Amyloid-beta and phosphorylated tau pathological aggregates (Aβ and p-tau aggregates)

Amyloid-beta (Aβ) and phosphorylated tau (p-tau) pathological aggregates represent the two defining neuropathological hallmarks of Alzheimer's disease (AD). Aβ peptides, derived from the amyloid precursor protein (APP), aggregate into extracellular senile plaques, while hyperphosphorylated tau proteins, encoded by the MAPT gene, form intracellular neurofibrillary tangles (NFTs) [Jack et al., 2018, Lancet Neurology]. The accumulation of these misfolded proteins is thought to drive a cascade of neurotoxicity, including synaptic loss, microglial activation, and eventual neuronal death [Sperling et al., 2011, Alzheimer's & Dementia]. Therapeutic interventions primarily focus on monoclonal antibodies that target specific conformational epitopes of these aggregates to promote their clearance via microglial phagocytosis or to block the 'seeding' process that spreads pathology through the brain [Mintun et al., 2021, NEJM]. While Aβ-targeting therapies like lecanemab and donanemab have recently demonstrated clinical efficacy in slowing cognitive decline, tau-targeting agents are currently being explored to address the stronger correlation between tau pathology and symptomatic progression [van Dyck et al., 2023, NEJM]. Managing these targets involves significant safety monitoring, particularly for amyloid-related imaging abnormalities (ARIA) associated with vascular amyloid clearance [Budd Haeberlein et al., 2022, J Prev Alz Dis].

Other names

Amyloid plaques and neurofibrillary tanglesAβ plaques and tau tanglesAlzheimer's disease pathological proteinsSenile plaques and NFTs

Monoclonal antibodies bind to specific epitopes of misfolded Amyloid-beta or tau to facilitate microglial-mediated clearance or prevent the recruitment of monomers into growing aggregates.