Advances in APOE‑Targeted Therapies for Alzheimer's Disease: A

Comprehensive Review of Current Research

Xuanhui Quan

Suzhou Foreign Language School, Suzhou, Jiangsu, China

Keywords: APOE4, Alzheimer's Disease, Targeted Therapy.

Abstract: Alzheimer’s disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) plaques, tau

tangles, neuroinflammation, and lipid imbalances, with the APOE4 allele being a major genetic risk factor.

Recent therapeutic advances include APOE4-targeted strategies such as small molecules, CRISPR-Cas9 gene

editing, and immunotherapies, alongside monoclonal antibodies that reduce Aβ plaques but pose safety risks.

Lipid nanoparticles (LNPs) enhance drug delivery, while anti-inflammatory approaches and lipid regulators

address multiple pathways. However, no therapy fully cures AD, and challenges like low gene-editing

efficiency limit clinical translation. This review analyzes APOE4’s role in AD pathology and evaluates

therapies targeting Aβ, tau, inflammation, and lipid metabolism. Findings reveal monoclonal antibodies offer

short-term cognitive benefits with safety trade-offs, lipid regulators show broader mechanistic potential, and

neuroinflammation strategies integrate drug and lifestyle interventions. Combined approaches, such as Aβ

clearance with lipid restoration, demonstrate cooperative promise. This article emphasizes APOE4’s

centrality and advocates for personalized therapies based on genetic profiles. Future research could prioritize

optimizing gene-editing systems, refining the delivery efficiency of LNPs, and investigating synergistic

interactions between neuroinflammation and lipid metabolism. These directions can advance multi-target

therapeutic strategies, offering innovative approaches to address fundamental mechanisms in AD.

1 INTRODUCTION

Alzheimer’s disease (AD) is a progressive

neurodegenerative disorder and the most common

cause of dementia worldwide, accounting for

approximately 60 to 80 percent of all dementia cases

associated with aging (Pires & Rego, 2023). It is

characterized by neurodegeneration, neural loss,

neurofibrillary tangles (NFTs) and amyloid-beta (Aβ

) plaques accumulation(Srivastava, et al., 2021).

Among the growing number of genetic risk factors for

AD discovered, the apolipoprotein E (APOE) gene

including ε2 allele, ε3 allele and ε4 allele has

been the most predominant, as the cause of over half

of AD patients. People with the ε4 allele of the

APOE gene have a higher likelihood of being

susceptible to AD, whereas the ε2 allele reduces the

risk of AD, and the ε 3 allele has no significant

influence on AD (Pires & Rego, 2023).

Researchers have developed innovative small

molecules and peptides to target APOE4's detrimental

effects in AD. For instance, CBA2 as a small molecule

has been shown to modulate lipid metabolism and

enhance APOE-mediated A β clearance, reducing

amyloid plaque formation and improving cognitive

function in preclinical models (Balasubramaniam, et

al., 2024). Similarly, APOE-mimetic peptides have

demonstrated potential in reducing Aβ aggregation

and tau pathology in animal models. APOE-mimetic

peptides similarly reduce Aβ aggregation and tau

tangles, confirming APOE4’s role in driving AD

progression (Ahmed, et al., 2022).

Researchers used CRISPR-Cas9 delivered via

Synthetic Exosomes (SEs) to edit ApoE4 to ApoE3 in

an AD mouse model, achieving 0.14% editing in the

brain and confirming functional ApoE3 mRNA

expression (Teter, et al., 2024; Hanafy, et al., 2020).

This proof-of-concept demonstrates the feasibility of

gene editing for APOE4-related risk reduction, though

higher efficiency is needed for clinical translation.

Immunotherapy targeting APOE4 has shown

promise in AD treatment. For example, HAE-4, an

APOE4-specific antibody, reduces Aβ plaques and

tau pathology in preclinical models by blocking

Quan, X.

