# Novel Early Retinal Imaging Biomarkers for Treating Later Spatial Memory Loss in Experimental Alzheimer's Disease

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2024 · $1,086,200

## Abstract

Therapeutically delaying the progressive decline in cognition in patients with Alzheimer’s
disease (AD) would transform AD into a manageable morbidity, a goal that has not been
achieved using drugs targeted to β-amyloid (Aβ) plaque deposition. Accumulating results
indicate that cognitive loss (linked to circuit / synaptic dysfunction) and β-amyloid (Aβ) plaque
deposition can occur independent of each other, with both driven by a cross-linked soluble
amyloid β-peptide oligomer - neuronal hyperactivity “AD cycle”. Remarkably, the prediction that
cognitive dysfunction can be restored without altering plaque deposition has been confirmed in
several AD models, for example, by drugs that prolong the opening time of the endoplasmic
reticulum (ER) ryanodine receptor type 2 (RyR2) calcium channel and suppress neuronal
hyperactivity.
 Conventional biomarkers are unable to interrogate either part of the “AD cycle” in patients at
cellular resolution, an unmet goal for evaluating treatment efficacy at the prodromal stage. Here,
we propose a novel solution to this problem based on the retina, a readily accessible part of the
nervous system with damage similar to that found in the brain of patients with AD. The retina
develops soluble amyloid β-peptide oligomers and plaque deposition before their appearance in
the brain, as well as phosphorylated tau and neurofibrillary tangles. Before overt AD pathology
and cognitive decline are evident, patients report impaired contrast sensitivity (CS), a major risk
factor for falls as well as decreased survival. CS is driven by photoreceptors.
 Our first-in-kind preliminary results in an AD model when there is sparse plaque deposition in
the retina show early impairment of CS, and rod hyperactivity measured using three OCT
mitochondria-driven biomarkers developed in our laboratory. We have also discovered that CS
impairment and rod hyperactivity biomarkers in 5xFAD male C57BL6/J (B6J) mice occur faster
than in 5xFAD male C57BL/6Tac (B6NTac) mice. In WT male B6J mice, rods showed a lower
OCT energy signature than in age-matched WT male B6NTac mice, indicating strain differences
in baseline mitochondria activity.
 We propose to test two working hypotheses with three Specific Aims. First, that impaired CS,
a hyperactive rod energy signature, and/or synaptic dysfunction occur earlier B6J 5xFAD mice
than in B6NTac 5xFAD mice. Second that in 5xFAD mice, RyR2-targeted treatments that delay
cognitive declines mitigate changes in early CS and energy biomarkers, declines in rod synaptic
activity, and later spatial memory deficits but do not change the rate of plaque deposition.

## Key facts

- **NIH application ID:** 10927324
- **Project number:** 5R01AG081981-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** BRUCE A. BERKOWITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,086,200
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10927324

## Citation

> US National Institutes of Health, RePORTER application 10927324, Novel Early Retinal Imaging Biomarkers for Treating Later Spatial Memory Loss in Experimental Alzheimer's Disease (5R01AG081981-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10927324. Licensed CC0.

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