps (NETs), exacerbating neuroinflammation and contributing to
the accumulation of amyloid plaque and tau fibril tangles [138]. Moreover, this cascade of
events obstructs cerebral blood flow (CBF), leading to cognitive dysfunction and dementia.
In studies using APP/PS1 and 5XFAD models of AD, the depletion of neutrophils with
anti-Ly6G antibodies reduces the number of stalled capillaries, promoting revascularization
in CBF and improving cognitive dysfunctions [138,139]. Additionally, blocking neutrophil
trafficking and infiltration into the brain by inhibiting integrin LFA-1 reduces neurotox-
icity and ameliorates memory deficits in AD mice. Furthermore, activated astrocytes
also contribute to triggering inflammatory signaling, thereby secreting pro-inflammatory
cytokines and chemokines that increase oxidative stress and, ultimately, neuronal cell
death [140]. The transmembrane protein CD33, expressed on the microglia receptor, ex-
hibits increased expression in AD. It modulates Aβ1–42 levels in microglia and monocytes,
enhancing microglia phagocytosis of amyloid β in the AD brain [131]. APOE genes are
implicated in neuroinflammation in both the microglia and astrocytes [141]. One GWAS
identified APOE as a potential risk factor for AD, where APOE4 was strongly associated
with AD progression and Aβ deposition compared with APOE2 and APOE3 in late-onset
AD [25,141]. In APP, transgenic mice expression of APOE4 leads to an increase in fibrillar
Aβ plaque burden compared with mice expressing APOE3 or APOE2. This increase has
also been verified in APOE4 carrier individuals who show an increase in both vascular and
parenchymal Aβ plaques [2–4]. In vivo studies using transgenic mice (P301S) showed that
the expression of APOE4 induced neuronal atrophy and increased tau and p-tau levels in
the brain, highlighting its significant role in AD pathology [25,84]. In vitro studies with
APOE4 (iPSC)-derived glia revealed increased accumulation of unesterified cholesterol,
triggering the expression of proinflammatory cytokines and chemokines, leading to neu-
ronal cell death [83]. Triggering receptor expressed on myeloid cells 2 (TREM2), expressed
Int. J. Mol. Sci. 2024, 25, 6901 12 of 28

in microglia, is reported as a risk factor modulating Aβ levels in AD [131,142,143]. Most

