Explore the role of CR1 genetic variants in late-onset Alzheimer’s disease susceptibility

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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Investigation on the role of genetic variants of the adaptor protein ARH on traits related to dyslipidemias and late-onset Alzheimer's disease

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/s0939-4753(04)80076-0 ◽

2004 ◽

Vol 14 (5) ◽

pp. 286

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Late Onset ◽

Adaptor Protein

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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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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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Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk

International Journal of Molecular Sciences ◽

10.3390/ijms21218338 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8338

Author(s):

Kimberley D. Bruce ◽

Maoping Tang ◽

Philip Reigan ◽

Robert H. Eckel

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipoprotein Lipase ◽

Genetic Variants ◽

Disease Risk ◽

Lipoprotein Metabolism ◽

Protective Role ◽

Direct Role ◽

The Brain

Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.

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P1-155: ASSOCIATION BETWEEN COMMON GENETIC VARIANTS OF LATE-ONSET ALZHEIMER'S DISEASE AND FAMILY HISTORY OF ALZHEIMER'S DEMENTIA: A PRELIMINARY STUDY

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.159 ◽

2006 ◽

Vol 14 (7S_Part_6) ◽

pp. P336-P336

Author(s):

Min Soo Byun ◽

Jieun Seo ◽

Dahyun Yi ◽

Jun Ho Lee ◽

Younghwa Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Family History ◽

Genetic Variants ◽

Late Onset ◽

Alzheimer’S Dementia ◽

Alzheimer's Dementia ◽

Common Genetic Variants ◽

History Of ◽

Preliminary Study

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Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

International Journal of Molecular Sciences ◽

10.3390/ijms21197079 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7079

Author(s):

Seonggyun Han ◽

Kwangsik Nho ◽

Younghee Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Alternative Splicing ◽

Genetic Variants ◽

Temporal Cortex ◽

Integrative Approach ◽

Splicing Regulation ◽

Rna Seq ◽

Risk Variant

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.

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

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2016.12 ◽

2016 ◽

Vol 18 ◽

Cited By ~ 9

Author(s):

Sonia Moreno-Grau ◽

Agustín Ruiz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Subjective Cognitive Decline ◽

Genetic Profile ◽

Amyloid Deposits ◽

Dementia Risk ◽

Meta Analyses ◽

Brain Insults

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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