Asymptomatic Versus Symptomatic Alzheimer's Disease Neuropathology: A Systematic Review of Differences Reported in Post-Mortem Studies.

A subset of individuals exhibit substantial Alzheimer's disease (AD) neuropathology but remain asymptomatic (ASYMAD). The biological processes underlying this phenomenon remain poorly understood. We searched the PubMed/MEDLINE, Web of Science and CAPES databases to synthesise post-mortem brain tissue findings that differ between symptomatic and asymptomatic AD. Thirty-four studies met the predefined eligibility criteria. Multiple reports described lower levels of oligomeric Aβ and p-tau in ASYMAD, with reduced accumulation at synapses. Consistent with synaptic resilience, ASYMAD showed preserved expression of markers and proteomic signatures linked to synaptic function, homeostasis and plasticity. Further analyses supported preserved parenchymal architecture and dendritic and axonal morphology in ASYMAD. Some authors also described compensatory adaptations, including neuronal hypertrophy, increased neurogenesis and cellular antioxidant responses in ASYMAD brains. Additional findings indicated partial resistance to disruption of brain glucose, polyunsaturated fatty acid and one-carbon/polyamine metabolism. Glial and immune findings suggested a profile characterised by increased glial reactivity in specific regions and disease stages, alongside preserved glial homeostasis and lower cytokine expression in other contexts. In conclusion, although this review identified multiple processes potentially associated with the ASYMAD phenotype, the current evidence remains largely descriptive. Additionally, this synthesis is limited by substantial methodological heterogeneity and inconsistencies in data reporting. Future research should prioritise standardised clinicopathological definitions, pathology stage matching between ASYMAD and symptomatic AD groups, systematic assessment of mixed pathologies and further replication of exploratory findings to better elucidate the mechanisms underlying clinical resilience to AD neuropathology.