The Neuroscience of Alzheimer’s Disease: Emerging Mechanisms and Therapeutic Frontiers

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder defined by memory

loss, cognitive decline, and ultimately loss of independence. Although the condition has

traditionally been linked to the buildup of amyloid-beta plaques and tau tangles, recent

research points to broader mechanisms such as neuroinflammation, microglial dysfunction,

immune system involvement, and epigenetic changes. This paper explores these

developments in neuroscience and highlights new approaches in diagnostics and treatment.

Introduction

Alzheimer’s disease affects more than 55 million people globally and remains a leading

cause of dementia and age-related disability. While amyloid-beta (Aβ) plaques and tau

tangles have historically been considered the main culprits, these biological hallmarks have

not led to consistently effective treatments. This has shifted attention to additional

pathological contributors (Nature).

Microglial Dysfunction and Neuroinflammation

Microglia, the immune cells of the brain, normally maintain neuronal health by removing

waste and supporting synapses. In AD, however, they become overactive, causing chronic

inflammation and releasing toxic substances that accelerate neurodegeneration. Recent

research identifies a distinct class of “dark microglia,” which secrete harmful lipids and

contribute to the loss of synapses. These are driven by activation of the integrated stress

response (ISR), and scientists are exploring ways to target ISR to reverse AD symptoms

(Advanced Science Research Center).

Immune System Involvement

In addition to microglial activity, the broader immune system plays a role in Alzheimer’s

pathology. CD8+ T cells infiltrate the brain and interact with microglia through the

CXCL10–CXCR3 signaling pathway, enhancing inflammatory damage and worsening

neuronal death (Nature). These findings suggest that AD is not only a brain disorder but

also an immune-mediated condition.

Epigenetic Modifications

Epigenetics—the study of how gene activity is regulated without changing DNA—has

opened new doors in Alzheimer’s research. Abnormal methylation of genes such as APP and

BACE1, which are involved in amyloid processing, has been observed in AD patients.

Moreover, changes in microRNAs, particularly miR-9 and miR-128, impair synaptic

plasticity and immune responses (Wikipedia). These alterations may serve both as

biomarkers and therapeutic targets.

Advances in Diagnostics

Traditionally, diagnosing Alzheimer’s required PET scans or spinal fluid tests. In 2024,

however, the FDA approved Lumipulse, a blood test that detects the ratio of phosphorylated

tau (pTau217) to beta-amyloid 1-42—two proteins associated with AD. This non-invasive

test improves early detection and broadens access to care (Miller).

Therapeutic Innovations

Several promising treatments are emerging:

- Donanemab (Kisunla) is a monoclonal antibody recently approved in Australia that targets

amyloid plaques and has shown success in slowing cognitive decline in early AD (Davey).

- VG-3927 focuses on modulating TREM2, a receptor involved in microglial activity, to

reduce inflammation and protect neurons (Gonzalez).

- RI-AG03 is a novel compound designed to prevent tau aggregation. Early trials suggest it

could reduce tau tangles and improve memory in patients (Williams).

These therapeutics aim to slow, halt, or even reverse disease progression.

Conclusion

The neuroscience of Alzheimer’s disease has evolved far beyond the amyloid hypothesis.

Research now points to inflammation, immune signaling, and epigenetic shifts as central to

disease progression. Simultaneously, advances in diagnostic testing and treatment

development offer hope for earlier intervention and better outcomes. Continued research

into these emerging areas is essential to finding a cure for one of the most devastating

neurological disorders of our time.

Works Cited

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