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Amylin deposition in the brain: A second amyloid in Alzheimer disease?

ABSTRACT: Hyperamylinemia, a common pancreatic disorder in obese and insulin-resistant patients, is known to cause amylin oligomerization and cytotoxicity in pancreatic islets, leading to ?-cell mass depletion and development of type 2 diabetes. Recent data has revealed that hyperamylinemia also affects the vascular system, heart, and kidneys. We therefore hypothesized that oligomerized amylin might accumulate in the cerebrovascular system and brain parenchyma of diabetic patients.Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer disease (AD), nondiabetic patients with AD, and age-matched healthy controls was assessed by quantitative real time polymerase chain reaction, immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay.Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late onset AD without clinically apparent diabetes. Mixed amylin and amyloid ? (A?) deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of A? deposition. Tissues infiltrated by amylin showed increased interstitial space, vacuolation, spongiform change, and capillaries bent at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain.Metabolic disorders and aging promote accumulation of amylin amyloid in the cerebrovascular system and gray matter, altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of A? from the brain, thus contributing to the etiology of AD.

SUBMITTER: Jackson K

PROVIDER: S-EPMC3818462 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Amylin deposition in the brain: A second amyloid in Alzheimer disease?

Jackson Kaleena K Barisone Gustavo A GA Diaz Elva E Jin Lee-way LW DeCarli Charles C Despa Florin F

Annals of neurology 20130712 4

<h4>Objective</h4>Hyperamylinemia, a common pancreatic disorder in obese and insulin-resistant patients, is known to cause amylin oligomerization and cytotoxicity in pancreatic islets, leading to β-cell mass depletion and development of type 2 diabetes. Recent data has revealed that hyperamylinemia also affects the vascular system, heart, and kidneys. We therefore hypothesized that oligomerized amylin might accumulate in the cerebrovascular system and brain parenchyma of diabetic patients.<h4>Me ...[more]

PMID: 23794448

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Project description:Background and objectivesBrain amyloid deposition, a major risk factor for Alzheimer's disease (AD), is currently estimated by measuring cerebrospinal fluid or plasma amyloid peptide levels, or by positron-emission tomography imaging. Assessing genetic risks relating to amyloid deposition before any accumulation has occurred would allow for earlier intervention in persons at increased risk for developing AD. Previous work linking amyloid burden and genetic risk relied almost exclusively on APOE, a major AD genetic risk factor. Here, we ask whether a polygenic risk score (PRS) that incorporates an optimized list of common variants linked to AD and excludes APOE is associated with brain amyloid load in cognitively unimpaired elderly adults.MethodsWe included 291 elderly asymptomatic participants from the INveStIGation of AlzHeimer's PredicTors (INSIGHT-preAD) cohort who underwent amyloid imaging, including 83 amyloid-positive (+) participants. We used an Alzheimer's (A) PRS composed of 33 AD risk variants excluding APOE, and selected the 17 variants that showed the strongest association with amyloid positivity to define an optimized (oA) PRS. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study [228 participants, 90 amyloid (+)] were tested as a validation cohort. Finally, 2,300 AD patients and 6,994 controls from the European Alzheimer's Disease Initiative (EADI) were evaluated.ResultsA-PRS was not significantly associated with amyloid burden in the INSIGHT or ADNI cohorts with or without correction for APOE genotype. However, oA-PRS was significantly associated with amyloid status independently of APOE adjustment (INSIGHT OR: 5.26 [1.71-16.88]; ADNI OR: 3.38 [1.02-11.63]). Interestingly, oA-PRS accurately discriminated amyloid (+) and (-) APOE ε4 carriers (INSIGHT OR: 181.6 [7.53-10,674.6]; ADNI OR: 44.94 [3.03-1,277]). A-PRS and oA-PRS showed a significant association with disease status in the EADI cohort (OR: 1.68 [1.53-1.85] and 2.06 [1.73-2.45] respectively). Genes assigned to oA-PRS variants were enriched in ontologies related to Aβ metabolism and deposition.DiscussionPRSs relying on AD genetic risk factors excluding APOE may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their APOE status.

Project description:ImportancePreclinical studies suggest that amylin has a U-shaped dose-response association with risk of Alzheimer disease (AD). The association of plasma amylin with AD in humans is unknown.ObjectivesTo measure amylin concentration in plasma by using enzyme-linked immunosorbent assay and to study the association between plasma amylin, incidence of AD, and brain structure in humans.Design, setting, and participantsThis cohort study used data from the Framingham Heart Study offspring cohort from 1998 to 2015. Using a Monte Carlo approach, participants were divided into 3 plasma amylin concentration groups: (1) low (<75 pmol/L), (2) high (75-2800 pmol/L), and (3) extremely high (≥2800 pmol/L). Data analyses were conducted October 5, 2017, to December 18, 2018.ExposuresBaseline plasma amylin concentrations at examination 7.Main outcomes and measuresIncidence of dementia or AD and brain volumetric measures from structural magnetic resonance imaging data.ResultsFrom the Framingham Heart Study offspring cohort, 3061 participants (mean [SD] age at baseline, 61.0 [9.5] years; 1653 [54.0%] women) who had plasma amylin measurements, dementia incidence, and brain volume measurements on record were included in this study. The distribution of plasma amylin concentrations was highly skewed (median [interquartile range], 7.5 [4.6-18.9] pmol/L; mean [SD], 302.3 [1941.0] pmol/L; range, 0.03-44 623.7 pmol/L). Compared with the low plasma amylin concentration group, the high plasma amylin concentration group had a lower rate of AD incidence (2.3% vs 5.6%; P = .04), but the extremely high plasma amylin concentration group had a higher rate of AD incidence (14.3%; P < .001). After adjusting for age, sex, education, body mass index, diabetes, cardiovascular disease, high-density lipoprotein level, and APOE4, high plasma amylin was not associated with decreased AD risk (hazard ratio, 0.42 [95% CI, 0.16-1.14]; P = .09) but was positively associated with volume of gray matter in the temporal lobe (β = 0.17 [SE, 0.05]; P < .001). In contrast, extremely high plasma amylin concentration was associated with a higher AD risk (hazard ratio, 2.51 [95% CI, 1.38-4.57]; P = .003) but not associated with temporal lobe volume (β = 0.02 [SE, 0.07]; P = .82).Conclusions and relevanceThis study found that plasma amylin concentration was associated with AD incidence and brain structure with a U-shaped pattern. These findings are consistent with preclinical findings that suggest amylin is a neuropeptide that is physiological; however, at extremely high concentrations, it may lead to amylin aggregation and therefore may be a risk factor for AD.

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Amylin deposition in the brain: A second amyloid in Alzheimer disease?

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Amylin deposition in the brain: A second amyloid in Alzheimer disease?

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