AS712 - Plasma proteomic signatures for Alzheimer's disease and related dementias: the Women's Health Initiative Memory Study

Investigator Names and Contact Information

Aladdin H. Shadyab (ahshadya@health.ucsd.edu) Linda K. McEvoy (lkmcevoy@health.ucsd.edu)

Introduction/Intent

There is a great need to determine molecular signatures of the long clinically silent phase of Alzheimer’s disease (AD) to identify and target AD in the preclinical stage. The plasma proteome is an ideal resource in which to identify molecular signatures, as proteins perform essential biological functions and are direct therapeutic targets. We identified a plasma proteomic signature associated with cognitive impairment, cognitive decline, and brain atrophy in AD-sensitive regions. The ‘NIA proteomic clock,’ a novel 76-protein proteomic signature measuring biological age that we developed, showed that proteomic age acceleration, an indicator of accelerated biological aging, was associated with faster accumulation of multiple morbidities including cognitive impairment. Yet, the proteomic changes preceding AD are not completely understood. We propose to improve understanding of the proteomics of ADRD by leveraging a nested case-cohort of 2,836 women in WHIMS. SOMAscan, the most comprehensive proteomics platform measuring 7,000 clinically relevant human proteins across numerous biological pathways, will be used to characterize the plasma proteome using 100 μl of plasma from two study visits 14-18 years apart. We will also analyze these blood samples for plasma biomarkers of AD pathology and neurodegeneration using 300 μl of plasma. 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. We will validate top ADRD-associated proteins with ELISA using 250 μl of plasma. This study will advance understanding of the molecular mechanisms of ADRD pathogenesis, help identify risk and protective proteomic factors associated with ADRD, and suggest candidate proteomic targets for pathophysiology-targeted interventions in ADRD. The Specific Aims of this study are:

Aim 1. Determine associations of validated proteomic clocks of aging with: (i) incident MCI/ADRD and (ii) 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: (i) incident MCI/ADRD and (ii) cognitively healthy longevity. Aim 3. Relate proteomic clocks of aging and ADRD-associated proteins to neuroimaging outcomes and plasma biomarkers of AD pathology. Aim 4. Leverage the 7,000-protein SOMAscan to identify novel multi-protein signatures that predict MCI/ADRD, cognitively healthy longevity, and plasma biomarkers of AD pathology