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Human Cerebrospinal Fluid Extracellular Vesicles: Utility as Disease Specific Biomarkers and Impact on Alzheimer's Disease Pathology

Award Number: R01AG079356
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Human Cerebrospinal Fluid Extracellular Vesicles: Utility as Disease Specific Biomarkers and Impact on Alzheimer's Disease Pathology - PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death for those age 65 and older. Costs of care for individuals with AD are substantial: total payments in 2022 are estimated at $321 billion, and costs will increase by $1 billion each year. AD risk factors include age, sex, and genetics. Of Americans living with AD, 4 million are women and 2.5 million are men, and the apolipoprotein E (APOE) -e4 allele is the most important genetic risk factor for sporadic AD. In addition, female APOE-e4 carriers are more likely to progress from mild cognitive impairment (MCI) to AD, have more brain atrophy and memory loss, and develop AD more frequently than age matched males. Hallmark features of AD include the buildup of amyloid beta (Aβ) and abnormal phosphorylation of Tau, resulting in plaques and neurofibrillary tangles in the brain. Importantly in AD, disruptions to extracellular vesicle (EV) biogenesis result in altered EV miRNA and protein cargo, and neuronal EVs in AD contain and propagate both Aβ and Tau. Our previous studies identified miRNAs in human cerebrospinal fluid (CSF) from living donors that discriminate AD patients from healthy control (CTL) participants, and we found that combining CSF miRNAs plus CSF Aβ42:total Tau measurements improves classification of AD and MCI vs. CTL. In the studies proposed herein, we focus on the utility of CSF EVs and their cargo as more robust biomarkers for AD, that show distinct differences in females vs. males and those with the APOE-e4 vs. APOE-e3 genotype. Our pilot data in human CSF EVs and postmortem brain shows that: i) the size of membranous particles is larger in AD vs. CTL CSF; ii) CSF EVs have surface marker proteins that are unique to AD and/or Parkinson's disease (PD) vs. CTL; iii) CSF EV miRNAs have improved predictive power for AD vs. total CSF; iv) CSF EV miRNAs show sex and APOE dependent changes in expression; v) there is increased miR-16-5p in female AD CSF EVs vs. CTL; and vi) a predicted gene target of miR-16-5p, SNAP-25, is decreased in female AD hippocampus. Together, these studies support that sex and APOE-e4 both contribute to changes in AD CSF EVs, which may account in part for the higher prevalence of AD in females, and the increased risk for AD in people with the APOE-e4 genotype. Thus, we propose to establish the physical features and molecular cargo of AD CSF EVs vs. CTL, within the context of sex and APOE genotype. We will use our Information Theory method to identify the strongest dependencies that can distinguish AD from PD from CTL, and to identify candidate biomarkers for high-risk AD. We include male and female PD to identify CSF EV surface markers and cargo that are unique from AD. We will then identify and verify gene targets of CSF EV miRNAs that are relevant to AD. Together, our studies will establish specific biomarkers for AD by combining the physical features, surface marker profiles, miRNAs, and proteins in CSF EVs. They will also establish the neurologically relevant gene targets of AD EV miRNAs in human brain, which may contribute to the processes underlying AD pathogenesis and serve as novel therapeutic targets for AD.


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 = $788,933 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	000	4	2/26/2026	NON-COMPETING CONTINUATION	$788,933
														Subtotal = $788,933

Issue Date FY: 2025 ( Subtotal = $748,595 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	001	3	6/9/2025	NON-COMPETING CONTINUATION	$61,110
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	000	3	3/7/2025	NON-COMPETING CONTINUATION	$687,485
														Subtotal = $748,595

Issue Date FY: 2024 ( Subtotal = $721,871 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	001	2	3/13/2024	NON-COMPETING CONTINUATION	$649,685
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	002	2	6/28/2024	NON-COMPETING CONTINUATION	$72,186
2024	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	000	1	1/29/2024	NEW	$0
														Subtotal = $721,871

Issue Date FY: 2023 ( Subtotal = $737,653 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Aging Research	000	1	4/7/2023	NEW	$737,653
														Subtotal = $737,653

Grand Total All Awards = $2,997,052

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Human Cerebrospinal Fluid Extracellular Vesicles: Utility as Disease Specific Biomarkers and Impact on Alzheimer's Disease Pathology

Award Number: R01AG079356

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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