Late-onset Alzheimer's Disease Patients Research Articles

Dysregulated AEBP1 and COLEC12 Genes in Late-Onset Alzheimer's Disease: Insights from Brain Cortex and Peripheral Blood Analysis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive impairment, often accompanied by alterations in mood, confusion, and, ultimately, a state of acute mental disturbance. The cerebral cortex is considered a promising area for investigating the underlying causes of AD by analyzing transcriptional patterns, which could be complemented by investigating blood samples obtained from patients. We analyzed the RNA expression profiles of three distinct areas of the brain cortex, including the frontal cortex (FC), temporal cortex (TC), and entorhinal cortex (EC) in patients with AD. Functional enrichment analysis was performed on the differentially expressed genes (DEGs) across the three regions. The two genes with the most significant expression changes in the EC region were selected for assessing mRNA expression levels in the peripheral blood of late-onset AD patients using quantitative PCR (qPCR). We identified eight shared DEGs in these regions, including AEBP1 and COLEC12, which exhibited prominent changes in expression. Functional enrichment analysis uncovered a significant association of these DEGs with the transforming growth factor-β (TGF-β) signaling pathway and processes related to angiogenesis. Importantly, we established a robust connection between the up-regulation of AEBP1 and COLEC12 in both the brain and peripheral blood. Furthermore, we have demonstrated the potential of AEBP1 and COLEC12 genes as effective diagnostic tools for distinguishing between late-onset AD patients and healthy controls. This study unveils the intricate interplay between AEBP1 and COLEC12 in AD and underscores their potential as markers for disease detection and monitoring.

Comparison of Extracellular Vesicles from Induced Pluripotent Stem Cell-Derived Brain Cells.

The pathophysiology of many neuropsychiatric disorders is still poorly understood. Identification of biomarkers for these diseases could benefit patients due to better classification and stratification. Exosomes excreted into the circulatory system can cross the blood-brain barrier and carry a cell type-specific set of molecules. Thus, exosomes are a source of potential biomarkers for many diseases, including neuropsychiatric disorders. Here, we investigated exosomal proteins produced from human-induced pluripotent stem cells (iPSCs) and iPSC-derived neural stem cells, neural progenitors, neurons, astrocytes, microglia-like cells, and brain capillary endothelial cells. Of the 31 exosome surface markers analyzed, a subset of biomarkers were significantly enriched in astrocytes (CD29, CD44, and CD49e), microglia-like cells (CD44), and neural stem cells (SSEA4). To identify molecular fingerprints associated with disease, circulating exosomes derived from healthy control (HC) individuals were compared against schizophrenia (SCZ) patients and late-onset Alzheimer's disease (LOAD) patients. A significant epitope pattern was identified for LOAD (CD1c and CD2) but not for SCZ compared to HC. Thus, analysis of cell type- and disease-specific exosome signatures of iPSC-derived cell cultures may provide a valuable model system to explore proteomic biomarkers for the identification of novel disease profiles.

Increased Neuronal Nitric Oxide Synthase in Alzheimer's Disease Mediates Spontaneous Calcium Signaling and Divergent Glutamatergic Calcium Responses.

Nitrosative stress is a feature of Alzheimer's disease (AD). Aims: We aimed to identify the cause underpinning increased nitric oxide (NO) in neurons and the impact of NO on neuronal function in AD. Results: We analyzed neuronal nitric oxide synthase (nNOS) protein levels in postmortem tissue and induced pluripotent stem cell (iPSC)-derived neurons from Alzheimer's patients and controls by immunohistochemistry and Western blots. Furthermore, we assessed the impact of modulating nNOS function or NO levels on neuronal glutamatergic signaling using calcium imaging. We show that nNOS protein levels are increased in early and severely affected brain regions of AD postmortem tissue, but not late and mildly affected regions, or cognitively normal individuals. The increased nNOS phenotype was also present in iPSC-derived neurons from late-onset Alzheimer's disease (LOAD) patients compared with controls, along with increased levels of nitrite, a stable marker of NO. Innovation: We observed a divergent functional impact of NO that included strengthening the calcium response in control neurons, while dysregulating calcium signaling and altering the amplitude and kinetics of the calcium responses to glutamate in the AD neurons. Pharmacological scavenging of NO or inhibition of nNOS prevented aberrant spontaneous calcium signaling in AD neurons. Conclusion: Together these data identify increases in nNOS protein in AD. Functional data suggest that NO modulation of glutamatergic calcium signaling is neuroprotective under nonpathogenic conditions, with increased nNOS and NO contributing to dysregulated spontaneous calcium signaling in AD neurons.

