AS637 - Investigating the Biology of Cognitive Resilience in WHIMS “APOE ε4 Escapees” using Blood Exosomes

Investigator Names and Contact Information

Dimitrios Kapogiannis (kapogiannisd@mail.nih.gov)

Susan Resnick (resnicks@grc.nia.nih.gov)

Introduction/Intent

The overall aim of this proposal is to identify potential biological pathways and factors that promote cognitive resilience and their interplay with APOE genotype. This study will extend AS615 by examining exosomal markers in a subset of participants in AS615 most of whom have later blood samples through the Long Life Study (LLS). We propose to conduct a coordinated investigation using data from WHIMS and specimens from WHI baseline and the LLS to investigate blood-based exosome biomarkers that may provide mechanistic insights into factors underlying cognitive resilience despite the presence of one or more APOE e4 genetic risk allele(s) for AD ("APOE escapees" as described by Alison Goate). We will focus on pathways that have been considered in relation to risk for AD and for which we have successfully identified biomarkers in exosomes enriched for neuronal and astrocytic origin to determine physiologic profiles at WHI baseline in women who maintain cognitive health through old age versus those who develop cognitive impairment. We will measure exosome biomarkers related to the processing of Tau (p181-tau, p231-tau, total tau), insulin resistance (p-IRS-1), inflammation (complement proteins, NFK-b signaling mediators), and synaptic proteins.

Hypothesis 1: Women who remain cognitively healthy after age 80 in the presence of APOE e4 (APOE e4 "escapees") have a different biological signature many years prior to the development of disease, especially compared to those that develop cognitive impairment before age 80, and to a lesser degree compared to those that develop cognitive impairment after age 80.

SA1: a. Compare nEV biomarkers between APOE e4 carriers who remain cognitively normal after age 80 with APOE e4 carriers who are cognitively impaired before or at age 80 (extreme groups analysis: highest vs. lowest resilience groups); b. Compare nEV biomarkers between APOE e4 carriers who remain cognitively normal after age 80 with APOE e4 carriers who develop cognitive impairment after age 80 (highest vs. middle resilience groups). These comparisons aim to identify biological factors that confer cognitive resilience in the presence of APOE e4.

Hypothesis 2: Women who remain cognitively healthy after age 80 have a different biological signature many years prior to the development of disease. Further, this signature overlaps partially but not fully with the biological signature of APOE e4 "escapees".

SA2: a. Compare nEV biomarkers between APOE e3/e3 carriers who remain cognitively normal after age 80 with APOE e3/e3 carriers who are cognitively impaired before or at age 80 (extreme groups analysis: highest vs. lowest resilience groups); b. Compare nEV biomarkers between APOE e3/e3 carriers who remain cognitively normal after age 80 with APOE e3/e3 carriers who develop cognitive impairment after age 80 (highest vs. middle resilience groups).