Increases in a pivotal bioactive peptide in specific brain regions reflect the progression of pathology in Alzheimer’s disease

Abnormal activation of a developmental process driven by a bioactive peptide T14, is posited as a key mechanism in the degeneration of the primarily vulnerable nuclei during the prodromal phase of Alzheimer’s Disease (AD). We use a range of anatomical, biochemical and genetic approaches to explore changes in T14 and its target, α7nAChR, in AD and in individuals with mood disorders, a frequent prelude to the disease. Using paired samples from the same patients, levels of T14 and α7nAChR increased in the hippocampus across the AD continuum. In contrast, in early Braak stages, T14 levels in the midbrain reach a plateau and are primarily localised to glia. Moreover, in a cognitively healthy cohort, CSF derived ex vivo revealed a differential profile between T14 and tau levels in individuals with mood disorders, a well-known precursor to AD. These observations confirm a key role of T14 in the neuropathology of AD. Finally, we show a Braak-stage dependant and selective increase in an acetylcholinesterase isoform (AChE-R) already associated with AD pathology, where the profile corresponds closely to that of T14, thereby providing further clues regarding its provenance. By highlighting region and cell-specific changes in the T14 profile as AD progresses, this study further validates a key role for T14 in the progression of neurodegeneration. Finally, the mood disorder-dependent changes based on T14 in CSF might reflect dysfunction in the primarily vulnerable isodendritic core and as such be viewed as a possible, albeit non-exclusive, prelude to AD. Collectively, these results underscore the importance of T14 in AD aetiology and could aid the development of precise and effective therapeutics to target its progression.