Gene expression investigation of four key regulators of polyadenylation and alternative adenylation in the periphery of late-onset Alzheimer's disease patients

BackgroundAlzheimer's disease (AD) is a genetic and sporadic neurodegenerative disease considered by an archetypal cognitive impairment and a decrease in less common cognitive impairment. Notably, the discovery of goals in this paradigm is still a challenge, and understanding basic mechanisms is an important step toward improving disease management. Polyadenylation (PA) and alternative polyadenylation (APA) are two of the most critical RNA processing stages in 3′UTRs that influence various AD-related genes. MethodsIn this study, we assessed Cleavage and polyadenylation specificity factors 1 and 6 (CPSF1 and CPSF6), cleavage stimulation factor 1 (CSTF1), and WD Repeat Domain 33 (WDR33) genes expression in the periphery of 50 AD patients and 50 healthy individuals with age and gender-matched by quantitative real-time PCR. ResultsComparing AD patients with healthy people using expression analysis revealed a substantial increase in CSTF1 (posterior beta = 0.773, adjusted P-value = 0.042). Significant positive correlations were found between CSTF1 and CPSF1 (r = 0.365, P < 0.001), WDR33 (r = 0.506, P < 0.001), and CPSF6 (r = 0.446, P < 0.001) expression levels. ConclusionAlthough further research is required to determine their potential contribution to AD, our findings offer a fresh perspective on molecular regulatory pathways associated with AD pathogenic mechanisms associated with PA and APA.

Effects of copy number variations on longevity in late-onset Alzheimer's disease patients: insights from a causality network analysis.

Alzheimer's disease (AD), particularly late-onset Alzheimer's disease (LOAD), is a prevalent form of dementia that significantly affects patients' cognitive and behavioral capacities and longevity. Although approximately 70 genetic risk factors linked with AD have been identified, their influence on patient longevity remains unclear. Further, recent studies have associated copy number variations (CNVs) with the longevity of healthy individuals and immune-related pathways in AD patients. This study aims to investigate the role of CNVs on the longevity of AD patients by integrating the Whole Genome Sequencing (WGS) and transcriptomics data from the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort through causality network inference. Our comprehensive analysis led to the construction of a CNV-Gene-Age of Death (AOD) causality network. We successfully identified three key CNVs (DEL5006, mCNV14192, and DUP42180) and seven AD-longevity causal genes (PLGRKT, TLR1, PLAU, CALB2, SYTL2, OTOF, and NT5DC1) impacting AD patient longevity, independent of disease severity. This outcome emphasizes the potential role of plasminogen activation and chemotaxis in longevity. We propose several hypotheses regarding the role of identified CNVs and the plasminogen system on patient longevity. However, experimental validation is required to further corroborate these findings and uncover precise mechanisms. Despite these limitations, our study offers promising insights into the genetic influence on AD patient longevity and contributes to paving the way for potential therapeutic interventions.

Neuronal Stem Cells from Late-Onset Alzheimer Patients Show Altered Regulation of Sirtuin 1 Depending on Apolipoprotein E Indicating Disturbed Stem Cell Plasticity.