AD-associated TREM2 variants are characterized by loss-of-function variants that lead to
reduced protein expression or activity [144]. The most common variant, R47H TREM2, is
linked to an increased risk of AD. The R47H TREM2 variant contributes to the disruption
of synaptic connectivity and functions in the early stages of AD, preceding the onset of
clinical symptoms [58]. Additionally, ATP-binding cassette transporter A7 expression was
induced by Aβ1–42 in microglial cells in the brain, as revealed by GWASs [145].
Astrocyte activation and release of complement protein C3, binding to C3aR in neu-
rons, induces neuronal damage [146]. Moreover, soluble C40 ligands from astrocytes bind
to their cognate surface receptors in microglia, releasing TNF-α in AD, which promotes
neuronal cell degradation [131]. For instance, in the hippocampus, TNF-mediated inflam-
mation triggers necroptosis, a form of neuronal cell death driven by enhanced inflammation
depending on TNFR1 signaling, was reported in the AD postmortem brain [147]. Specifi-
cally, the interaction between TNF and TNFR1 activates a phosphorylate cascade involving
receptor-interacting protein kinase 1 (RIPK1). RIPK3 and mixed lineage kinase domain-like
(MLKL) kinase induce inflammation-mediated necroptosis in the hippocampus in AD [148].
Importantly, targeting TNFR1 and RIPK1 has been shown to prevent neuronal cell death,
suggesting a novel therapeutic target for AD treatment [149].
IL1β and IL-18 expression induced in glial cells during AD progression are regulated
by NLRP3 inflammasome, which activates pyroptosis in glial cells and neurons. These
activated cells release proinflammatory cytokines and chemokines, including TNF-α, IL1β,
IL-6, and C3 ligand, which favors Aβ1–42 production and accumulation, ultimately lead-
ing to cell death [150]. The upregulation of TGF-β1, produced by SOD1 G93A reactive
astrocytes, leads to cytoplasmic aggregation and disrupted autophagy in AD [151]. Several
anti-inflammatory agents target NLRP3 inflammasome signaling. Various proteins includ-
ing Neutrophil gelatinase-associated lipocalin (LCN2), progranulin (GRN), glia fibrillary
acidic protein (GFAP), and TMEM106B have been identified in the cerebrospinal fluid of
patients with AD and other types of dementia, such as amyotrophic lateral sclerosis, fron-
totemporal, dementia, and Parkinson’s disease, and are correlated with reactive astrocyte
pathology [152,153]. Despite these findings, the role of reactive astrocytes and microglia in
enhancing cytokine release, leading to increased NF-kβ activation and impaired autophagy
in AD progression, warrants further investigation.
Microglia, the resident immune cells in the brain, play a critical role in phagocyto-
sis and the autophagic clearance of cellular waste and toxic protein aggregates. In AD,
microglial activation leads to cytokine secretion and increased phagocytosis activity. The
efficacy of microglia responses to stress stimuli and their phagocytic functions relies on
functional lysosomal regulatory circuits [154]. Studies have demonstrated that defective
lysosomal acidification in microglia results in impaired lysosomal function, which in turn
enhances the release of inflammatory cytokines and induces neuronal cell death via mecha-
nisms such as necroptosis [155]. This impairment in lysosomal acidification compromises
microglia phagocytosis and involves various cellular modulations, including presenilin
modifications, cytokine and inflammatory stimulation, and mitochondrial dysfunction,
whose mechanism remains unclear and needs to be investigated [156]. Presenilin 1 (PSEN1,
PS1) and Presenilin 2 (PSEN2, PS2) are essential for APP cleavage and Aβ generation.
PS1 is particularly important for microglia activation and cytokine release [157], with its
phosphorylation being crucial for microglia activation and lysosomal acidification. In
contrast, PS2 N1411 mutant mice exhibit increased cytokine release and activated microglia,
highlighting its role in Aβ phagocytosis and its significance in AD pathology [158]. Another
key factor in lysosomal acidification is the activity of vacuolar (H+)-ATPase, which is linked
with mitochondrial dysfunctions and increased ROS. The interplay between lysosome and
mitochondria dysfunction in AD pathology is well documented, though the precise mech-
anism underlying these deficits remains incompletely understood and warrants further
detailed investigation [159,160].
Int. J. Mol. Sci. 2024, 25, 6901 13 of 28

Restoring lysosomal acidification has been shown to mitigate microglial impairment

