Alzheimer?s disease (AD) is a progressive neurodegenerative disorder that afflicts 5.1 million Americans aged 65 or older. Chronic inflammation is a central feature of the pathology present in AD-affected brains. Inflammatory responses to neurodegeneration increase production of reactive oxygen species, and expression of cytokines, adhesion molecules, complement proteins, and degradative proteins, cellular activation of microglia and astrocytes, and production of beta amyloid. Complement C1q is necessary for amyloid-B synaptoxicity in murine models. In the cerebrospinal fluid of individuals diagnosed with normal cognitive function, mild cognitive impairment and AD, APOE4 genotype was associated with cerebrospinal fluid complement 3, amyloid ? beta and hyperphosphorylated tau (ptau). The association between C3 and tau was significant only after adjustment for amyloid. These data suggest that the complement cascade and APOE4 results in elevated AD neurodegeneration and that amyloid regulates the effect of the complement cascade on downstream tau pathology. Emerging evidence from genetic, clinical and experimental studies support the involvement of high-density lipoprotein (HDL) constituents in inflammation, cognitive function and progression to AD. Cognitive impairment (CI) has been associated with lower levels of the HDL proteins apoA-I, apoA-II and apoH and higher levels of apoE and apoJ (clusterin). More than 20 loci associated with HDL metabolism contribute to the risk of AD including variants in clusterin. This study is designed to determine the association between (1) the high-density lipoprotein (HDL) proteome and (2) single nucleotide polymorphisms (SNPs) related with HDL and inflammatory proteins with CI and AD in African-American and white adults. This study will be conducted from a genome wide association study of validated cases of AD in REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants.

Public Health Relevance

This research aims to determine the association between (1) the high-density lipoprotein (HDL) proteome and (2) single nucleotide polymorphisms (SNPs) related with HDL and inflammatory proteins with CI and AD in African-American and white adults. This study will be conducted from a genome wide association study of validated cases of AD in REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG061186-01
Application #
9641731
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Luo, Yuan
Project Start
2019-03-01
Project End
2022-12-31
Budget Start
2019-03-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029