Advances in APOE-Targeted Therapies for Alzheimer’s Disease: A Comprehensive Review of Current Research.

DOI: 10.5220/0014401600004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 105-111

ISBN: 978-989-758-789-4

105

APOE4's harmful interactions (Lemprière, 2021).

These findings validate APOE4 as a druggable target

for slowing AD progression.

Lipid nanoparticles (LNPs) have emerged as a

promising drug delivery system for targeting AD

pathology, particularly due to their ability to cross the

blood-brain barrier (BBB) without requiring

functionalization. Their small size and lipid-based

nature make them highly biocompatible and efficient

for delivering therapeutic agents to the brain. LNPs,

including liposomes, niosomes, and nanostructured

lipid carriers (NLCs), can be produced at scale,

offering a practical solution for large-scale therapeutic

applications (Chakraborty, et al., 2024). LNPs

efficiently transport drugs like CRISPR components

or lipid regulators to the brain, with scalable

production methods supporting future clinical use (Lu,

et al., 2021).

This article aims to review the pathological

mechanisms of AD related to the APOE4 allele,

including its role in Aβaggregation, tau pathology,

neuroinflammation, and lipid metabolism disruption.

It evaluates the efficacy of APOE-targeted therapies,

aiming to identify more promising strategies. The

study not only highlights innovative therapeutic

approaches but also deepens the understanding of

APOE's role in neurodegeneration, offering hope for

millions of patients worldwide.

2 MECHANISM

2.1 Amyloid Hypothesis

Amyloid precursor protein (APP) as a transmembrane

protein is located in the cell membrane of neurons in

the brain, and its function is to help repair damaged

neurons. It is usually cleaved by the beta site APP

cleaving enzyme 1 (BACE1) and γ -secretase.

Under physiological conditions, BACE1 cleaves APP

at the extracellular N-terminal domain, releasing a

soluble fragment (sAPPβ) and leaving a 99-amino

acid membrane-bound C-terminal fragment (CTF)

C99. This process is followed by γ-secretase, which

is a multi-subunit protease complex containing

presenilin, nicastrin, PEN-2, and APH-1. This

secretase cleaves C99 to different-length A β

peptides, primarily Aβ 40 and Aβ 42, within its

transmembrane region. With a long term, the

aggregation of Aβ leads to Aβ plaques forming.

These plaques clump around neurons and can block

neuron communication. Hence, brain cells gradually

cannot send signals, leading to AD (Hampel, et al.,

2021; Neațu, et al., 2024).

2.2 Tau Protein Hypothesis

Tau hypothesis explains how changes in Tau protein

in the brain lead to AD. Normally, Tau helps keep

brain cells healthy by supporting microtubules, which

help transport nutrients and signals, inside nerve cells.

Tau protein attaches to these microtubules, and a

process controlled by chemical changes like adding

or removing phosphate groups after the protein is

made. However, in AD, too many phosphate groups

are added to Tau, resulting in hyperphosphorylation.

This happens when enzymes that add phosphates (like

GSK-3β) become overactive, while enzymes that

remove phosphates do not work well. The extra

phosphate groups change the shape of Tau protein

and charge, making it separate from microtubules.

Without the support of Tau, the microtubules break

down, disrupting nutrient transport in nerve cells.

Freed Tau proteins then clump together, and then first

form oligomers that damage connections between

brain cells and mitochondria. Over time, these clumps

grow into twisted fibers and finally form NFTs inside

brain cells. These NFTs are a key sign of AD and are

linked to brain cell death and memory loss

(Wegmann, et al., 2021; Zhang, et al., 2024).

