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Updated: Apr 1, 2026
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Microglial malfunction: the third rail in the development of Alzheimer's disease
Siddhita D Mhatre1, Connie A Tsai2, Amanda J Rubin2
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Institute, Stanford, CA, USA.
Abstract:
Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-β (Aβ) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Aβ accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Aβ pathology.
Insights
Alzheimer's disease (AD) progression requires amyloid-beta and tau pathology, but a faulty microglial immune response is the key driver. This aberrant response fuels the spread of both pathologies, leading to dementia.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Alzheimer's disease (AD) research traditionally focuses on amyloid-beta (Aβ) and tau pathologies.
- These pathologies can exist independently and asymptomatically for decades.
- Clinical dementia often requires an interaction between Aβ and tau, not just their presence.
Purpose of the Study:
- To investigate the role of microglial immune response in Alzheimer's disease progression.
- To understand how microglial dysfunction interacts with Aβ and tau pathologies.
- To identify key factors driving the transition from asymptomatic pathology to widespread neurodegeneration.
Main Methods:
- Multidisciplinary research integrating findings from various scientific fields.
- Analysis of pathological hallmarks and their temporal accumulation.
- Examination of the immune system's role, specifically microglial function, in neurodegenerative processes.
Main Results:
- Aberrant microglial immune response is identified as a critical third factor in AD progression.
- Initially beneficial microglial responses can become maladaptive.
- Maladaptive microglial activity promotes a feed-forward cycle of Aβ and tau pathology spread.
Conclusions:
- Microglial immune response is essential for AD pathogenesis, beyond Aβ and tau.
- Dysfunctional microglia can accelerate neurodegeneration by exacerbating proteinopathies.
- Targeting microglial pathways may offer novel therapeutic strategies for Alzheimer's disease.
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