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Apolipoproteins and Alzheimer's pathophysiology.

ABSTRACT: Introduction:Apolipoproteins of demonstrated importance to brain cholesterol and ß-amyloid metabolism may serve as novel risk markers for Alzheimer's pathology. Methods:We measured apolipoproteins (apoE, apoJ, apoA-I, and apoC-III and their uniquely defined subspecies) by enzyme-linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia-free participants of the Ginkgo Evaluation of Memory Study and related these to ß-amyloid on positron emission tomography scans, hippocampal volume, and white matter lesion volume in 2009. Results:Higher apoE was associated with lower ß-amyloid deposition. Despite apoA-I being unrelated to hippocampal volume, subspecies of apoA-I containing or lacking apoJ or apoC-III showed opposite associations with hippocampal volume. Higher apoJ and apoE lacking apoJ were associated with higher hippocampal volume and higher white matter lesion volume, respectively. Associations were similar in participants without cognitive impairment or APOE ?4 noncarrier and when analyzing apolipoproteins in 2000-2002. Discussion:Apolipoproteins may be important minimally invasive biomarkers indicative of Alzheimer's pathology.

SUBMITTER: Koch M

PROVIDER: S-EPMC6199693 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Apolipoproteins and Alzheimer's pathophysiology.

Koch Manja M DeKosky Steven T ST Fitzpatrick Annette L AL Furtado Jeremy D JD Lopez Oscar L OL Kuller Lewis H LH Mackey Rachel H RH Hughes Timothy M TM Mukamal Kenneth J KJ Jensen Majken K MK

Alzheimer's & dementia (Amsterdam, Netherlands) 20180810

<h4>Introduction</h4>Apolipoproteins of demonstrated importance to brain cholesterol and ß-amyloid metabolism may serve as novel risk markers for Alzheimer's pathology.<h4>Methods</h4>We measured apolipoproteins (apoE, apoJ, apoA-I, and apoC-III and their uniquely defined subspecies) by enzyme-linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia-free participants of the Ginkgo Evaluation of Memory Study and related these to ß-amyloid on positron emission tomography s ...[more]

PMID: 30370330

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Project description:The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post-mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin-1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin-associated glycoprotein:proteolipid protein-1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III-IV). Although MAG:PLP1 remained low in advanced AD (stage V-VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin-converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin-converting enzyme-2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42-mediated upregulation of ECE2, is a contributor.

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Apolipoproteins and Alzheimer's pathophysiology.

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Apolipoproteins and Alzheimer's pathophysiology.

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