2.3 Neuroinflammation Hypothesis

The neuroinflammation hypothesis explains how

long-term brain inflammation causes AD. Microglia,

the brain's immune cells, normally protect the brain

by cleaning up harmful proteins like Aβ. However,

when people age, these cells become less efficient and

start releasing harmful chemicals like IL-1β and

ROS that damage brain cells. Aβ proteins activate a

dangerous protein complex called NLRP3, which

makes A β clump together faster and harms

connections between nerve cells. Aging also weakens

microglia's ability to clean up waste, making

inflammation worse. In addition, there are other

factors that exacerbate inflammation. Genes like

APOE4 increase A β accumulation and

inflammation, and senescent cells release toxic

chemicals that keep inflammation active. Hence, this

creates a cycle that inflammation damages neurons,

which releases more toxins, causing more

inflammation. The neuroinflammation gradually

causes neuron damage and synaptic loss (Maylin, et

al., 2023; Zhang, et al., 2024).

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2.4 Lipid Metabolism Hypothesis

The lipid metabolism hypothesis explains how

imbalances in brain fats contribute to AD. The blood-

brain barrier (BBB) typically blocks large

lipoproteins like LDL and VLDL, as well as free fatty

acids (FFAs), from entering the brain. However,

aging, genetic factors (e.g., APOE4), and

environmental stressors such as hypertension and

trauma can weaken the BBB. When they are

compromised, the BBB allows lipoproteins

containing ApoB and FFAs to infiltrate the brain,

disrupting normal lipid regulation by astrocytes.

Excess cholesterol from peripheral lipoproteins

interferes with neuronal cholesterol balance. While

astrocytes usually provide cholesterol through HDL-

like particles, an overload of LDL triggers β- and

γ -secretase activity, increasing A β production.

This cholesterol buildup can also encourage A β

aggregation and tau hyperphosphorylation, leading to

NFT formation (Estes, et al., 2021). Additionally,

FFAs enter the brain as monomers through a

weakened BBB and overstimulate TLR4 and

extrasynaptic GABAA receptors, contributing to

neuroinflammation, memory impairment, and

oxidative stress. APOE4 further worsens lipid

accumulation and promotes BBB damage,

intensifying neurodegeneration (Rudge, 2023).

These four hypotheses collectively explain AD

through interconnected mechanisms. While amyloid

plaques and tau tangles directly damage neurons,

chronic neuroinflammation and lipid imbalances

accelerate neurodegeneration. Although these

hypotheses focus on different pathways, they likely

interact synergistically – Aβ and tau

abnormalities may trigger inflammation, while lipid

disorders worsen amyloid and tau pathologies.

Understanding these connections helps develop

multi-target therapies, such as reducing A β

production, blocking tau phosphorylation, controlling

microglial activation, and restoring lipid balance to

protect brain function.

3 TREATMENT

3.1 Protein Regulation

Current therapeutic approaches for AD focus on

modulating enzymatic activity to reduce A β

accumulation. Key targets include BACE1 and γ-

secretase, enzymes critical for A β generation.

BACE1 inhibitors were designed to block the initial

cleavage step in A β formation. For instance,

LY2886721 demonstrated efficacy in lowering Aβ

levels in cerebrospinal fluid (CSF) but was withdrawn

due to hepatotoxicity. Subsequent candidates,

including atabecestat, elenbecestat, and umibecestat,

faced challenges in clinical trials with limited BBB

permeability and off-target interactions caused by

structural similarities between BACE1 and other

aspartyl proteases. These issues hindered their

therapeutic potential. Similarly, γ -secretase

inhibitors (GSIs) aimed to suppress Aβ production

but exhibited adverse effects by disrupting Notch

signaling, a pathway vital for cellular homeostasis.

Although avagacestat selectively reduced A β

without Notch interference, trial discontinuation

occurred due to toxicity in gastrointestinal and skin

tissues. To address this, γ -secretase modulators

(GSMs) emerged as an alternative strategy, adjusting

enzyme activity to decrease toxic Aβ42 isoforms

while maintaining physiological functions. Promising

GSM candidates such as SGSM-36 and EVP-0962

showed selective A β 42 reduction but did not

advance to clinical use. Despite extensive research,

no protein-targeted therapy has achieved regulatory

approval for AD (Zhang, et al., 2023).

