# Neural and Biochemical Mechanisms of Cognitive Aging

> **NIH NIH R01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2020 · $841,951

## Abstract

PROJECT SUMMARY/ABSTRACT
This project is focused on the basis of altered memory function at the boundary between normal aging and
what has recently been described as preclinical Alzheimer's disease (AD). Both aging and AD are
characterized by the aggregated proteins tau and β-amyloid (Aβ). In the model that underlies the project, tau in
the medial temporal lobe (MTL) is hypothesized as a major factor associated with mild age-related decline in
episodic memory and disruption of hippocampal function. In preclinical AD, however, early Aβ accumulation
occurs in the posterior cingulate (PCC) and retrosplenial cortex (RSC); as this Aβ accumulation occurs, tau
accumulation is found outside the MTL and connectivity of the hippocampus to neocortex (PCC/RSC) is
disrupted. These effects severely disrupt memory function and also affect other cognitive processes. We plan
to test this model by recruiting a lifespan cohort of healthy people ranging in age from 20 to 90. The previous
phase of this study recruited 157 older subjects, all of whom will have approximately 6 years of longitudinal
follow up. All participants will undergo tau imaging using the novel ligand [18F]AV-1451, amyloid imaging using
[11C]PIB, structural MRI scanning, and resting state MRI scanning. Recruitment of those over 60 will be
balanced by PIB status (PIB+/PIB-). All subjects will also be studied using task-based functional MRI (fMRI)
while they perform an episodic memory task using a pattern separation paradigm. In this task subjects must
discriminate between visual stimuli that are similar, but not identical, to previously viewed stimuli. Identification
of these similar stimuli as “old” is evidence of pattern completion and failure of memory processing; this has
characteristically been associated with hippocampal hyperactivation which is likely detrimental. We anticipate
that increasing MTL tau will bias subjects towards pattern completion, and that tau accumulation, and Aβ-
related hippocampal disconnection will be related to hippocampal hyperactivation. Other key hypotheses are
that (1) age will be associated with increased MTL tau, while Aβ will be associated with tau in neocortex and
(2) episodic memory function will be related to MTL tau while global cognition will be related to both Aβ and
neocortical tau. The ultimate goal of the project is to define relationships between age, tau, and Aβ and to
show that the mechanisms underlying memory failure in aging and preclinical AD involve qualitatively different
effects of Aβ and tau on behavior, hippocampal connectivity and hippocampal function. Differentiating normal
cognitive aging from AD by studying these effects will be important for early detection of AD, selection of
subjects for clinical trials, and developing diagnostic and therapeutic approaches to non-AD age-related
cognitive decline.

## Key facts

- **NIH application ID:** 9934072
- **Project number:** 5R01AG034570-10
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** William J. Jagust
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $841,951
- **Award type:** 5
- **Project period:** 2009-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934072

## Citation

> US National Institutes of Health, RePORTER application 9934072, Neural and Biochemical Mechanisms of Cognitive Aging (5R01AG034570-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934072. Licensed CC0.

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