Genome research in pre-dementia stages of Alzheimer's disease

Genetic characterization of individuals at risk of Alzheimer's disease (AD), i.e. people having amyloid deposits in the brain without symptoms, people suffering from subjective cognitive decline (SCD) or mild cognitive impairment (MCI), has spurred the interests of researchers. However, their pre-dementia genetic profile remains mostly unexplored. In this study, we reviewed the loci related to phenotypes of AD, MCI and SCD from literature and performed the first meta-analyses evaluating the role of apolipoprotein E (APOE) in the risk of conversion from a healthy status to MCI and SCD. For AD dementia risk, an increased number of loci have been identified; to date, 28 genes have been associated with Late Onset AD. In MCI syndrome,APOEis confirmed as a pheno-conversion factor leading from MCI to AD, and clusterin is a promising candidate. Additionally, our meta-analyses revealedAPOEas genetic risk factor to convert from a healthy status to MCI [OR = 1.849 (1.587–2.153);P = 2.80 × 10−15] and to a lesser extent from healthy status to SCD [OR = 1.151 (1.015–1.304);P = 0.028]. Thus, we believe that genetic studies in longitudinal SCD and MCI series may provide new therapeutic targets and improve the existing knowledge of AD. This type of studies must be completed on healthy subjects to better understand the natural disease resistance to brain insults and neurodegeneration.

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ABCA7—A Member of the ABC Transporter Family in Healthy and Ailing Brain

Brain Sciences ◽

10.3390/brainsci10020121 ◽

2020 ◽

Vol 10 (2) ◽

pp. 121

Author(s):

Alexei A. Surguchev ◽

Andrei Surguchov

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Late Onset ◽

Transporter Family ◽

New Findings ◽

A Cell ◽

Underlying Mechanisms ◽

Meta Analyses

Identification of genetic markers of a human disease, which is generally sporadic, may become an essential tool for the investigation of its molecular mechanisms. The role of ABCA7 in Alzheimer’s disease (AD) was discovered less than ten years ago when meta-analyses provided evidence that rs3764650 is a new AD susceptibility locus. Recent research advances in this locus and new evidence regarding ABCA7 contribution to the AD pathogenesis brought a new understanding of the underlying mechanisms of this disorder. An interesting, up-to-date review article "ABCA7 and Pathogenic Pathways of Alzheimer’s Disease" by Aikawa et al. (2018), outlines the ABCA7 role in AD and summarizes new findings in this exciting area. ABC transporters or ATP-binding cassette transporters are a superfamily of proteins belonging to a cell transport system. Currently, members of the family are the focus of attention because of their central role in drug pharmacokinetics. Two recent findings are the reason why much attention is drawn to the ABCA7 family. First, is the biochemical data showing a role of ABCA7 in amyloid pathology. Second, genetic data identifying ABCA7 gene variants as loci responsible for the late-onset AD. These results point to the ABCA7 as a significant new contributor to the pathogenesis of AD.

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Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

Current Protein and Peptide Science ◽

10.2174/1389203721666200921152246 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1164-1173

Author(s):

Siju Ellickal Narayanan ◽

Nikhila Sekhar ◽

Rajalakshmi Ganesan Rajamma ◽

Akash Marathakam ◽

Abdullah Al Mamun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Early Onset ◽

Late Onset ◽

Precursor Protein ◽

Brain Disorder ◽

Amyloid Aβ ◽

T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

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Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

Translational Psychiatry ◽

10.1038/s41398-021-01218-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hao Hu ◽

Lan Tan ◽

Yan-Lin Bi ◽

Wei Xu ◽

Lin Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Peripheral Blood ◽

Late Onset ◽

Early Stage ◽

Susceptibility Gene ◽

Subjective Cognitive Decline ◽

Preclinical Ad ◽

T Tau ◽

New Evidence

AbstractThe bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

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The Role of Microglia in Sporadic Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201248 ◽

2021 ◽

Vol 79 (3) ◽

pp. 961-968

Author(s):

Wolfgang J. Streit ◽

Habibeh Khoshbouei ◽

Ingo Bechmann

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Genetic Mutations ◽

Sporadic Alzheimer’S Disease ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells ◽

Amyloid Cascade

Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

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Association Study of Genetic Variants inCDKN2A/CDKN2BGenes/Loci with Late-Onset Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/374631 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4

Author(s):

Andrea Tedde ◽

Irene Piaceri ◽

Silvia Bagnoli ◽

Ersilia Lucenteforte ◽

Uwe Ueberham ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Genetic Variant ◽

Case Control Study ◽

Late Onset ◽

Common Genetic Variant ◽

Genome Wide ◽

Control Study

Alzheimer's disease (AD) is the most common form of dementia clinically characterized by progressive impairment of memory and other cognitive functions. Many genetic researches in AD identified one common genetic variant (ε4) in Apolipoprotein E (APOE) gene as a risk factor for the disease. Two independent genome-wide studies demonstrated a new locus on chromosome 9p21.3 implicated in Late-Onset Alzheimer's Disease (LOAD) susceptibility in Caucasians. In the present study, we investigated the role of three SNP's in theCDKN2Agene (rs15515, rs3731246, and rs3731211) and one in theCDKN2Bgene (rs598664) located in 9p21.3 using an association case-control study carried out in a group of Caucasian subjects including 238 LOAD cases and 250 controls. The role ofCDKN2AandCDKN2Bgenetic variants in AD is not confirmed in our LOAD patients, and further studies are needed to elucidate the role of these genes in the susceptibility of AD.

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TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models

Journal of Experimental Medicine ◽

10.1084/jem.20142322 ◽

2015 ◽

Vol 212 (3) ◽

pp. 287-295 ◽

Cited By ~ 333

Author(s):

Taylor R. Jay ◽

Crystal M. Miller ◽

Paul J. Cheng ◽

Leah C. Graham ◽

Shane Bemiller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Risk ◽

Mouse Models ◽

Myeloid Cells ◽

Cell Types ◽

Targeted Therapeutics ◽

Amyloid Deposits ◽

Inflammatory Macrophages

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2’s involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45hiLy6C+ myeloid cells, but not on P2RY12+ parenchymal microglia. In AD mice deficient for TREM2, the CD45hiLy6C+ macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2+ macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.

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