Late-onset Alzheimer's disease (AD) is a complex multifactorial disease. The greatest known risk factor for late-onset AD is the E4 allele of the apolipoprotein E (APOE), while increasing age is the greatest known non-genetic risk factor. The cell type-specific functions of neural stem cells (NSCs), in particular their stem cell plasticity, remain poorly explored in the context of AD pathology. Here, we describe a new model that employs late-onset AD patient-derived induced pluripotent stem cells (iPSCs) to generate NSCs and to examine the role played by APOE4 in the expression of aging markers such as sirtuin 1 (SIRT1) in comparison to healthy subjects carrying APOE3. The effect of aging was investigated by using iPSC-derived NSCs from old age subjects as healthy matched controls. Transcript and protein analysis revealed that genes were expressed differently in NSCs from late-onset AD patients, e.g., exhibiting reduced autophagy-related protein 7 (ATG7), phosphatase and tensin homolog (PTEN), and fibroblast growth factor 2 (FGF2). Since SIRT1 expression differed between APOE3 and APOE4 NSCs, the suppression of APOE function in NSCs also repressed the expression of SIRT1. However, the forced expression of APOE3 by plasmids did not recover differently expressed genes. The altered aging markers indicate decreased plasticity of NSCs. Our study provides a suitable in vitro model to investigate changes in human NSCs associated with aging, APOE4, and late-onset AD.

Expression analysis of inhibitory B7 family members in Alzheimer's disease.

Alzheimer's disease (AD) is a global health problem due to its complexity, which frequently makes the development of treatment methods extremely difficult. Therefore, new methodologies are necessary to investigate the pathophysiology of AD and to treat AD. The interaction of immune modulation and neurodegeneration has added new dimensions in current knowledge of AD etiology and offers an attractive opportunity for the discovery of novel biomarkers and therapies. Using quantitative polymerase chain reaction, we compared the expression levels of inhibitory B7 family members (B7-1, B7-2, B7-H1, B7-DC, B7-H3, B7-H4, B7-H5, B7-H7, and ILDR2), as immune regulators, in the peripheral blood of late-onset AD (LOAD) patients (n = 50) and healthy individuals (n = 50). The levels of B7-2, B7-H4, ILDR2, and B7-DC expression were significantly higher in-patient blood samples than in control blood samples. Furthermore, we discovered a substantial positive correlation between all gene expression levels. In addition, the current study indicated that ILDR2, B7-H4, B7-2, and B7-DC might serve as diagnostic biomarkers to identify LOAD patients from healthy persons. The present work provides additional evidence for the significance of inhibitory B7 family members to the etiology of LOAD.

Exome sequence analysis of rare frequency variants in Late-Onset Alzheimer Disease

Alzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.

Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key Regulator of Protein Trafficking, a Pathway Underlying Alzheimer's Disease Pathogenesis.

Current treatments for Alzheimer's disease (AD) help reduce symptoms for a limited time but do not treat the underlying pathology. To identify potential therapeutic targets for AD, an integrative network analysis was previously carried out using 364 human postmortem control, mild cognitive impairment, and AD brains. This analysis identified proline endopeptidase-like protein (PREPL), an understudied protein, as a downregulated protein in late-onset AD patients. In this study we investigate the role of PREPL. Analyses of data from human postmortem samples and PREPL knockdown (KD) cells suggest that PREPL expression modulates pathways associated with protein trafficking, synaptic activities, and lipid metabolism. Furthermore, PREPL KD impairs cell proliferation and modulates the structure of vesicles, levels of neuropeptide-processing enzymes, and secretion of neuropeptides. In addition, decrease in PREPL levels leads to changes in the levels of a number of synaptic proteins as well as changes in the levels of secreted amyloid beta (Aβ) 42 peptide and Tau phosphorylation. Finally, we report that local decrease in PREPL levels in mouse hippocampus attenuates long-term potentiation, suggesting a role in synaptic plasticity. Together, our results indicate that PREPL affects neuronal function by modulating protein trafficking and synaptic function, an important mechanism of AD pathogenesis. SIGNIFICANCE STATEMENT: Integrative network analysis reveals proline endopeptidase-like protein (PREPL) to be downregulated in human sporadic late-onset Alzheimer's disease brains. Down regulation of PREPL leads to increases in amyloid beta secretion, Tau phosphorylation, and decreases in protein trafficking and long-term potentiation.

