Alzheimer’s disease (AD) is the most common form of neurodegeneration presented mainly as late-onset AD (LOAD), and in younger individuals early-onset AD (EOAD). The pathological hallmarks of AD are the hyperphosphorylated tau neurofibrillary tangles and the amyloid beta (Aβ) plaques. We examined changes in the proteome of post-mortem temporal cortex from individuals with EOAD and LOAD, and revealed that EOAD represents a more aggressive form of the disease. Notably, we observed up-regulation of AD biomarkers p-tau181, p-tau217, and p-tau23, and tau MTBR243, in AD tissues. Two abundant tau peptides phosphorylated at p-231/p-235 and p-231/p-235/p-237 were present largely in AD tissues, which may be developed as biomarkers. Aβ was detected in about half of the cognitively unimpaired elderly controls with subtle proteome changes that resembled in part the changes of biological processes in AD. This could indicate an early stage of neurodegeneration preceding clinical AD symptoms or represent an AD-resilient state.