and improve lysosomal functions. Various small molecules have been employed to achieve
this, such as C381 and EN6, which act on the V-ATPase complex to maintain lysoso-
mal pH [161]. Other modifiers include SF-22 and its analog, which targets TRP channel
protein to regulate lysosomal pH [162]. Tetrandrine, which inhibits TPC2, facilitates lyso-
somal acidification and enhances the autophagic degradation of pathogenic tau aggre-
gates [162,163]. Curcumin analog C1 and PF11 promote lysosomal biogenesis and luminal
acidification [164]. Additionally, mTOR inhibitors such as OS1–027 and PP242 improve
autophagic function and lysosomal acidification by increasing cathepsin D activity [165].
Nanoparticle-based compounds have also shown efficacy in restoring lysosomal acidifi-
cation under pathological conditions. These include poly (lactic-co-glycolic acid) (PLGA)
nanoparticles (NPs), acidic NPs (ACNPs), photo-activated NPs (PaNPs), and acidic nu-
cleolipid nanoemulsions (NL-NEs) [166–168]. Further optimization is needed for clinical
application, including the development of BBB-penetrating peptides on the surface of NPs
and the selection of suitable acids that are well metabolized in the body with minimal side
effects [169].
Astrocytes play a crucial role in maintaining energy levels through different ion
channels, which have been found to be dysregulated in patients with LOAD [170,171].
Numerous studies indicate that metabolic dysfunction exacerbates Aβ production and im-
pairs the clearance of Aβ plaques and tau neurofibrillary tangles because of compromised
degradative pathways. Importantly, metabolic dysfunction in astrocytes leads to oxida-
tive stress and neuroinflammation, contributing to Aβ pathology [125,172]. Additionally,
microglial activation exacerbates inflammation and tau seeding in AD mice, selectively
increasing NF-κB signaling in microglia, which induces inflammation and tau-mediated
synaptic loss. In vivo, it has been observed that microglia support the spread of tau by tak-
ing up and breaking down the seed-component form of tau [173]. Inhibition of microglial
proliferation has been shown to attenuate tau-induced neurodegeneration and cognitive
deficits [174]. In LOAD, increased Aβ production is modulated by NF-κB signaling in the
AD brain. In vitro studies have demonstrated that inhibiting NF-κB signaling in microglia
via p65 deacetylation reduces Aβ production, suggesting NF-κB as a promising target in
AD [175,176]. These observations indicate a crosstalk between glial cells and astrocytes
in modulating Aβ levels in early- and late-onset AD, warranting further investigation in
AD models.

4. Clearance and Degradation Pathways Implicated in AD

4.1. Receptor for Advance Glycation End Product-Mediated Aβ Clearance
The Receptor for Advance Glycation End Product (RAGE) is a multiligand receptor
belonging to the immunoglobulin superfamily. It is involved in neuronal cell migration
and differentiation during development, is susceptible to perturbation by Aβ, and plays
a role in the inflammatory response [177]. RAGE exists in two isoforms including a full-
length-membrane bound form (mRAGE) and a soluble form (sRAGE) lacking both the
transmembrane and cytosolic domains [178,179]. Research indicates that the expression
of RAGE changes in various brain cell types, including neurons, glia, astrocytes, and
microglia. RAGE plays a crucial role as a transporter by regulating the influx of circulating
Aβ into the brain across the blood–brain barrier (BBB), while the efflux of brain-derived Aβ
into the circulation from the BBB is facilitated by LRP1 and P-glycoprotein [180,181]. The
activation of RAGE in microglia also triggers the release of pro-inflammatory cytokines,
such as IL-1β and TNF-α, contributing to neuronal impairment during the progression
of AD. The binding of Aβ to RAGE in neurons and microglia leads to oxidative stress
and inflammation, resulting in cellular perturbation and decreased learning ability in AD
mouse models [182]. Moreover, p38 MAPK activation is essential for RAGE-dependent
NF-κB activation, induction of target gene expression, and secretion of pro-inflammatory
cytokines from monocytes.
Int. J. Mol. Sci. 2024, 25, 6901 14 of 28

NF-κB, an oxidant-sensitive transcription factor, exacerbates the pro-inflammatory

response by regulating gene expression in RAGE ligands associated with aging, vascular
pathology, inflammation, and hyperglycemia, thereby generating oxidative stress. Thus, the
RAGE signaling axis, involving p38MAPK activation in neuronal and non-neuronal cells,
contributes to the development of inflammatory responses and neuronal perturbation, par-
ticularly in response to increased Aβ accumulation during AD progression. In vivo studies
have demonstrated that perturbation of p38MAPK leads to a reduction in Aβ-induced
cytokine production and neuronal cell death in mouse models [183,184]. Conversely, the
inhibition of RAGE significantly ameliorates Aβ-mediated sustained neuronal and mi-
croglial stress, consequently enhancing cognitive function in AD mice [185]. Despite these
promising findings, there is currently no clinical RAGE inhibitor available for AD patients.
Therefore, RAGE stands out as a potential therapeutic target for reducing the burden of
amyloid-β in the brain, mitigating neuroinflammation, and preserving cognitive functions.

