Peptide-centric proteomics reveals molecular subtypes of sporadic Alzheimer's disease

Alzheimer's disease (AD) is a complex, age-related disease that continues to increase in incidence worldwide. Although some cases are caused by known pathogenic mutations, the majority of cases are sporadic, with uncertain etiology and commonly complicated by comorbid diseases. To better understand the molecular landscape of AD we constructed a unique brain sample set free from neuropathologic comorbidities. This cohort consists of autosomal dominant AD dementia, sporadic AD dementia, cognitively normal individuals with high AD neuropathologic change - a condition called resilient to AD, and cognitively normal cases with no or minimal AD neuropathologic change. Through quantitative mass spectrometry proteomics we obtain measures of peptides mapping to A-beta; and to tau, capturing differences in the histopathologic burden of disease. Correlations of these peptide abundance differences within sporadic AD dementia cases in the superior and medial temporal gyrus indicate the presence of two separate sporadic AD phenotypes. Additional differences are characterized at a peptide level between sporadic AD dementia and autosomal dominant AD dementia in the inferior parietal lobe and caudate nucleus. These findings indicate both shared and distinct molecular features in AD influenced by cause and age of onset of disease.