Article

Markers of cholesterol transport are associated with amyloid deposition in the brain

Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, USA. Electronic address: .
Neurobiology of aging (Impact Factor: 5.01). 10/2013; 35(4). DOI: 10.1016/j.neurobiolaging.2013.09.040
Source: PubMed

ABSTRACT

Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.

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    • "An association with amyloid deposition has been described for ABCA7 rs3764650 (Shulman et al., 2013), ABCA7 rs3752246 (Hughes et al., 2014), BIN1 rs744373 (Hohman et al., 2013), CR1 rs6701713 (Shulman et al., 2013), CR1 rs3818361 (Thambisetty et al., 2013), CR1 rs6656401, and CLU rs3818361 (Hohman et al., 2013). CD2AP rs9349407 has been associated with postmortem neuritic plaque burden in the advanced stages of the disease (Shulman et al., 2013), but interestingly not with PiB binding in nondemented elderly (Hughes et al., 2014). "

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    • "The hypothesis is further substantiated by findings showing direct interaction between CLU and Aβ [25], [26]. However, despite these suggestive preclinical findings, clinical data is lacking to corroborate a significant effect of CLU on Aβ burden as a major mechanism underlying the genetic link to AD [27], [28]. Healthy carriers of the CLU rs11136000 risk allele C show decreased white matter integrity [29], altered coupling between hippocampus and prefrontal cortex during memory processing [30], and significant longitudinal increases of cerebral blood flow in the hippocampus and anterior cingulate cortex [31], indicating that CLU may also participate in non-Aβ pathways that could modulate vulnerability to AD. "
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    • "Thus, oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle characterize AD as a protein misfolding disease, with protein clearance defects through the ubiquitin-proteasome system (Hong et al., 2014; Valasani et al., 2014). There is strong evidence, also, that APP may act as a trophic factor relevant to neurite outgrowth and synaptogenesis, as well as growth and cell proliferation (Abramov et al., 2009; Jiang et al., 2013; Bukanova et al., 2014; Dawkins and Small, 2014; Hughes et al., 2014). However, future research are required to fully clarify mechanisms of APP action (Dawkins and Small, 2014). "
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