4.2. Endoplasmic Reticulum-Associated Aβ Clearance

Alzheimer’s disease (AD) involves alterations in endoplasmic reticulum (ER) functions
and associated proteins, impacting disease progression and disease etiology. Amyloid-β
plaque formation is linked to improper protein folding and aggregation of Aβ peptides.
Unfolded Protein Response (UPR) triggers endoplasmic reticulum (ER) stress and ER-
associated degradation (ERAD) implicated in AD pathology. The ER lumen, where protein
folding occurs, relies on chaperones like BiP/GRP78, protein disulfide isomerase, calnexin,
and calreticulin for proper folding and glycosylation of newly synthesized protein [186].
Furthermore, folded proteins proceed to the Golgi apparatus by vesicles, while misfolded
proteins are either refolded or directed to degradation via ERAD [187]. ERAD prevents
misfolded protein accumulation by translocating peptides to lysosomes for degradation via
the ubiquitin–proteasome system or autophagy as well as lysosomal pathways to eliminate
misfolded proteins [187,188]. Several studies indicated that mutant PS1 (A246E) and dE9
(deletion of exon 9) induce ER stress/UPR in 3xTg-AD mice and neuronal cell line SK-N-SH
cells more than WT PS1, implicating UPR in AD and suggesting it as a treatment target.
This suggests that ER stress and UPR are implicated in AD and can be a novel target for
AD treatment.
ER stress triggers a complex network of signaling events and cellular processes in-
volved in the degradation of unfolded or misfolded protein through the Ubiquitous Pro-
teasomal system (UPS). Under ER stress inositol-requiring protein I (IRE1), a type I trans-
membrane protein, catalyzes the processing of X-box binding protein 1 (XBP1), leading to
the activation of UPR-targeted genes that regulate the degradation of APP in steady-state
conditions through the ERAD pathway [182]. Clinical AD brain samples show increased
expression of ER stress and UPR-related genes like XBP1, CANX, PDIA3, PDIA6, HSPA5
(BiP/GRP78), and DNAJC3 at the mRNA level though protein levels vary across Braak
stages 0-VI [189,190]. GWASs support ER genes like protein kinase RNA-like ER kinase
(PERK) and inositol-requiring protein I (IRE1), a type I transmembrane protein, as a risk
factor for AD [108,191]. The ablation of IRE1 in the mouse central nervous system reduces
Aβ and amyloid proteins, attenuates astrocyte proliferation, and improves synaptic func-
tion [96]. Downstream target X-box binding protein (XBP1) degrades mRNA, rRNAs, and
microRNAs, reducing UPR in ER. Inducing XBP1 expression in the AD mice hippocampus
reduces Aβ levels and improves synaptic plasticity and memory function [192].
Studies have shown that the eIF2α kinases, PERK, GCN2 (general control non-
derepressible 2), and PKR (double-stranded RNA-dependent protein kinase), play crucial
roles in deficits observed in brain mRNA translation, synaptic plasticity, and memory in
APP/PS1 mouse. In vitro, Aβ elevates eIF2α levels, and the knockout of either PKR or
ATF4 renders neurons less susceptible to Aβ-induced toxicity. Consequently, the inhibition
of PERK/eIF2α signaling reduces amyloid plaque formation and restores synaptic func-
tions [107,193]. UPR activation ultimately restores mitochondrial functions, reducing Aβ
toxicity and enhancing neuronal survival, thus indicating ER-associated protein degrada-
Int. J. Mol. Sci. 2024, 25, 6901 15 of 28

tion as a promising target for AD treatment. Further molecular investigation is essential to

elucidate how ERAD regulates amyloid-β levels accurately in AD.

