The goal of this K24 application is to provide protected time for the candidate to conduct patient-oriented research and to expand her current program of mentoring. While the candidate has established a record of clinical research in neurodegeneration, she also has track record of advancing her mentees' careers and research as well. Recent studies have shown that mild cognitive impairment (amnestic MCI) and Alzheimer's disease (AD) patients have a lower concentration of amylin in plasma than the elderly who had normal cognition. In cross-sectional analyses, higher concentrations of plasma amylin are related to better cognitive function, especially in memory and executive domains. Amylin is a gut-brain axis hormone, which readily crosses the blood brain barrier (BBB) and mediates activities including regulating glucose metabolism, relaxing cerebrovascular structure and modulating inflammation, all of which could be beneficial for AD. From the Framingham Heart Study Offspring and Omni Generation 1 cohorts, we propose using plasma samples collected from 1995-1998 to relate to incident change in cognition and brain structure up to 15 years later. We posit that high levels of plasma amylin are protective for cognitive decline and brain atrophy in aging process. We have five specific aims including 1) studying the distribution of plasma amylin in FHS community based population; 2) determining the relationship between baseline plasma amylin and cognitive changes, including incident mild cognitive impairment and dementia; 3) examining the association between plasma amylin and changes in brain morphology; 4) stratifying these analyses by the presence of ApoE4 allele, diabetes and other vascular diseases and 5) studying the relationship between amylin, A, lipids, other gut- brain axis peptides and inflammation in FHS. Pramlintide is an amylin analog and an FDA approved drug for diabetes with a favorable safety profile in clinical use. Should we find that high levels f plasma amylin are protective for the incidence of AD; our study will provide additional rationale for a large phase 2 or 3 trial with pramlintide to determine if amylin type peptides can prevent and treat AD. We anticipate that this study may help open a new and unconventional avenue for the therapeutic of AD.
The significance of the proposed study is to provide evidence in support of an alternative and innovative drug target to treat Alzheimer's disease (AD). Results from the study will be important for two reasons including using existing plasma samples and data on cognition and brain imaging from Framingham Heart Study (FHS) to test the hypothesis of amylin on AD and indicating an FDA approved diabetic drug for the AD treatment. Finally and most importantly, this study will also provide a vehicle for the candidate to mentor junior faculty members and trainees who would like to pursue their careers in the translational research of neurodegeneration.
|Qiu, Wei Qiao (2017) Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer's disease. Neuroscience 356:44-51|
|Zhu, Andrea Q; Kivork, Christine; Vu, Linh et al. (2017) The association between hope and mortality in homebound elders. Int J Geriatr Psychiatry 32:e150-e156|
|Zhu, Haihao; Stern, Robert A; Tao, Qiushan et al. (2017) An amylin analog used as a challenge test for Alzheimer's disease. Alzheimers Dement (N Y) 3:33-43|
|Mohamed, Loqman A; Zhu, Haihao; Mousa, Youssef M et al. (2017) Amylin Enhances Amyloid-? Peptide Brain to Blood Efflux Across the Blood-Brain Barrier. J Alzheimers Dis 56:1087-1099|
|Wang, Erming; Zhu, Haihao; Wang, Xiaofan et al. (2017) Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model. J Alzheimers Dis 56:47-61|
|Qiu, Wei Qiao; Himali, Jayandra J; Wolf, Philip A et al. (2017) Effects of white matter integrity and brain volumes on late life depression in the Framingham Heart Study. Int J Geriatr Psychiatry 32:214-221|
|Li, Huajie; Zhu, Haihao; Wallack, Max et al. (2016) Age and its association with low insulin and high amyloid-? peptides in blood. J Alzheimers Dis 49:129-37|
|Qiu, Wei Qiao; Zhu, Haihao; Dean, Michael et al. (2016) Amyloid-associated depression and ApoE4 allele: longitudinal follow-up for the development of Alzheimer's disease. Int J Geriatr Psychiatry 31:316-22|
|Mwamburi, Mkaya; Qiu, Wei Qiao (2016) Different associations of premorbid intelligencevs. current cognition with BMI, insulin and diabetes in the homebound elderly. Integr Mol Med 3:547-552|
|Sawaengsri, Hathairat; Bergethon, Peter R; Qiu, Wei Qiao et al. (2016) Transcobalamin 776C?G polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake. Am J Clin Nutr 104:1665-1670|
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