# Memory Circuitry in MCI and Early Alzheimer’s Disease Prodrome: Molecular Drivers

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $672,826

## Abstract

Abstract
The renewal of this research program addresses two critical bottlenecks in Alzheimer's disease (AD) research:
earlier detection of those at risk and identification of important biological processes during preclinical and early
stages of disease. These challenges are the key to development of diagnostic and therapeutic approaches, as
well as prevention strategies that will need to be implemented at least 5-10 years before dementia onset.
During the prior funding period, this project contributed novel information on individuals with amnestic mild
cognitive impairment (MCI) and helped drive the field toward a focus on pre-MCI stages. A major innovation
has been the investigation of euthymic older adults with cognitive complaints that score within the normal
range on cognitive testing. In this group we have reported alterations in brain structure, functional activation,
and connectivity in a network of memory-related regions that are typically intermediate between the pattern
seen in cognitively normal controls (CN) and individuals with MCI. This phenotype, now referred to as
subjective cognitive decline (SCD) and defined by an international consensus panel in 2013, is influencing
large-scale studies including the Alzheimer's Disease Neuroimaging Initiative (ADNI), which adopted the
Cognitive Change Index (CCI) developed in this project to recruit a similar group (SMC). We piloted a dual-
tracer PET approach to study molecular signatures as a function of stage of disease, initially examining the
relationship of amyloid burden and immune activation (microglia). With the new availability of PET tracers for in
vivo measurement of tau burden, we will measure both tau and amyloid in preclinical and prodromal stages of
AD, focusing on targeted regions based on neuropathological studies. The role of amyloid and tau deposition
as molecular drivers of early functional disruption of brain activity and connectivity, as well as
neurodegeneration, will be investigated using an integrated ensemble of advanced MRI approaches including
structural MRI, memory task and resting state fMRI, arterial spin labeled perfusion (3D pCASL), and diffusion
imaging (DTI and NODDI) on the Prisma 3T platform with 64 channel RF coil and new multiband acquisition
sequences. Banking and analysis of fluid biomarkers (blood, CSF) and analysis of APOE and other candidate
genes will provide a biological context and new opportunities to understand very early changes from a systems
biology perspective. The overall objectives of this research are to validate early prognostic biomarkers and
enhance the understanding of biological mechanisms in early stages through accomplishing three specific
aims: (1) Determine the stage-specific profile of functional disruption of brain activity and connectivity, tau and
amyloid burden, microvascular pathology, neurodegeneration, and inflammation in preclinical and prodromal
AD; (2) Determine the temporal relationships and interactions among pathop...

## Key facts

- **NIH application ID:** 9966841
- **Project number:** 5R01AG019771-14
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** ANDREW J SAYKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $672,826
- **Award type:** 5
- **Project period:** 2001-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966841

## Citation

> US National Institutes of Health, RePORTER application 9966841, Memory Circuitry in MCI and Early Alzheimer’s Disease Prodrome: Molecular Drivers (5R01AG019771-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966841. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*