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Network hyperexcitability and response to amyloid-immunotherapies in AD

Award Number: R01AG103106
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Network hyperexcitability and response to amyloid-immunotherapies in AD - PROJECT SUMMARY Alzheimer’s disease is a neurodegenerative disorder marked by progressive cognitive decline and pathology marked by accumulating amyloid-beta (Aβ) and tau proteins. Recently, monoclonal antibodies targeting Aβ, including lecanemab and donanemab, have shown promising results in reducing cognitive decline compared to placebo in patients with mild cognitive impairment or mild Alzheimer’s disease dementia. Although these therapies significantly reduce Aβ burden in the brain, their therapeutic benefits show a high degree of heterogeneity. This study investigates the role of neural circuit hyperexcitability—a key functional consequence of Alzheimer’s disease tauopathy—as a modulator of the efficacy and safety of Aβ immunotherapies. Hyperexcitability has also been linked to blood-brain barrier disruption, a high-risk factor for amyloid-related imaging abnormalities (ARIA), the most serious treatment-limiting side effect of Aβ immunotherapies. Using high- resolution magnetoencephalography (MEG), this study will quantify hyperexcitability in AD patients receiving donanemab for 18 months. We will perform standard clinical tests, novel plasma assays including eMTBR-tau- 243, to examine biological response and dynamic contrast-enhanced MRI (DCE-MRI) to examine the neurovascular dysfunction. Specifically, we aim to determine if baseline hyperexcitability can predict clinical benefits and ARIA risk and to determine the neural correlates of disease modifying effects. Aim-1 will investigate whether higher baseline hyperexcitability predicts poorer clinical outcomes and greater ARIA risk. Aim-2 will investigate the associations between hyperexcitability and the biological response (measured from plasma markers of Alzheimer’s disease pathobiology) and whether hyperexcitability mediates the effects of tau (quantified from plasma eMTBR-tau-243) on cognitive outcomes and the effects of vascular dysfunction (quantified as blood brain barrier dysfunction using DCE-MRI) on ARIA. This study addresses critical knowledge gaps in the field of Alzheimer’s disease research by: (1) Investigating hyperexcitability as a factor influencing Aβ immunotherapy outcomes, which may explain response heterogeneity and potentially enabling tailored therapies to improve outcomes; (2) Assessing whether hyperexcitability increases the risk of ARIA, thereby identifying patients vulnerable to these side effects; and (3) Determining the role of hyperexcitability in mediating the known effects of tau and vascular dysfunction on clinical outcomes, thus refining the understanding of mechanistic associations. The study findings not only could inform future clinical trials to investigate adjunct therapies, such as anti-epileptics, to improve both the efficacy and safety of anti-Aβ immunotherapies, but also may establish hyperexcitability as a novel, modifiable therapeutic target in Alzheimer’s 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 = $688,798 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	1	9/14/2026	NEW	$688,798
														Subtotal = $688,798

Grand Total All Awards = $688,798

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Network hyperexcitability and response to amyloid-immunotherapies in AD

Award Number: R01AG103106

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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