Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Advancing Therapeutic Development for Early-Stage Alzheimer's Disease.

Award Number: U01AG097469
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

Group Awards By:

View Award Description

Advancing Therapeutic Development for Early-Stage Alzheimer's Disease. - ABSTRACT Alzheimer's disease (AD) remains a challenging and unmet medical need, lacking effective therapeutic interventions. The pathophysiological characteristics of late-stage AD are well-documented, but the critical mechanisms initiating early-phase AD remain elusive. Uncovering druggable mechanisms associated with early AD, evaluated through clinically meaningful biomarkers, has the potential to transform the landscape of AD treatment, significantly reducing its progression and incidence. Our approach is guided by a compelling biological rationale. Extensive evidence suggests that network hyperexcitability (NH) is an early translational AD-related phenotype. In patients, this NH is associated with subclinical epilepsy discharges (ED), which can be readily monitored in both humans and rodents using electroencephalogram (EEG). This phenomenon results from the dysregulation of ion channels influencing the firing of hippocampal neurons. It is considered a triggering event preceding the global decline in synaptic function characteristic of late-stage AD. Our breakthrough discovery reveals that NH is mechanistically linked to the hyperactivation of the voltage-gated Na+ (Nav) channel Nav1.6, driven by an enhanced interaction with glycogen synthase kinase 3β (GSK3β). Remarkably, we have identified a brain-permeant small molecule, 1063, and generated non-commercial analogs, which target an unexplored druggable pocket at the GSK3β/Nav1.6 protein-protein interaction interface, reducing complex formation without affecting GSK3β's enzymatic activity. We show that compound 1063 restores the NH phenotype to healthy control levels in AD models, in a GSK3β-dependent manner, and exhibits dose-dependent in vivo efficacy against ED in AD with no signs of systemic toxicity. The objective of this proposal is to build on our discovery, launching a lead optimization campaign to develop drug candidates suitable for future Investigational New Drug (IND) efforts to treat early-stage AD. Our optimization process will involve a rigorous multi-tiered platform encompassing primary, secondary, and orthogonal assays, alongside cutting-edge synaptic assays, and preclinical in vivo efficacy studies using EEG and cognitive behavioral testing. Our drug discovery campaign holds the potential to pave the way to a groundbreaking class of neurotherapeutics, based on precision medicine, capable of treating the prodromal phases of neurodegeneration at its inception, thus preventing the devastating clinical consequences of the disease.


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 = $2,476,157 )
2026	2026	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Aging Research	000	1	9/10/2026	NEW	$2,476,157
														Subtotal = $2,476,157

Grand Total All Awards = $2,476,157

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Advancing Therapeutic Development for Early-Stage Alzheimer's Disease.

Award Number: U01AG097469

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer