what causes Alzheimer's disease amyloid tau neuroinflammation

Overview

note that it is the most common cause of dementia globally, and that no effective treatment options exist for the great majority of patients.

Amyloid-β Pathology

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Mutations in the genes for APP and presenilins (PS1, PS2) increase production of Aβ42 and cause familial AD. Oakley et al. (2006) demonstrated in transgenic mice coexpressing five familial AD mutations that Aβ42 production is dramatically elevated, leading to rapid amyloid deposition beginning at 2 months of age, and that intraneuronal Aβ42 accumulates even before plaques form.

One proposed mechanism for Aβ accumulation is the failure of perivascular drainage. Weller et al. (2008) found that as arteries stiffen with age, the amplitude of vessel pulsations is reduced, impairing the perivascular pathways by which interstitial fluid and solutes are eliminated from the brain, causing insoluble Aβ to deposit in those drainage pathways.

Strong evidence also implicates astrocytes in Aβ dynamics: a large amount of Aβ is secreted by astrocytes, contributing to total Aβ deposition in the brain, and astrogliosis and reactive astrocytosis may cause neuronal damage in AD. Shaheen et al. (2023)

Tau Pathology

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Neuroinflammation

Neuroinflammation is described as one of the cardinal features of AD. Sujata et al. (2023) report that Aβ deposition initiates a spectrum of microglia-activated neuroinflammation, and that microglia and astrocyte activation elicit expressions of various inflammatory and anti-inflammatory cytokines. Numerous pathways — including NF-κB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX — are involved in triggering brain immune cells to secrete inflammatory cytokines, which affect neuronal function and cause cell death .

Pablo & T (2024) further underscore that while microglia (the brain's resident macrophages) have been pivotal to the study of central immune inflammation, other cellular entities also contribute to the neuroinflammatory process, including astrocytes through their interactions with Aβ deposition and tau tangle formation.

There is also a tight interplay between tau pathology and neuroinflammation: accumulating evidence indicates that inflammation has a complex, bidirectional relationship with tau post-translational modification and dissemination .

An Integrated, Multi-Pathway View

The field has moved beyond a simple linear amyloid cascade hypothesis. Xutong (2025) conceptualizes AD as a cross-talk of intricately interacting pathologies, encompassing Aβ, tau, and neuroinflammation as the foundation of a phase-adapted pathological network model. This understanding has shifted diagnostic paradigms toward biomarker-based strategies such as the AT(N) framework for early disease detection .

Huang et al. (2020) similarly conclude that an in-depth and comprehensive understanding of the contribution of amyloid beta and other factors is crucial for developing novel pharmacotherapies, noting that many clinical trials targeting amyloid clearing alone have failed, suggesting the amyloid hypothesis alone may not be completely feasible.