MMP2 rs243866 and rs2285053 Polymorphisms and Alzheimer's Disease Risk in Slovak Caucasian Population.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterised by progressive loss of memory. In the AD brain, matrix metalloproteinases (MMPs) are involved in the disruption of the blood-brain barrier resulting in a neuroinflammatory response. The objective of our investigation was to assess the association of MMP2 rs243866 and rs2285053 polymorphisms with susceptibility to AD, to assess the interaction of MMP2 variants with APOE ε4 risk allele, and to evaluate their influence on the age at disease onset and MoCA score. A total of 215 late-onset AD patients and 373 control subjects from Slovakia were genotyped for MMP2 rs243866 and rs2285053 polymorphisms. The MMP2 association with AD risk and clinical parameters was evaluated by logistic and linear regression analyses. No statistically significant differences in either MMP2 rs243866 and rs2285053 allele or genotype frequencies between AD patients and the control group have been observed (p > 0.05). However, the correlation with clinical findings revealed a higher age at disease onset in MMP2 rs243866 GG carriers in the dominant model as compared to other MMP2 genotype carriers (p = 0.024). Our results suggest that MMP2 rs243866 promoter polymorphism may have an impact on the age at AD onset in the patients.

Hyperconnectivity matters in early-onset Alzheimer's disease: a resting-state EEG connectivity study

ObjectivesThe aim of this study was to differentiate individuals with early-onset Alzheimer's disease (EOAD) and identify differences of functional connectivity in resting-state EEG between individuals with EOAD and late-onset AD (LOAD) in comparison with both healthy young and elderly individuals. MethodsForty EOAD and 56 LOAD patients were included along with 51 demographically matched young, and 54 elderly healthy individuals as controls to the EOAD and LOAD groups. Four minutes of resting-state EEG were recorded during the eyes-closed condition. The absolute value of imaginary coherence (ICoh) was measured for connectivity. The maximum values of ICoh were measured at delta (0.5-3.5 Hz), theta (4-7.5Hz), alpha (8-13 Hz), alpha-1 (8-10 Hz), alpha-2 (10.5-13 Hz), beta (13-30 Hz), beta-1 (13-20 Hz), and beta-2 (20.5-30 Hz) frequency bands. ResultsIndividuals with EOAD showed higher coherence values in all frequency bands than LOAD patients. Compared to young healthy controls (YHC), EOAD had increased ICoh values in theta and beta-2 bands, whereas LOAD had lower ICoh values in the alpha-1 band than elderly healthy controls (EHC). Lastly, patients with EOAD demonstrated negative moderate correlations between language domains and beta-1 ICoh values. ConclusionTo the authors’ knowledge, this is the first study evaluating coherence alterations among early-and late-onset AD patients and the diagnostic value of coherence measures. It was suggested that EOAD patients had more severe pathological changes compared with LOAD.

A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer's Disease.

In the current study, for the first time, we study mitophagy enhancer urolithin A and a combination of urolithin A+green tea extract EGCG against human Aβ peptide-induced mitochondrial and synaptic, dendritic, inflammatory toxicities and behavioral changes in humanized homozygous amyloid beta knockin (hAbKI) mice of late-onset Alzheimer’s disease (AD). Our findings reveal significantly increased positive effects of urolithin A and a combination treatment of urolithin A+EGCG in hAbKI mice for phenotypic behavioral changes including motor coordination, locomotion/exploratory activity, spatial learning and working memory. mRNA and protein levels of mitochondrial fusion, synaptic, mitophagy and autophagy genes were upregulated, and mitochondrial fission genes are downregulated in urolithin A and combine treatment in hAbKI mice; however, the effect is stronger in combined treatment. Immunofluorescence analysis of hippocampal brain sections shows similar findings of mRNA and protein levels. Mitochondrial dysfunction is significantly reduced in both treatment groups, but a stronger reduction is observed in combined treatment. Dendritic spines and lengths are significantly increased in both treatment groups, but the effect is stronger in combined treatment. The fragmented number of mitochondria is reduced, and mitochondrial length is increased, and mitophagosomal formations are increased in both the groups, but the effect is stronger in the combined treatment. The levels of amyloid beta (Aβ) 40 and Aβ42 are reduced in both treatments, however, the reduction is higher for combined treatment. These observations suggest that urolithin A is protective against human Aβ peptide-induced toxicities; however, combined treatment of urolithin A+EGCG is effective and stronger, indicating that combined therapy is promising to treat late-onset AD patients.