4.3. Autophagy-Mediated Amyloid-β Clearance in Alzheimer’s Disease

The progression of AD involves enhanced production of Aβ because of mutations
in APP and PS1/2 genes in familial AD cases or dysfunction of Aβ clearance pathways in
sporadic AD cases. Clearance mechanisms encompass processes like phagocytosis, endocy-
tosis, and enzymatic degradation by neprilysin, insulin-degrading enzymes, and matrix
metalloproteinases. Various brain cells, including microglia, perivascular macrophages, and
astrocytes, participate in Aβ clearance processes [14]. The in-depth clearance mechanism
shows that Aβ in various brain cells effluxes from the brain to the periphery. Aβ effluxes
are normally mediated via its receptors on the brain endothelium, mainly mediated by LDL
receptor-related protein-1 (LRP-1). LDL receptor proteins bind with phosphatidylinositol-
binding clathrin assembly (PICALM) to clear Aβ monomers, oligomers, and aggregates
from the brain across the blood–brain barrier (BBB) [99]. LDL receptor binding protein 2
also aids Aβ trafficking across the BBB via binding with apolipoprotein J [102]. In mice,
LRP1 knockout is embryonically lethal. Therefore, studying the role of LRPI in embryonic
stages in mice is very critical. However, specific conditional knockout of LRP1 using Cre-
recombinase in mice leads to reduced Aβ efflux from the brain, potentially contributing to
the progression of AD [101]. Furthermore, LRP1 modulates the transport and clearance
pathway involved in the uptake and clearance of Aβ from the brain [194]. Genetic evi-
dence indicates that MEOX2, a homeobox gene, regulates LRP1 expression at the BBB [195]
and potentially links to neurovascular dysfunction in AD. However, modulation of the
MEOX2 gene in APP/PS1 mice did not show a significant effect on plaque deposition [196].
Therefore, further investigation is necessary to provide deep insight into LRP1 activity in
AD that can be utilized for AD prevention. Furthermore, the ubiquitinated proteasome
system, implicated in Aβ clearance, is impaired because of induced levels of Aβ and tau
hyperphosphorylation, leading to increased amyloid plaques and NFTs in AD. Aβ plaques
resist proteolytic degradation, and the role of the ubiquitin–proteasome system in Aβ
clearance remains unclear, necessitating further investigation to reduce Aβ burden [14].
Autophagy is a crucial pathway for the degradation and clearance of aggregated Aβ
proteins, plaques, and NFTs. Autophagy exhibits a complex enzyme system, containing
acidic proteases and acid hydrolases, which form autophagosomes and ultimately fuse
with late endosomes for the lysis of aggregated or misfolded proteins from the brain. The
dysregulation of autophagy is attributed to the defective transport of autophagic vesicles
from the axonal terminal to the soma, impairing lysosomal degradation and leading to
the accumulation of immature autophagosomes and dystrophic neurites. This results in
elevated levels of Aβ1–42 level in AD [197]. With aging, the autophagic pathway becomes
impaired, as observed in human and animal models, such as mice, flies, zebrafish, and
Xenopus, which showed increased extracellular Aβ levels due to high Aβ secretion and
impaired exocytosis. Impaired exocytosis leads to the accumulation of Aβ in intracellular
vesicles and subsequent impaired memory in AD mice [198,199]. Depletion of essential
autophagy genes, such as atg5 and atg7, in mice results in progressive neurodegeneration
and accumulation of aggregated proteins in the brain [200,201]. The expression of atg5,
atg7, and beclin-1 declines with aging, affecting the lysosomal-mediated degradation of Aβ
and NFTs plaques in the brain and contributing to late-onset neurodegeneration, including
AD [202,203].
In 3XTg-AD mice, the expression of the autophagy-related genes beclin-1 and p62
decreases with AD progression compared with normal individuals [204,205]. In ApoE4
transgenic mice, elevated levels of Aβ42 in the lysosomes lead to neuronal cell death in the
hippocampus [100]. Furthermore, sirtuins play a crucial role in triggering the autophagy
pathway. SIRT2 exerts a negative influence on the autophagy process. Induced expression
of SIRT2 decreases autophagy in the brain by deacetylation of FOXO1, a member of the
Forkhead O family of proteins. Various studies indicated that mitochondrial dysfunction
Int. J. Mol. Sci. 2024, 25, 6901 16 of 28

