Effect of Complement CR1 on Brain Amyloid Burden During Aging and Its Modification byAPOEGenotype.

Laboratory of Neurogenetics (MN, ABS), National Institute on Aging, National Institutes of Health, Bethesda, Maryland
Biological psychiatry (Impact Factor: 8.93). 09/2012; DOI: 10.1016/j.biopsych.2012.08.015
Source: PubMed

ABSTRACT BACKGROUND: The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals. METHODS: We used (11)C-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed (11)C-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset. RESULTS: Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE ε4 individuals showed significantly higher brain amyloid burden relative to APOE ε4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample. CONCLUSIONS: Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Aβ in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer's disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid-β peptides that form the characteristic plaques in AD brains. Moreover, some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound in effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease.
    Journal of Alzheimer's disease: JAD 06/2014; 42(3). DOI:10.3233/JAD-140144 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid imaging has been clinically approved for measuring β amyloid plaque load in patients being evaluated for Alzheimer's disease or other causes of cognitive decline. Here we explore a multidimensional approach to cognitive decline, where we situate amyloid plaque burden among a number of other relevant dimensions, such as aging, volume loss, other proteinopathies such as TDP43 and Lewy bodies, and functional reorganisation of cognitive brain systems. The multidimensional model incorporates a 'pure AD' trajectory, corresponding to e.g. monogenic Alzheimer's disease, but leaves room for other combinations of biomarker abnormalities (e.g. volume loss without amyloid positivity) and other trajectories. More tools will become available in the future that allow one to carve out a causal-mechanistic space for explaing cognitive decline in a personalized manner, enhancing progress towards more efficacious interventions.
    Current Neurology and Neuroscience Reports 11/2014; 14(11):498. DOI:10.1007/s11910-014-0498-9 · 3.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The complement component receptor 1 gene (CR1), which encodes a type-I transmembrane glycoprotein, has recently been identified as one of the most important risk genes for late-onset Alzheimer's disease (LOAD). In this article, we reviewed the recent evidence concerning the role of CR1 in LOAD. First, we introduced the structure, localization and physiological function of CR1 in humans. Afterward, we summarized the relation of CR1 polymorphisms with LOAD risk. Finally, we discussed the possible impact of CR1 on the pathogenesis of AD including amyloid-β pathology, tauopathy, immune dysfunction and glial-mediated neuroinflammation. We hope that a more comprehensive understanding of the role that CR1 played in AD may lead to the development of novel therapeutics for the prevention and treatment of AD.
    Molecular Neurobiology 05/2014; 51(2). DOI:10.1007/s12035-014-8723-8 · 5.29 Impact Factor