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 Alzheimer's disease (AD). Recent studies have shown that mild cognitive impairment (amnestic MCI) and 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. Using AD mouse models, our recent study demonstrates that intraperitoneal injection (i.p) of amylin improves learning and memory as well as reduces indices of AD pathology in the brain. Although these studies suggest that exogenous administration of amylin type peptides may be beneficial for AD, amylin can also form amyloid in the pancreas of type 2 diabetes and in the cerebrovasculature of AD brain that may lead to worsened cognition. Thus, it is important and critical to study the longitudinal relationship between the baseline concentration of plasma amylin and cognitive decline during aging process. 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 of 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.

Public Health Relevance

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. First, the proposed study will use existing plasma samples and data on cognition and brain imaging from Framingham Heart Study (FHS) to test the concept that a high level of plasma amylin will be a protective factor for cognitive decline and brain aging. Positive findings will provide a rationale for opening a new therapeutic avenue for AD with amylin type peptides. Second, pramlintide is an amylin analog and an FDA approved diabetic drug with a favorable safety profile. Should this study show plasma amylin's protective effect on cognitive decline and the development of AD, it will serve as evidence for a large clinical trial of pramlintide. Repurposing of pramlintide for AD treatment will involve shortr trial time at a substantially lower cost than developing a new drug. Finally, this study can provid 'go or no go' information regarding an amylin pathway as a target for the therapeutics of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG049899-04
Application #
9427949
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Anderson, Dallas
Project Start
2015-05-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
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
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
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
Mwamburi, Mkaya; Qiu, Wei Qiao (2016) Different associations of premorbid intelligence vs. current cognition with BMI, insulin and diabetes in the homebound elderly. Integr Mol Med 3:547-552
Qiu, Wei Qiao; Li, Huajie; Zhu, Haihao et al. (2014) Plasma Amylin and Cognition in Diabetes in the Absence and the Presence of Insulin Treatment. J Diabetes Metab 5: