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Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain

Award Number: R01AG070921
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain - Aging in humans is associated with a host of brain diseases, including tumors of glial progenitor cells and degeneration of neuronal cells. However, the mechanisms by which age and disease risk interact are poorly understood. Recent studies from our group have shown that somatic single nucleotide variants (sSNV) accumulate even in nondividing neurons in the human cortex, resulting in thousands of sSNV per neuronal genome by old age. Further, the patterns of sSNV that are found can be classified, and normal brains appear to have somatic variants that were present at birth, variants that accumulate over time, and variants caused by oxidative damage. Our studies also find a significantly higher rate of sSNV accumulation in neurons from Alzheimer’s disease (AD) brain, likely related to increased oxidative damage. These studies relied on new techniques that allow deep whole genome sequencing of DNA isolated from a single neuron taken from frozen postmortem brain. This new study aims to further characterize the rates and patters of somatic variants that accumulate in single neurons and glia as an individual ages, and determine how this accumulation of mutations is related to AD as well as the formation of glial tumors. The first aim will examine neurons form different regions of normal brain at different ages. This will give us a better understanding of how these mutations accumulate with age, and the specific mutational forces at work in different brain areas. The second aim will perform a similar analysis, this time focused on glial cells instead of neurons. In the final aim, we will look at neurons in the brains of individuals who had AD, and analyze how the rate and patter of mutations differ compared to aged- matched normal brain. This will provide valuable insight into the causes of somatic mutations in AD. There is compelling evidence to suggest that somatic mutations in individual neurons are an important factor in at least some neurodegenerative disorders, and our data implicate them in normal cognitive aging. For the first time, the tools exist to examine these questions, and this study is designed to determine how somatic SNV impact normal aging, brain tumor formation, and AD. This is a crucial step in understanding the molecular cause of AD, and a prerequisite to the development of treatments and cures.


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: 2025 ( Subtotal = $809,811 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	5	6/10/2025	NON-COMPETING CONTINUATION	$66,107
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	5	3/24/2025	NON-COMPETING CONTINUATION	$743,704
														Subtotal = $809,811

Issue Date FY: 2024 ( Subtotal = $840,497 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	4	4/17/2024	NON-COMPETING CONTINUATION	$840,497
														Subtotal = $840,497

Issue Date FY: 2023 ( Subtotal = $853,949 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	3/22/2023	NON-COMPETING CONTINUATION	$853,949
														Subtotal = $853,949

Issue Date FY: 2022 ( Subtotal = $865,985 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	5/5/2022	NON-COMPETING CONTINUATION	$865,985
														Subtotal = $865,985

Issue Date FY: 2021 ( Subtotal = $898,687 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	3/23/2021	NEW	$898,687
														Subtotal = $898,687

Grand Total All Awards = $4,268,929

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Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain

Award Number: R01AG070921

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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