Alzheimer’s Disease and Age-Related Macular Degeneration: Shared and Distinct Immune Mechanisms

Rheumatology and Immunology Neurology Ophthalmology Life Sciences Medicine Immunology
Alzheimer's Disease Age-Related Macular Degeneration Immune Mechanisms Neuroinflammation Therapeutic Strategies

Academic Background

Alzheimer’s disease (AD) and age-related macular degeneration (AMD) are the leading causes of cognitive impairment and vision loss in the elderly population worldwide. Although they affect different organs (the brain and the retina, respectively), recent studies have revealed shared pathological features, such as β-amyloid (Aβ) deposition, complement system activation, and chronic inflammation. However, research on these two diseases has long been conducted independently, lacking interdisciplinary integration. This paper systematically compares the immune mechanisms of AD and AMD, explores cross-therapeutic strategies, and reveals how tissue specificity (brain vs. retina) leads to divergent outcomes of the same immune pathways.

Source of the Paper

This paper was authored by the team of Oleg Butovsky and Neta Rosenzweig from Brigham and Women’s Hospital at Harvard Medical School and published in the May 2025 issue of Immunity (DOI: 10.1016/j.immuni.2025.04.013). The authors are affiliated with the Ann Romney Center for Neurologic Diseases and the Gene Lay Institute of Immunology and Inflammation, specializing in immune mechanisms of neurodegenerative diseases.

Key Arguments and Evidence

1. Shared Pathological Features: Aβ Deposition and Complement Activation

Argument: Both amyloid plaques in AD and drusen in AMD contain Aβ, apolipoprotein E (ApoE), and complement proteins (e.g., C3, C5b9), suggesting a common mechanism of impaired immune clearance.
Evidence:
- AD Evidence: Aβ deposits have been detected in the retinas of AD patients and are transported via the brain-retina glymphatic pathway (Cao et al., 2024).
- AMD Evidence: AAV-mediated Aβ overexpression induces drusen-like deposits in mouse retinas (Prasad et al., 2017).
- Complement System: In AD, C1q mediates synaptic pruning (Hong et al., 2016), while in AMD, CFH gene variants (e.g., Y402H) lead to excessive complement activation (Armento et al., 2021).

2. The Dual Role of the ApoE Gene

Argument: The ApoE ε4 allele increases AD risk but reduces AMD risk, highlighting tissue-specific immune regulation.
Evidence:
- AD Mechanism: ApoE4 suppresses the microglial neurodegenerative phenotype (MGND), impairing Aβ clearance (Butovsky et al., 2025).
- AMD Mechanism: ApoE4 reduces subretinal mononuclear phagocyte accumulation, protecting against retinal pigment epithelium (RPE) degeneration (Rasmussen et al., 2023).

3. Divergent Roles of Microglia and Macrophages

Argument: The MGND phenotype is neuroprotective in AD but may exacerbate inflammation in AMD.
Evidence:
- AD Data: Activation of the SYK-CLEC7A pathway enhances microglial Aβ phagocytosis (Dejanovic et al., 2022).
- AMD Data: Galectin-3+ microglia limit photoreceptor apoptosis in retinal atrophy zones (Yu et al., 2024), while infiltrating peripheral macrophages drive choroidal neovascularization (CNV) (Ambati et al., 2013).

4. Cross-Disease Impact of Neutrophils and T Cells

Argument: Neutrophil extracellular traps (NETs) and IL-17 contribute to disease progression in both disorders.
Evidence:
- AD Model: NET deposition in the brains of 5xFAD mice correlates with cognitive decline (Butovsky et al., 2025).
- AMD Model: Neutrophil-microglia interactions accelerate degeneration in the retinas of Cryba1 knockout mice (Shi et al., 2020).

5. Potential for Cross-Application of Therapeutic Strategies

Argument: Aβ-targeted therapies for AD (e.g., Lecanemab) may be applicable to AMD, while anti-VEGF therapies for AMD could modulate vascular abnormalities in AD.
Evidence:
- Preclinical Trials: Anti-Aβ monoclonal antibodies reduce drusen in APOE4 mouse retinas (Ding et al., 2011).
- Emerging Therapies: Xenon gas inhalation activates microglia to alleviate AD pathology (Butovsky Lab Patent).

Significance and Value

  1. Theoretical Innovation: The first systematic integration of immune mechanisms in AD and AMD, proposing the hypothesis that “tissue-specific immune microenvironments determine disease outcomes.”
  2. Clinical Translation: Provides a rationale for drug repurposing (e.g., anti-Aβ therapies for AMD) and promotes interdisciplinary clinical trial design.
  3. Technological Advancement: AI-driven retinal imaging (e.g., De Fauw et al., 2018) may serve as an early diagnostic tool for AD.

Highlights

  • Genetic Paradox: Reveals the opposing roles of ApoE ε4 in the brain and retina.
  • Cell-Specific Targeting: Emphasizes the double-edged sword effect of MGND microglia.
  • Cross-Disease Therapeutic Framework: Proposes the potential application of complement inhibitors (e.g., Pegcetacoplan) in AD.

Additional Valuable Information

  • Diagnostic Innovation: Retinal Aβ imaging (Koronyo et al., 2017) has entered clinical trials.
  • Microbiome Association: Gut dysbiosis may exacerbate AD and AMD via IL-17 (Ruan et al., 2021).