Plasma Proteomic Signatures for Alzheimer's Disease and Related Dementias

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There is a great need to determine molecular signatures of Alzheimer’s disease (AD) to better understand AD pathophysiology, to detect AD in the preclinical stage, and to identify novel therapeutic targets. The plasma proteome is an ideal resource in which to identify molecular signatures, as proteins perform essential biological functions, are direct therapeutic targets, and shed light on disease mechanisms. Our preliminary data identified several plasma proteomic biomarkers associated with cognitive impairment and AD-related brain atrophy. We also found that accelerated biological (i.e., proteomic) aging relative to chronological age, as measured by our validated proteomic signature of aging (known as a ‘proteomic clock’), was associated with higher risk of multiple age-related conditions, including cognitive impairment. Yet, study of the proteomic changes preceding AD is still in its early stages. The objective of this study is to improve understanding of the proteomics of AD and related dementias (ADRD) by leveraging a nested case-cohort of 2,836 women in the racially diverse Women’s Health Initiative Memory Study (WHIMS). WHIMS contains longitudinal cognitive and neuroimaging measures; 1,336 incident cases of MCI and ADRD rigorously ascertained during 26 years of follow-up; rich phenotypic data; and preserved biospecimens. SOMAscan, the most comprehensive proteomics platform measuring 7,000 clinically relevant human proteins across numerous biological pathways, will be used to characterize the proteome longitudinally from blood samples collected at baseline and 14-18 years later. We will also obtain longitudinal plasma biomarkers of AD pathology from these samples. Our central hypotheses are that: (i) accelerated proteomic aging will be associated with higher risk of MCI/ADRD and lower likelihood of cognitively healthy longevity; and (ii) the 7,000-protein SOMAscan will enable identification of novel proteomic biomarkers, signatures, and biological pathways for MCI/ADRD and related endophenotypes. Our Aims are: Aim 1) Determine associations of validated proteomic clocks of aging with incident MCI/ADRD and cognitively healthy longevity (i.e., survival to age 90 without cognitive impairment); Aim 2) Determine associations of the plasma proteome at baseline, and 14-18-year changes in the proteome, with incident MCI/ADRD and cognitively healthy longevity; Aim 3) Relate proteomic clocks of aging and ADRD-associated proteins identified in Aim 2 to neuroimaging measures and plasma biomarkers of AD pathology; and Aim 4) Identify novel multi-protein signatures that predict MCI/ADRD, cognitively healthy longevity, and plasma biomarkers of AD pathology. Key proteins will be validated on a separate platform (ELISA) and replicated in external cohorts. This study will advance understanding of the heterogeneous mechanisms of ADRD pathogenesis and cognitive impairment in aging, identify risk and protective proteomic factors, and suggest candidate proteins for pathophysiology-targeted interventions in ADRD. The novel proteomic data will be a rich and valuable resource for the broader scientific community to identify novel proteomic biomarkers for a wealth of phenotypes, thus having an enduring impact.