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Identifying variations in gamma-secretase function that are critical determinants of clinical and biomarker progression of Autosomal Dominant Alzheimer's disease: From mechanism to clinical trials

Award Number: K01AG084816
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Identifying variations in gamma-secretase function that are critical determinants of clinical and biomarker progression of Autosomal Dominant Alzheimer's disease: From mechanism to clinical trials - PROJECT ABSTRACT There is an urgent need for novel therapies for Alzheimer’s disease (AD) and related dementias (ADRD). The over-production of longer, aggregation-prone β-amyloid (Aβ) fragments (including Aβ42 and 43) relative to shorter, non-aggregating fragments (including Aβ37 and 38) are likely critical drivers of disease in both late- onset, sporadic AD (LOAD) and autosomal dominant AD (ADAD). The balance between production of aggregating and non-aggregating forms of Aβ is a direct result of the kinetics by which the γ-secretase complex sequentially cleaves amyloid precursor protein. Alterations in γ-secretase function can have profound neurodegenerative and cognitive consequences, while modulation of γ-secretase has therapeutic potential in LOAD and ADAD. Pathogenic variants in Presenilin-1 (PSEN1), the key catalytic subunit in the γ-secretase complex, are the most common cause of ADAD. There is substantial heterogeneity in Age of Symptom Onset (a range of >30 years) and biomarker progression across PSEN1 variants. The proposed K01 project will characterize differences in γ-secretase function across ~250 unique ADAD-causing PSEN1 variants in the presence and absence of two structurally distinct γ-secretase modulators (GSMs), measured in a cell-based model system (Aim 1). In Aim 2, variant-specific characteristics will be combined with cross-sectional cognitive and biomarker measures from carriers of corresponding PSEN1 variants participating in the Dominantly Inherited Alzheimer’s Network Observational Study (DIAN-Obs), a large international study in which over 80 unique PSEN1 pathogenic variants are represented. This translational dataset will be used to examine whether differences in γ-secretase function between PSEN1 mutations can account for the heterogeneity in Age of Symptom Onset, cognition, and AD biomarkers. Aim 3 will utilize longitudinal data from DIAN-Obs to examine whether mutation-specific characteristics 1) predict change in biomarkers and cognition and 2) increase power to detect estimated treatment effects for relevant trial outcomes. Leveraging available data from DIAN Trials Unit, exploratory analyses will assess whether inclusion of variant-dependent characteristics can improve stratification approaches for future clinical trials. This K01 will elucidate mechanisms underlying AD, facilitate ongoing ADAD clinical trials, and support the development of GSMs as possible therapeutics. To help Dr. Stephanie Schultz achieve these aims, a multidisciplinary mentorship team has been assembled from the Harvard Medical School community and DIAN Leadership team to complement coursework in protein characterization, translational research, advanced statistical analysis, and clinical trials. Dr. Jasmeer Chhatwal will be the primary mentor overseeing research and career progress. Dr. Schultz will receive mentoring from Dr. Dennis Selkoe on the mechanisms underlying AD, Drs. Reisa Sperling and Eric McDade on translational and clinical trial design, and Dr. Chengjie Xiong on advanced statistical methods for translational research. This comprehensive training plan will enable Dr. Schultz to become an independent translational scientist.


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 = $129,166 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	3	1/14/2026	NON-COMPETING CONTINUATION	$129,166
														Subtotal = $129,166

Issue Date FY: 2025 ( Subtotal = $129,166 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	2	11/19/2024	NON-COMPETING CONTINUATION	$129,166
														Subtotal = $129,166

Issue Date FY: 2024 ( Subtotal = $129,166 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	1	11/7/2023	NEW	$129,166
														Subtotal = $129,166

Grand Total All Awards = $387,498

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Identifying variations in gamma-secretase function that are critical determinants of clinical and biomarker progression of Autosomal Dominant Alzheimer's disease: From mechanism to clinical trials

Award Number: K01AG084816

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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