Aβ- and tau-associated neuroinflammatory signatures in Alzheimer's disease

Neuroinflammation is increasingly recognized as a key contributor to Alzheimer's disease (AD) progression, with distinct responses linked to amyloid beta (Aβ) and tau pathology. Two detrimental waves of neuroinflammation have been proposed, the first during early Aβ accumulation, and the second during widespread tau deposition. However, the neuroinflammatory signatures associated with each phase remain unclear.

We studied 63 individuals who underwent Aβ and tau positron emission tomography imaging along with cerebrospinal fluid profiling of 368 inflammation-related proteins. Protein contrasts between cognitively unimpaired Aβ-negative and Aβ-positive individuals defined the signature of the Aβ phase, while comparisons between cognitively impaired Aβ-positive individuals with early versus late tau pathology characterized the tau phase. Gene Ontology enrichment identified biological processes associated with differentially expressed proteins.

During the Aβ phase, 34 proteins were downregulated and mapped to 157 biological processes, including Toll-like receptor signaling, nuclear factor kappa beta activation, and cytokine production. The tau phase showed upregulation of 23 proteins associated with 82 biological processes enriched in adaptive immune responses. A set of 48 biological processes and three proteins including interleukin 4 receptor, cystosolic phospholipidase A₂, and secretoglobin family 3A member 2 showed opposite regulation patterns, being downregulated in the Aβ phase and upregulated in the tau phase.

Our results revealed distinct neuroinflammatory signatures and biological processes associated with Aβ- and tau-dominant stages of AD. The reversal in protein expression patterns across these stages underscores the need for stage-specific neuroimmune therapeutic strategies.