triggers SIRT2 activation, resulting in microtubule (MT) disruption and impairment of

the autophagic–lysosomal pathway in AD. SIRT2 inhibition or knockdown can prevent
dysregulation of the autophagy–lysosomal pathway and subsequent toxicity caused by the
accumulation of damaged mitochondria and Aβ peptides [206,207]. Therefore, SIRT2 could
be a promising candidate for Aβ clearance via the induction of autophagy. Rapamycin, an
mTOR pathway inhibitor, activates autophagy and reduces amyloid-β deposition in EOAD
mice models; however, no effects are observed in LOAD. This raises an ambiguity in the role
of mTOR-mediated autophagy activation in AD that warrants further investigation [193].
It remains unclear whether the accumulation of Aβ in LOAD is due to a lack of an
efficient clearing system or enhanced production of Aβ (Figure 3). Genetic ablation of
autophagy components leads to reduced Aβ secretion and decreased accumulation of intra-
cellular Aβ, exacerbating neurodegeneration [198]. Thus, autophagy plays a dual role either
as pro-survival or pro-death functions and depends on the Aβ level in neurons, necessitating
further molecular investigations to gain insights into the underlying mechanisms.

Figure 3. This image represents different conditions of AD in normal (A), AD (B), and treatment
conditions (C). The image illustrates the imbalance in Aβ formation and clearance of Aβ aggregates
in human brains over the course of aging. The equilibrium state depicts a balance between Aβ
production and Aβ clearance. However, in the AD condition, there is an increase in Aβ production
and decreased Aβ clearance, which contribute to disease progression. AD treatment aims to restore
brain functions by reducing Aβ aggregate formation and inducing Aβ clearance via various treatment
strategies such as induced autophagy, ubiquitination, immunotherapy, small molecule therapy, and
degradation of Aβ and NFTs.

5. Conclusions and Future Prospects

In this review, various factors and molecular targets have been highlighted to gain
more insight into therapeutic targets in AD. Numerous studies have identified various
genetic risk factors, mutations, and changes in cerebrospinal fluid (CSF) and plasma-based
biomarkers associated with AD pathology. Despite these findings, the exact cause of AD
remains elusive [208]. While a plethora of genes and proteins have been identified as
biomarkers in different brain regions, they have not yet provided a complete cure for AD,
only offering ways to slow its progression [209]. Consequently, no approved therapy exists
to cure AD fully. However, early detection is crucial for effective treatment. Genome-wide
association studies (GWASs) hold promise for identifying precise targets for early detection,
either through neuroimaging or plasma-based biomarkers. These targets could aid in
developing potential therapies to combat AD.
Currently, several drugs have undergone Phase II clinical trials, including mono-
clonal antibodies (mAbs), which have emerged as promising disease-modifying agents.
Some of these include Gosuranemab, Tilavonemab, Semorinemab, Zagotenemab, Adu-
canumab [210], Lecanemab [211], and anti-tau antibodies, which have shown significant
improvement in patients at early stages [20]. However, vaccines targeting the tau pro-
tein, such as the anti-tau vaccine (AADvac1) and ACI-35, are yet to demonstrate thera-
Int. J. Mol. Sci. 2024, 25, 6901 17 of 28

peutic outcomes [212,213]. Additionally, pharmacological treatments such as donepezil,

