Proteomics of post mortem brains in early- and late-onset Alzheimer's disease: Unraveling differential Aβ effects and potential AD biomarkers.

BACKGROUND

Alzheimer's disease (AD) occurs primarily as late‑onset (LOAD) and less frequently as early‑onset (EOAD). Its defining pathologies are hyperphosphorylated tau tangles and amyloid beta (Aβ) plaques.

METHODS

We analyzed the proteomes of 115 post mortem temporal lobe samples by mass spectrometry and searched with a dedicated AD spectral library including tau post‑translational modifications and Aβ isoforms to examine global protein changes in LOAD and EOAD.

RESULTS

AD tissues showed mitochondrial and synaptic pathway downregulation and immune and small‑molecule metabolic process upregulation, with EOAD exhibiting larger fold changes. AD biomarkers were elevated, and two multi‑phosphorylated tau peptides (p‑tau231/p-tau235 and p-tau231/p-tau235/p-tau237) were detected predominantly in AD. Aβ was present in 45% of cognitively unimpaired elderly controls, with subtle proteome changes resembling an early stage of neurodegeneration.

DISCUSSION: EOAD appears more aggressive. Tau p-tau231/p-tau235 and p-tau231/p-tau235/p-tau237 hold promise as novel AD biomarkers. Aβ's detection in cognitively unimpaired elderly controls precedes clinical AD symptoms.