Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci

Holton, Patrick; Ryten, Mina; Nalls, Michael A.; Trabzuni, Daniah; Weale, Michael E.; Hernandez, Dena G.; Crehan, Helen; Gibbs, J. Raphael; Mayeux, Richard; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak‐Vance, Margaret A.; Schellenberg, Gerard D.; Ramirez-Restrepo, Manuel; Engel, Anzhelika; Myers, Amanda; Corneveaux, Jason J.; Huentelman, Matthew J.; Dillman, Allissa; Cookson, Mark; Reiman, Eric M.; Singleton, Andrew B.; Hardy, John; Guerreiro, Rita

doi:10.1111/ahg.12000

Cited by 46 publications

(43 citation statements)

References 69 publications

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“…Examining the neuropathologic effects (if any) of these genes (and polymorphisms and amino acid changes within them) will be a challenge to neuropathologists. As Holton et al (94) have stated, "Measuring changes in damage induced expression in tissue with changing cell populations and developing rigorous algorithms to interpret such data is problematic." One of the most interesting observations has been that variants in triggering receptor expressed on myeloid cells 2 (TREM2) result in susceptibility to late-onset AD (95,96,97).…”

Section: Figurementioning

confidence: 99%

Emerging Concepts in Alzheimer's Disease

Vinters

2015

Annu. Rev. Pathol. Mech. Dis.

212

145

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Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.

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Section: Figurementioning

confidence: 99%

Emerging Concepts in Alzheimer's Disease

Vinters

2015

Annu. Rev. Pathol. Mech. Dis.

212

145

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“…Recent GWA studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long-established ApoE as loci for AD [39][40][41][42]44].…”

Section: The Genetics Of Admentioning

confidence: 99%

FDG PET and the genetics of dementia

Nacmias

Berti

Piaceri

et al. 2013

Clin Transl Imaging

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Dementias are the most common neurodegenerative diseases and they are increasingly becoming a major public health problem. The most common form of dementia, affecting over 20 million people worldwide, is Alzheimer's disease (AD). AD is a neurodegenerative disease of the central nervous system mainly found in older adults, with an incidence that increases with age. With the development of newer technologies, including genetic screening technologies and PET/MRI scanning, the role of genetic studies and neuroimaging is being redefined; indeed, these approaches are able to provide support not only in the clinical diagnosis of dementia, but also in its presymptomatic evaluation. Many researchers agree that early identification of AD, before abnormal accumulation of amyloid and tau proteins, could provide an opportunity to hinder the progression of the disease. [18 F]2-fluoro-2-deoxy-D-glucose (FDG) PET studies have shown that decreased glucose metabolism in AD precedes clinical diagnosis and that the degree of clinical disability in AD correlates closely with the magnitude of the reduction in brain glucose metabolism. Data on presymptomatic mutation carriers from families with known early-onset autosomal dominant AD (familial AD) show reductions in the cerebral metabolic rate of glucose (CMRglc), consistent with the expected AD PET pattern, in the absence of severe atrophy on MRI. These results suggest that PET CMRglc measures have the potential to serve as preclinical biomarkers of dementia, useful also for tracking disease progression. This review highlights the role of genetics and FDG PET in understanding the pathogenesis of dementia.

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“…However, other than the wellestablished APP, MAPT, APOE, and closely related genes, the role of the vast majority of genes in AD remain unclear. The elucidation of the functional consequence of the genetic variations in the top GWAS genes has also proven to be challenging [5]. In light of the negative outcome of clinical trials with drugs targeting A␤ and tau, it becomes imperative to pursue alternative drug targets [6].…”

Section: Introductionmentioning

confidence: 99%

Robust Gene Dysregulation in Alzheimer's Disease Brains

Feng

Bai

Wang

et al. 2014

JAD

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The brain transcriptome of Alzheimer's disease (AD) reflects the prevailing disease mechanism at the gene expression level. However, thousands of genes have been reported to be dysregulated in AD brains in existing studies, and the consistency or discrepancy among these studies has not been thoroughly examined. Toward this end, we conducted a comprehensive survey of the brain transcriptome datasets for AD and other neurological diseases. We first demonstrated that the frequency of observed dysregulation in AD was highly correlated with the reproducibility of the dysregulation. Based on this observation, we selected 100 genes with the highest frequency of dysregulation to illustrate the core perturbation in AD brains. The dysregulation of these genes was validated in several independent datasets for AD. We further identified 12 genes with strong correlation of gene expression with disease progression. The relevance of these genes to disease progression was also validated in an independent dataset. Interestingly, we found a transcriptional "cushion" for these 100 genes in the less vulnerable visual cortex region, which may be a critical component of the protection mechanism for less vulnerable brain regions. To facilitate the research in this field, we have provided the expression information of ~8000 relevant genes on a publicly accessible web server AlzBIG (http://alz.big.ac.cn).

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Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci

Cited by 46 publications

References 69 publications

Emerging Concepts in Alzheimer's Disease

Emerging Concepts in Alzheimer's Disease

FDG PET and the genetics of dementia

Robust Gene Dysregulation in Alzheimer's Disease Brains

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