galantamine, rivastigmine, and memantine are currently available drugs that mostly in-
hibit acetylcholinesterase and activate NMDA receptors, offering symptomatic relief in
AD [20,212,214]. Moreover, the JAK2 inhibitor, TG101209, mitigated IFNγ-induced alter-
ations in cultured microglia and microglia derived from APP/PS1 mice [215]. Similarly,
the RAF inhibitor sorafenib reversed memory impairment and decreased the expression
of APP, Cox-2, and iNOS in the brain of an AD transgenic mouse model, highlighting
the potential of targeting RAF1 [215]. These findings suggest that JAK2 and RAF1 are
promising therapeutic targets for AD and strategies aimed at reducing neuroinflammation.
The limitations and potential side effects of monoclonal antibodies targeting Aβ and tau
fibrils in AD patients raise significant safety concerns. These therapeutics primarily manage
symptoms and delay the onset of AD, but they are insufficient for a complete cure (Figure 4).
Therefore, it is imperative to explore new targets that address the underlying causes of
AD rather than merely alleviating symptoms and to develop innovative drug therapies. In
this context, GWAS data can elucidate the functional significance of gene mutations and
SNPs in AD patients. Further validation of these risk factors genes and associated SNPs in
animal models and clinical samples from AD patients will aid in identifying targets related
to autophagy and ERAD for preventing AD progression. Most studies have focused on
inhibiting Aβ production through the inhibition of γ-secretase cleavage rather than Aβ
degradation or clearance. Therefore, further investigations are warranted to find novel
pathways and molecular mechanisms that reduce Aβ levels either by APP processing en-
zymes or other multifunctional enzyme systems, including different degradation pathways,
to prevent amyloidosis in LOAD.

Figure 4. This image illustrates various factors associated with AD and highlights the impact of
several stressors on a healthy brain and the subsequent consequences that lead to disease progression.
GWASs and related genetic factors, as well as specific pathways, are shown to ameliorate disease
conditions. Targeting different pathways can slow disease progression and improve cognitive
functions. However, genetic manipulations and gene therapy for AD treatment still require extensive
in vivo testing. This figure also depicts strategies to restore brain functions by reducing Aβ aggregates
and promoting Aβ clearance through induced autophagy, UPS, RAGE, and ERAD. Additionally,
immunotherapy and small molecule therapies are illustrated as approaches to reduce inflammation
and maintain energy homeostasis, ultimately slowing AD progression. Red ‘?’ shows the effects are
remains exclusive.

Prominent genetic risk factors associated with Alzheimer’s disease (AD), along with
numerous molecular factors, play a crucial role in the early detection of AD risk genes.
Int. J. Mol. Sci. 2024, 25, 6901 18 of 28

Additionally, genes exhibiting common variants in AD and other types of dementia and
neurodegeneration may establish an earlier link with AD progression, warranting in-
depth investigation to determine the precise time point markers at which they intersect.
Autophagy and ERAD pathways emerge as potential therapeutic avenues for managing
neurodegenerative diseases, including AD. Understanding the specific proteolytic processes
involved in the processing of proteins like APP and tau is paramount for unraveling the
molecular mechanisms underlying AD.
In AD, metabolic dysregulation plays a critical role in disease progression and synaptic
dysfunction. T2D, which is characterized by hyperglycemia and IR, affects brain glucose
levels and promotes the accumulation of Aβ in the brain [216]. T2D is recognized as a risk
factor for the progression of AD. However, the mechanism by which IR influences glucose
metabolism, including its effects on memory and synapse plasticity, remains inadequately
explored. Impaired glucose metabolism and the resulting formation of Aβ plaques and
NFTs induce oxidative stress, leading to elevated intracellular free Ca2+ levels and trig-
gering a cascade of detrimental effects that culminate in neuronal death [217]. Therefore,
maintaining optimal brain glucose metabolism could mitigate oxidative damage, reduce
the level of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and protect
the brain from adverse effects, thereby slowing disease progression. Continued research
into glucose metabolism, oxidative stress, and mitochondrial dysfunction is essential for a
more comprehensive understanding of AD pathogenesis and progression. These studies
will also enhance the ability to monitor the therapeutic efficacy of novel drugs and small
molecules targeting Aβ production and synaptic dysfunction, ultimately aiming to prevent
neuronal cell death [218].
Furthermore, defective lysosomal acidification plays a crucial role in AD pathogen-
esis and progression. Impaired functions of microglia and astrocytes contribute to the
accumulation and insufficient clearance of Aβ plaques and NFTs, leading to enhanced
neuroinflammation and ultimately neuronal cell death. Lysosomal acidification defects
and impaired glial functions occur early in the disease process, contributing to subsequent
neuronal dysfunction. Therefore, the early detection of lysosomal acidification dysfunction
and the development of therapeutic agents to restore lysosomal function are essential
for effective AD therapy. Non-invasive, real-time detection methods would significantly
advance this therapeutic approach [161,169]. Recent reports indicate that autolysosome
acidification declines in neurons well before extracellular amyloid deposition, characterized
by significantly reduced V-ATPase activity and the accumulation of Aβ/APP-βCTF within
enlarged deacidified autolysosomes. These profuse Aβ-positive autophagic vacuoles (AVs)
cluster into large membrane blebs, forming flower-like perikaryal rosettes known as PAN-
THOS, which are observed in AD brains. These AVs merge into perinuclear networks
of membrane tubules where fibrillar β-amyloid accumulates intraluminal. This process
leads to lysosomal membrane permeabilization, cathepsin release, and lysosomal cell
death, followed by microglial invasion and phagocytosis. Additionally, neurons exhibiting
PANTHOS are identified as the primary source of senile plaques in APP-associated AD
models. This hypothesis suggests that the early detection of these molecular markers could
serve as early diagnosis biomarkers for Alzheimer’s disease and aid in the development of
therapeutic agents [219].
Moreover, the role of autophagy and ERAD in neurodegenerative diseases remains
an active and evolving field of study. Optimizing pharmacological agents, such as small
molecules and nanomedicines, for clinical application is critical. This includes enhancing
their properties for better efficacy, bioavailability, and safety in therapeutic use [169].
Notably, these research strategies may provide deeper insights into the roles of specific
proteases within various cellular compartments, aiding in the development of targeted
therapies to inhibit plaque formation and prevent the development of NFTs. Future research
should prioritize obtaining more population-based GWAS data from diverse cohorts and
clinical samples. This approach will be crucial for identifying novel AD risk factors and
potential targets for innovative drug therapies and treatment strategies.
Int. J. Mol. Sci. 2024, 25, 6901 19 of 28

