Brain proteinopathies associated physiological changes leading to cognitive resilience in Alzheimer's disease

Alzheimer's disease (AD) is a well-documented condition, yet the factors that grant some individuals resilience against the disease remain poorly understood. Recent advances in multiomics data analysis from multiple cohorts have allowed researchers to explore these mechanisms. This study combined long-term cognitive evaluations, regional neuropathology, and matched prefrontal proteomic and metabolomic profiles from donors in two separate cohorts.

The findings revealed that asymptomatic AD (AsymAD) brains displayed amyloid levels similar to those with AD, but with fewer dense plaques, reduced tau accumulation in specific brain regions, and a more localized TDP-43 pathology.

AsymAD brains exhibited notable differences in various biological processes when compared to AD brains. They maintained the normal process of mitochondrial translation and bioenergetics, synaptic function, levels of glutamatergic metabolites, and unsaturated lipids in the cell membrane. Longitudinal cognitive assessments further distinguished resilient individuals from those who were vulnerable, even when they had comparable amyloid and TDP-43 burdens.

The vulnerable individuals showed increased accumulation of neurofibrillary tangles. Despite these differences, both AsymAD groups retained a prefrontal proteome similar to that of cognitively healthy individuals, with the exception of proteins associated with amyloid plaques. The biological changes observed in AsymAD were primarily restricted to AD brains, such as alterations in mitochondrial function, synaptic connections, and immune responses.