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

Award Number: R01AG081981
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,086,201 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	000	4	5/22/2026	NON-COMPETING CONTINUATION	$1,086,201
														Subtotal = $1,086,201

Issue Date FY: 2025 ( Subtotal = $1,064,476 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	001	3	6/17/2025	NON-COMPETING CONTINUATION	$86,896
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	000	3	5/19/2025	NON-COMPETING CONTINUATION	$977,580
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	003	3	6/24/2025	NON-COMPETING CONTINUATION	$0
2025	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	002	2	6/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,064,476

Issue Date FY: 2024 ( Subtotal = $1,086,200 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	000	2	6/12/2024	NON-COMPETING CONTINUATION	$1,086,200
														Subtotal = $1,086,200

Issue Date FY: 2023 ( Subtotal = $1,135,580 )
2023	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Aging Research	000	1	9/11/2023	NEW	$1,135,580
														Subtotal = $1,135,580

Grand Total All Awards = $4,372,457

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

Award Number: R01AG081981

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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