Author Contributions: Conceptualization, M.K.S., I.K. and S.S.K.; resources, M.K.S., S.J., S.H. and
Y.S.; writing—original draft preparation, M.K.S. and S.H.; figures, M.K.S. and S.J.; review and
editing, M.K.S., Y.S. and S.H; supervision, M.K.S., S.S.K. and I.K.; project administration, S.S.K.
and I.K.; funding acquisition, S.S.K. All authors have read and agreed to the published version of
the manuscript.
Funding: This study was supported by the National Research Foundation of Korea (NRF) grants
funded by the Korean government (MEST) (grant NRF-2018R1A6A1A03025124).
Conflicts of Interest: The authors declare no conflicts of interest.

Abbreviations

AD Alzheimer’s disease
APP amyloid precursor protein
APH1 anterior pharynx defective 1
BACE1 β-site APP-cleaving enzyme-1
BBB blood–brain barrier
CSF cerebrospinal fluid
EOAD Early-Onset Alzheimer’s Disease
ER endoplasmic reticulum
ERAD ER-associated protein degradation
eQTL expression quantitative trait loci
eTWASs expression transcriptome-wide association studies
FTD familial frontotemporal dementia
GWASs genome-wide association studies
IGAP International Genomics of Alzheimer’s Project
LOAD late-onset Alzheimer’s disease
LRP-1 LDL receptor-related protein-1
LD linkage disequilibrium
MMPs matrix metalloproteinases
MAPT microtubule-associated protein
mQTL methylation QTL
NFTs neurofibrillary tangles
PICALM phosphatidylinositol-binding clathrin assembly
RAGE Receptor for Advanced Glycation End Product
SRP14 Single Recognition Particle 14
α7nAChRs α7-Nicotinic Acetylcholine Receptors
SNPs single nucleotide polymorphisms
TNF tumor necrosis factor
TREM2 triggering receptor expressed on myeloid cells 2
UPR unfolded protein response
UPS ubiquitous proteasomal system
XBP1 X-box binding protein 1

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