3.2 Monoclonal Antibodies (mAbs)

MAbs represent a promising therapeutic approach for

AD, focusing on neutralizing pathological A β

aggregates to slow disease progression. Two notable

examples, lecanemab and donanemab, demonstrate

distinct mechanisms of action, pharmacokinetic

profiles, and clinical outcomes. Lecanemab

(BAN2401) is a humanized monoclonal antibody that

selectively binds soluble A β species, including

oligomers and protofibrils, while sparing monomeric

and insoluble fibrillar forms. By interacting with the

N-terminal region (amino acids 1–16) of Aβ, it

facilitates the removal of protofibrils from the brain

and cerebrospinal fluid (CSF). Unlike many mAbs,

lecanemab does not exhibit target-mediated drug

disposition (TMDD), likely because its primary

targets are localized within the brain.

Pharmacokinetic studies report a half-life of

approximately 9.5 days, shorter than typical

antibodies. In clinical trials, lecanemab slowed

cognitive decline and reduced amyloid plaques,

leading to its accelerated FDA approval in January

2023 for mild cognitive impairment (MCI) and early-

stage AD. Donanemab (LY3002813) distinguishes

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107

itself by targeting the N-terminal pyroglutamate-

modified Aβ epitope, a structural feature exclusive

to aggregated amyloid plaques. This specificity

allows it to effectively clear existing plaque deposits

and delay functional and cognitive deterioration.

Pharmacokinetic analyses indicate a half-life of about

11.8 days, with drug clearance influenced by body

weight—higher elimination rates occur in individuals

with greater body mass. Additionally, donanemab

reduces plasma levels of phosphorylated tau (P-

tau217), a biomarker strongly associated with AD

pathology. However, its use carries an elevated risk

of amyloid-related imaging abnormalities (ARIA),

particularly in patients with the APOE ε4 genetic

variant, necessitating careful clinical monitoring.

Both antibodies demonstrate efficacy in reducing

amyloid burden and slowing disease progression in

early AD. Lecanemab’s action on soluble aggregates

contrasts with donanemab ’ s focus on plaque

removal, offering complementary strategies for Aβ

clearance. Key differences in pharmacokinetics —

such as half-life and weight-based clearance

patterns—highlight the importance of individualized

dosing. Safety remains a critical concern, as both

therapies are linked to ARIA, a side effect involving

brain swelling or microhemorrhages. Risk factors,

including APOE ε 4 carrier status, must guide

patient selection and monitoring protocols (Neațu, et

al., 2024).

3.3 Lipid Metabolism Regulation

Recent therapeutic strategies targeting lipid

metabolism show potential in AD management.

Dietary approaches, particularly omega-3 fatty acids

like DHA and EPA, may reduce AD-related cognitive

decline by supporting brain function. Statins, which

is commonly used to lower cholesterol, demonstrate

additional benefits in AD models by reducing brain

inflammation and improving cognitive performance.

For instance, atorvastatin was found to enhance

memory in AD mice by influencing TLR4 signaling

pathways, which interact with TREM2 —a protein

critical for lipid processing in brain immune cells.

Research highlights abnormal cholesterol storage in

microglia lacking functional TREM2, a genetic risk

factor in some AD cases. Inhibiting acetyl-CoA

acetyl transferase 1 effectively reduces these

cholesterol deposits, suggesting a treatment avenue

for TREM2-related dysfunction. While TREM2

mutations are rare, its activity is interconnected with

other AD-associated genes like APOE and TYROBP,

implying broader relevance for lipid-focused

therapies. Notably, correcting lipid imbalances

through TREM2-related pathways could benefit AD

patients regardless of specific genetic mutations.

Combining cholesterol regulation with anti-

inflammatory interventions may address multiple AD

mechanisms simultaneously (Estes, et al., 2021).

These findings emphasize lipid metabolism as a key

area for developing targeted AD treatments, offering

hope for both genetic and sporadic forms of the

disease.

