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C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia Prevent

Award Number: R01AG103000
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia Prevent - ABSTRACT A repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite the lifelong risk conferred by this genetic variation, carriers do not usually develop clinically manifest ALS or FTD until later in life, typically in their 50s and 60s. Knowledge of this genetic risk yields an opportunity for early therapeutic intervention, while expansion carriers are still pre- symptomatic, to prevent the emergence of clinically manifest ALS and FTD. A major challenge to the design and practical implementation of C9orf72 prevention trials, however, is that we are currently unable to predict, at the individual level, the age of future phenoconversion or whether ALS or FTD will emerge first. Unlike familial Alzheimer’s disease, where age of onset may be predicted upon that of family members, and unlike Huntington’s disease, where the size of the repeat expansion in the Huntingtin gene predicts age of onset, no reliable predictors of onset age have been identified among C9orf72 repeat expansion carriers. As such, time to phenoconversion cannot meaningfully be estimated for an individual. The C9 ALS/FTD Prevent study outlined in this proposal focuses on C9orf72 prevention trial readiness. Specifically, we aim to evaluate leading clinical markers and biomarkers (presence of a prodromal syndrome, thalamic volume, plasma NfL concentration, C9orf72 repeat length, and personalized penetrance estimates) for their utility in predicting time to phenoconversion to clinically manifest ALS or FTD, a likely primary endpoint in future prevention trials. Hypothesizing that the predictive utility of these markers will be greater when considered together, we will then combine these markers to develop and internally validate a composite risk score that identifies the subset of C9orf72 expansion carriers at the greatest short-term risk for ALS or FTD phenoconversion. In so doing, we will develop criteria that could be used to enrich C9orf72 prevention trial populations with those most likely to phenoconvert during the course of the trial. We will also determine the suitability of this risk score as a potential outcome measure for future prevention trials by characterizing its temporal course and assessing its reliability and sensitivity to change as pre-symptomatic disease evolves. While this C9 ALS/FTD Prevent study is agnostic to the specifics of any therapeutic candidate that might emerge, the foundations laid through the study outlined in this proposal are essential for all prevention trials. Moreover, this study is unique in the truly equal credence it gives to considerations around the motor neuron and cognition/behavior phenotypes, which is essential to preparing for trials that aim to prevent both ALS and FTD in pre-symptomatic C9orf72 carriers.


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 = $3,730,537 )
2026	2026	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Aging Research	000	1	9/1/2026	NEW	$3,730,537
														Subtotal = $3,730,537

Grand Total All Awards = $3,730,537

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C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia Prevent

Award Number: R01AG103000

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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