Amyloid-β peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer's disease with APPdup and Down syndrome

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-beta (A beta) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). A beta can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared A beta and tau pathologies in postmortem brain tissues across cases and A beta peptides using mass spectrometry (MS). We further characterized the spatial distribution of A beta peptides with MS-brain imaging. While intraparenchymal A beta deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, A beta deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high A beta deposits in capillaries. Investigation of A beta peptide profiles showed a specific increase in A beta x-37, A beta x-38 and A beta x-40 but not A beta x-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated A beta 2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter A beta peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of A beta deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific A beta peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.