3.4 Control of Neuroinflammation

Emerging therapies targeting neuroinflammation

offer new hope for AD treatment. Recent failures of

anti-amyloid and anti-tau therapies highlight the

urgency for alternative approaches. Modulating

microglia—the brain’s immune cells—has shown

particular promise. Depleting dysfunctional

microglia with CSF1R inhibitors reduces amyloid

plaques, protects neural connections, and improves

memory in AD mice. Conversely, boosting microglial

activity using TREM2-activating antibodies like

AL002a enhances plaque clearance and cognitive

outcomes. Suppressing harmful inflammation

pathways represents another strategy. Natural

substances such as pterostilbene and sulforaphane

block NLRP3 inflammasome activation, reducing

brain inflammation and cognitive decline. Similarly,

β -hydroxybutyrate, a ketone metabolite, combats

oxidative stress by activating Nrf2 while inhibiting

NLRP3 and NF-κB. Targeting the P2X7 receptor,

which drives amyloid-induced NLRP3 activation, has

also proven effective. Experimental drugs like

brilliant blue G disrupt Aβ-triggered inflammation

and memory loss in animal studies, though better

brain penetration is needed for clinical use. Dietary

interventions complement pharmacological efforts.

Vitamin D, plant-based foods, and culturally diverse

diets like the Multicultural Healthy Diet correlate

with slower cognitive decline. These combined

strategies underscore the dual potential of drug-based

and lifestyle interventions to control

neuroinflammation in AD (Liu, et al., 2023). While

challenges remain in optimizing drug delivery,

focusing on inflammatory mechanisms provides a

multifaceted framework for tackling this complex

disease.

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4 EVALUATION

Current approaches for AD management exhibit

distinct advantages and limitations based on their

mechanisms and clinical applicability. MAbs, such as

lecanemab and donanemab, represent the most

advanced strategies with demonstrated efficacy in

early-stage AD. Lecanemab selectively neutralizes

soluble Aβ oligomers, slowing cognitive decline by

27% over 18 months, while donanemab accelerates

plaque clearance by targeting pyroglutamate-

modified A β . However, both therapies carry

significant risks, including amyloid-related imaging

abnormalities (ARIA) in up to 35% of APOE ε4

carriers, necessitating rigorous safety monitoring.

Their short half-lives (9.5–11.8 days) and high costs

further limit accessibility, and neither halts

neurodegeneration in advanced disease stages (Neaț

u, et al., 2024).

In contrast, protein regulation therapies targeting

A β production through BACE1 or γ -secretase

inhibition face persistent challenges. Early BACE1

inhibitors reduced Aβ levels but were discontinued

due to hepatotoxicity and poor blood-brain barrier

penetration. GSMs showed selectivity in reducing

toxic Aβ42 isoforms but failed to achieve clinical

relevance due to modest efficacy and unresolved

safety concerns (Zhang, et al., 2023). While these

approaches directly address Aβ overproduction—a

core AD pathology—their lack of specificity disrupts

vital pathways like Notch signaling, leading to

systemic toxicity.

Strategies focusing on lipid metabolism regulation

offer broader mechanistic benefits. Omega-3 fatty

acids (DHA/EPA) and statins like atorvastatin

improve synaptic function and reduce

neuroinflammation via TLR4/TREM2 pathways.

Inhibiting acetyl-CoA acetyltransferase 1 resolves

cholesterol accumulation in TREM2-deficient

microglia, presenting a targeted repair mechanism.

However, lipid therapies face variability in patient

responses; statins may induce muscle toxicity or

cognitive side effects in elderly populations, and

TREM2-focused interventions remain experimental

for non-mutation carriers (Estes, et al., 2021).

Neuroinflammation control approaches, including

microglial modulation and inflammasome

suppression, address multiple AD pathways.

