Olfactory copy number association with age at onset of Alzheimer disease

Shaw, Chad A.; Li, Y.; Wiszniewska, Joanna; Chasse, Scott A.; Zaidi, Sameer; Jin, Weihong; Dawson, Brian; Wilhelmsen, Kirk C.; Lupski, James R.; Belmont, John W.; Doody, Rachelle S.; Szigeti, Kinga

doi:10.1212/wnl.0b013e3182166df5

Cited by 38 publications

(25 citation statements)

References 28 publications

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“…In addition, a higher copy number of a complex multiallelic segment (DGV variation_0316) containing the olfactory receptor genes on chromosome 14q11.2 was reported to be associated with a decrease in age at onset of AD using genotypes obtained from Affymetrix SNP 6.0 arrays (controls were not evaluated) (Shaw et al 2011). Although this region is 200 kb in size, it is poorly covered with SNPs in the 650Y array used for our study (three SNPs).…”

Section: Discussionmentioning

confidence: 90%

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Ghani

Pinto

Lee

et al. 2012

G3 Genes|Genomes|Genetics

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Recently genome-wide association studies have identified significant association between Alzheimer's disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (.100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a 470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs. Alzheimer's disease (AD) is the most common form of dementia, affecting 30% of individuals over 80 years of age (Mayeux 2003). The hallmark of AD brain pathology is characterized by the accumulation of a neurotoxic proteolytic derivative of the amyloid precursor protein (APP; Ab peptides) and the formation of intraneuronal tau-associated neurofibrillary tangles. The majority of AD cases are sporadic (95%), with onset after 65 years of age. One half of the genetic variance is attributable to mutations in APP, PSEN1, PSEN2, and the APOE e4-allele, and they have been shown to cause the overproduction or reduced clearance of Ab (Rogaeva et al. 2006). More recently, it was demonstrated that single nucleotide polymorphisms (SNP) in SORL1 are significantly associated with late-onset AD in several independent cohorts (Rogaeva et al. 2007;Reitz et al. 2011). In addition,

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Section: Discussionmentioning

confidence: 90%

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Ghani

Pinto

Lee

et al. 2012

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

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“…Unfortunately, it is precisely at this stage that the clinical diagnosis is most difficult. Recently, the possibility of using olfaction as a biomarker for AD has been explored in both patients (Shaw et al, 2011;Schofield et al, 2012) and animal models (Wesson et al, 2010;Kameshima et al, 2012). Our current data using an AD model that is specifically olfactory-based, indicate that olfactory behavior can indeed provide effective insight into the circuit organization of the brain.…”

Section: Discussionmentioning

confidence: 99%

Olfactory Functions Scale with Circuit Restoration in a Rapidly Reversible Alzheimer's Disease Model

Cheng

Bai

Steuer

et al. 2013

Journal of Neuroscience

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Neural circuits maintain a precise organization that is vital for normal brain functions and behaviors, but become disrupted during neurological disease. Understanding the connection between wiring accuracy and function to measure disease progression or recovery has been difficult because of the complexity of behavioral circuits. The olfactory system maintains well-defined neural connections that regenerate throughout life. We previously established a reversible in vivo model of Alzheimer's disease by overexpressing a humanized mutated amyloid precursor protein (hAPP) in olfactory sensory neurons (OSNs). Using this model, we currently show that hAPP is present in the OSN axons of mutant mice, which exhibit strong caspase3 signal and reduced synaptic protein expression by 3 weeks of age. In the olfactory bulb, we show that glomerular structure is distorted and OSN axonal convergence is lost. In vivo functional imaging experiments further demonstrate disruption of the glomerular circuitry, and behavioral assays reveal that olfactory function is significantly impaired. Because OSNs regenerate, we also tested if the system could recover from hAPP-induced disruption. We found that after 1 or 3 weeks of shutting-off hAPP expression, the glomerular circuit was partially restored both anatomically and functionally, with behavioral deficits similarly reversed. Interestingly, the degree of functional recovery tracked directly with circuit restoration. Together, these data demonstrate that hAPP-induced circuit disruption and subsequent recovery can occur rapidly and that behavior can provide a measure of circuit organization. Thus, olfaction may serve as a useful biomarker to both follow disease progression and gauge potential recovery.

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“…Interestingly, recent studies investigating multiple assay protocols for plasma A β in different laboratories found very good reproducibility of values (Okereke et al 2009). While this has not necessarily been the case for CSF measures (Mattsson et al 2011), a recent ADNI round-robin study of CSF tau and A β showed very good inter-lab reproducibility (Shaw et al 2011). …”

Section: Variables That Affect Plasma Aβmentioning

confidence: 99%

Longitudinal plasma amyloid beta as a biomarker of Alzheimer’s disease

et al. 2012

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Alzheimer’s disease (AD) affects more than twenty-five million people worldwide and is the most common form of dementia. Symptomatic treatments have been developed, but effective intervention to alter disease progression is needed. Targets have been identified for disease-modifying drugs, but the results of clinical trials have been disappointing. Peripheral biomarkers of disease state may improve clinical trial design and analysis, increasing the likelihood of successful drug development. Amyloid-related measures, presumably reflecting principal pathology of AD, are among the leading cerebrospinal fluid and neuroimaging biomarkers, and measurement of plasma levels of amyloid peptides has been the focus of much investigation. In this review, we discuss recent data on plasma β-amyloid (Aβ) and examine the issues that have arisen in establishing it as a reliable biomarker of AD.

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Olfactory copy number association with age at onset of Alzheimer disease

Cited by 38 publications

References 28 publications

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Olfactory Functions Scale with Circuit Restoration in a Rapidly Reversible Alzheimer's Disease Model

Longitudinal plasma amyloid beta as a biomarker of Alzheimer’s disease

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