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Investigating and targeting apolipoprotein E4 in Down syndrome-associated Alzheimer's disease

Award Number: R01AG078965
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Investigating and targeting apolipoprotein E4 in Down syndrome-associated Alzheimer's disease - PROJECT SUMMARY ABSTRACT By the age of forty, every person with Down syndrome has Alzheimer's disease brain pathology, and most will go on to develop Alzheimer's disease dementia, due to triplication of the amyloid precursor protein gene (APP) that resides on chromosome 21. As the strongest genetic risk factor and greatest overall risk factor for Alzheimer's disease in the typical population, other than increasing age itself, inheritance of the ε4 allele of the apolipoprotein E gene (APOE) also significantly increases the risk and severity of Alzheimer's disease in people with Down syndrome. We have found a key mechanism by which apoE promotes Alzheimer's disease: it binds to the Aβ peptide and converts it into a toxic species that kills neurons and causes neurodegeneration, with the apoE4 form being the most effective amyloid catalyst. In view of the essential contributions of apoE to Alzheimer's disease, it is critical that the mechanisms underlying the enhanced Alzheimer's disease risk for people with Down syndrome be elucidated and that new therapies be developed to effectively target its pathogenic activity. We have developed an in vitro assay to screen the NIH Clinical Collection (NCC) small molecule library for inhibitors of apoE4-catalyzed Aβ oligomer/fibril formation. We have identified eight hit compounds, each of which has been tested previously in Phase I-III clinical trials for other indications and thus have known safety profiles. In a secondary screen, we found that three out of the eight initial compounds were non-neurotoxic inhibitors of apoE that significantly reduced Aβ and tau pathology and cell death in neurons from two rodent models of Alzheimer's disease. Furthermore, an analysis of the National Alzheimer's Coordinating Center (NACC) database showed use of either one of two drugs we identified as apoE inhibitors by Alzheimer's patients was associated with improved cognition over time and increased odds of reverting to a better clinical diagnosis from Alzheimer's disease to mild cognitive impairment (MCI) or from MCI to normal cognition, providing translational support for their further study. Herein, we will use a panel of human induced pluripotent stem cell (iPSC)-derived cerebral organoid (CO) models of Down syndrome and Alzheimer's disease to study the mechanisms of apoE-induced Alzheimer's disease phenotypes and to evaluate whether our top candidate apoE inhibitors can block the development of Alzheimer's disease phenotypes in Down syndrome. We will also develop the first mouse model of Down syndrome expressing human APOE4 and assess the ability of our top candidate apoE inhibitors to prevent the development of cognitive deficits, cerebrovascular damage, synaptic dysfunction, neurodegeneration, and/or neuroinflammation in this novel model of Down syndrome-associated Alzheimer's disease in order to inform future clinical trials. Our proposed approach should result in highly targeted Alzheimer's disease therapies for people with Down syndrome with few side effects, because the drugs that inhibit the interaction of apoE4 and Aβ should not, or can be selected to not, affect the normal functions of apoE.


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 = $735,107 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	2	6/22/2026	EXTENSION WITH OR WITHOUT FUNDS	$735,107
														Subtotal = $735,107

Grand Total All Awards = $735,107

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Investigating and targeting apolipoprotein E4 in Down syndrome-associated Alzheimer's disease

Award Number: R01AG078965

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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