Depleting dysfunctional microglia with CSF1R

inhibitors restores cognition in preclinical models, but

risks over-suppressing brain immunity. Natural

NLRP3 inhibitors (e.g., sulforaphane) and P2X7R

antagonists reduce inflammation yet struggle with

bioavailability. Dietary interventions, though safer,

lack standardized protocols for consistent cognitive

benefits (Liu, et al., 2023). While these methods

synergistically target plaques, oxidative stress, and

inflammation, long-term microglial manipulation

may impair neural repair, and inflammasome drugs

require enhanced brain delivery systems (Liu, et al.,

2023).

Overall, mAbs provide the clearest short-term

clinical benefits but with safety trade-offs. Protein

regulation therapies, despite their conceptual appeal,

are hampered by toxicity and specificity issues. Lipid

and neuroinflammation strategies, though

mechanistically versatile, demand refinement for

reliability. Future advancements may lie in

combining Aβ-targeting agents with metabolic and

anti-inflammatory interventions, tailored to genetic

profiles (e.g., APOE ε 4 or TREM2 status) to

optimize efficacy and minimize risks. Such integrated

approaches could address AD’s multifactorial nature

more comprehensively than single-target therapies.

5 CONCLUSION

AD is a complex neurodegenerative disorder driven

by interconnected mechanisms, including A β

plaque accumulation, tau protein

hyperphosphorylation, neuroinflammation, and lipid

metabolism disruption. The APOE4 allele plays a

central role in exacerbating these pathologies, as a

critical therapeutic target. Current strategies, such as

mAbs, show clinical promise by reducing A β

burden and slowing cognitive decline in early-stage

AD, but have safety risks like amyloid-related

imaging abnormalities and limited accessibility due

to high costs. Other approaches, including protein

regulation and lipid metabolism interventions, face

issues such as toxicity, poor specificity, or variable

patient responses. Neuroinflammation control

through microglial modulation or NLRP3

suppression offers multi-target benefits but requires

optimization for brain delivery and long-term safety.

The findings underscore the importance of APOE4

in AD progression and validate innovative therapies

like CRISPR-Cas9 gene editing, APOE-specific

antibodies, and LNPs for targeting APOE4-related

pathways. These advancements focus on

understanding APOE4’s multifaceted role and

developing multi-mechanism treatments. By

addressing the four hypotheses, these strategies

Advances in APOE-Targeted Therapies for Alzheimer’s Disease: A Comprehensive Review of Current Research

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provide a foundation for future research to explore

synergistic interactions between AD pathways and

refine personalized therapeutic approaches.

Despite progress, current research has limitations.

Most studies rely on preclinical models that may not

fully replicate human AD complexity, particularly

regarding genetic diversity and disease progression.

MAbs, while effective, are restricted to early-stage

AD and pose safety risks for APOE4 carriers. Protein-

targeting drugs often lack specificity, leading to

systemic side effects. Lipid and neuroinflammation

therapies, though mechanistically versatile, lack

standardized protocols and long-term efficacy data.

Additionally, the interplay between AD hypotheses,

such as how lipid imbalances influence tau

phosphorylation or neuroinflammation, remains

underexplored. Few studies test combination

therapies, which could address AD’s multifactorial

nature more effectively.

Moving forward, research should prioritize

enhancing drug delivery systems, such as optimizing

LNPs for brain penetration or improving CRISPR-

Cas9 editing efficiency in vivo. Personalized

therapies based on APOE or TREM2 genotypes could

improve efficacy while minimizing side effects.

Investigating combination therapies, like pairing Aβ

-targeting antibodies with anti-inflammatory agents

or lipid regulators, may yield synergistic effects.

Further exploration of lipid metabolism’s role in

neuroinflammation and tau pathology could uncover

novel therapeutic targets. Clinical trials should adopt

diverse cohorts and long-term follow-ups to assess

real-world outcomes. By integrating genetic,

molecular, and lifestyle factors, future studies may

unlock transformative AD treatments that halt or

reverse neurodegeneration.

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