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Biomarker Predictors of Memantine Sensitivity in patients with Alzheimer's Disease

Award Number: R01AG059640
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Biomarker Predictors of Memantine Sensitivity in patients with Alzheimer's Disease - Abstract This application responds to PAR-16-365: “Pilot Clinical Trials for the Spectrum of Alzheimer's Disease ...”, and its calls for “Studies to define and refine the target population” and “address heterogeneity of response… identification of specific individuals… more [vs.] less likely to benefit from the intervention(s).” Alzheimer's Disease (AD) is a severe neurodegenerative brain disorder, with limited therapeutic options. The NMDA receptor antagonist, memantine (MEM) is approved for treatment of moderate-to-severe AD; its mechanisms are not well understood, but may include a blunting of glutamate-mediated neurotoxicity. While meta-analyses confirm MEM's effectiveness in delaying the progression of cognitive and behavioral disturbances in AD, the clinical response to MEM is modest, short-lived and highly heterogeneous, with many AD patients showing no gains even with an extended MEM trial. The utility of MEM in AD might be greatly enhanced if patients could be identified as “MEM-sensitive” vs. “MEM-insensitive” in advance of a therapeutic trial, using a predictive biomarker. For the past decade, the PI has studied the acute neurophysiological effects of MEM in laboratory animals, healthy human subjects (HS) and schizophrenia (SZ) patients. These studies demonstrated that a single “challenge dose” of MEM (20 mg) significantly enhanced specific laboratory measures of early auditory information processing (EAIP) in HS and SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and gamma band auditory steady-state response (ASSR; including gamma power and synchronization). This application will determine whether the EAIP response to an acute MEM-challenge can be used to predict a positive therapeutic response to MEM in patients with mild-to-moderate AD, over a 24 week trial. Aim 1 tests the hypothesis (H1) that a single dose of MEM (20 mg vs. placebo (PBO)) will significantly enhance EAIP measures in patients with mild-to-moderate severity AD (n=88). Assessed across the full cohort of patients, PPI, MMN and ASSR should be significantly greater after MEM vs. PBO. However, the magnitude of this “MEM effect” (MEM minus PBO) will vary across measures and patients. Aim 2 will leverage this response heterogeneity to test the hypothesis (H2) that patients exhibiting a larger “MEM effect” on EAIP will experience a significantly greater clinical response to MEM, compared to patients with a smaller “MEM effect” on EAIP. After Aim 1 testing, MEM treatment will be initiated and titrated to 10 mg bid in all patients. Clinical outcome measures will be assessed at baseline, 8, 16 and 24 weeks. Analyses will determine whether MEM effects on EAIP measures (individually, and in composite scores) predict the magnitude of the clinical response to MEM in these patients. Moderating factors will be tested, including specific single nucleotide polymorphisms known to moderate MEM sensitivity. This application leverages a unique set of empirical laboratory findings with MEM to develop a novel biomarker predicting sensitivity to MEM's therapeutic impact in patients with AD.


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 = $0 )
2026	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	12/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	3/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	6/16/2022	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $394,896 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	5/12/2021	NON-COMPETING CONTINUATION	$394,896
														Subtotal = $394,896

Issue Date FY: 2020 ( Subtotal = $393,750 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	5/28/2020	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2019 ( Subtotal = $393,646 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	2	5/30/2019	NON-COMPETING CONTINUATION	$393,646
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	10/23/2018	NEW	$0
														Subtotal = $393,646

Issue Date FY: 2018 ( Subtotal = $392,500 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	1	8/16/2018	NEW	$0
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	8/15/2018	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $1,969,792

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Biomarker Predictors of Memantine Sensitivity in patients with Alzheimer's Disease

Award Number: R01AG059640

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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