TREM2 coding variants in Slovak Alzheimer's disease patients.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an important modulator of innate immune responses. In the human brain, TREM2 is primarily expressed on microglia and is involved in cell survival, phagocytosis, and regulation of inflammation. TREM2 dysfunction has been linked to the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Rare coding variants of the TREM2 gene have been reported to modulate AD risk in several populations, however, data on their association with susceptibility to AD in the Slovak population have been missing. We have analyzed 10 non-synonymous coding variants located in TREM2 exon 2 by direct sequencing in 270 late-onset Alzheimer's disease (LOAD) patients and 331 controls. Four out of 10 TREM2 mutant variants have been identified in the analyzed groups, namely rs75932628 C > T (R47H), rs142232675 C > T (D87N), rs143332484 C > T (R62H), and rs2234253 G > T (T96K). R47H was found only in the AD group, while T96K was present only in the controls. Although no significant association between TREM2 coding variants and LOAD susceptibility has been detected, the observed odds ratio (OR) of 3.69 for R47H carriers suggests an increased risk of LOAD for this variant in the Slovak population. Moreover, we also found a higher OR for the rs143332484-T allele in APOEε4 non-carriers (1.99) when compared to APOEε4 carriers (0.62). Our results suggest an impact of specific TREM2 rare coding variants on AD risk in the Slovak population.

5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease.

5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

A Linguistic Profile of Narrative Speech in Early and Late-Onset Alzheimer’s Disease

Objective. Alzheimer’s Dementia is defined as multiple impairments in cognitive functions and language impairment is one of the observed problems in this disease. In order to analyse these problems, narrative speech transcriptions of Turkish patients with early and late-onset Alzheimer’s Disease (AD) and an age/education-matched control group were examined.&#x0D; Materials &amp; Methods. By using different language tests, the sentence production of Turkish patients with early (n: 23) and late-onset (n: 39) was examined and the results were compared within groups and within language tests. Our aim was to reveal the differences in sentence processing of Turkish Alzheimer patients. &#x0D; Results. According to the results, Turkish Alzheimer patients use short and simple sentences composed of fewer words in their speech. It was determined that these patients performed better in Picnic Picture Description test, which is thought to be easy to describe. In Cookie Theft Picture Description test, which is a complex one, and in the Subject-based Narration test, it was found that the speech amounts of AD patients were less. It was revealed that early-onset AD patients used shorter sentences including fewer words compared to late-onset AD patients. &#x0D; Conclusion. In the light of the data obtained, it can be said that AD patients have different sentence processing than normal individuals because of the problems in the language and memory areas of the disease. The fact that sentence processing is different means that these patients do not prefer the types of sentences that normal individuals prefer in their speeches, and use less words and simpler sentences.

A linguistic profile of narrative speech in early and late Alzheimer's disease

Objective. Alzheimer’s Dementia is defined as multiple impairments in cognitive functions and language impairment is one of the observed problems in this disease. In order to analyse these problems, narrative speech transcriptions of Turkish patients with early and late-onset Alzheimer’s Disease (AD) and an age/education-matched control group were examined. Materials & Methods. By using different language tests, the sentence production of Turkish patients with early (n: 23) and late-onset (n: 39) was examined and the results were compared within groups and within language tests. Our aim was to reveal the differences in sentence processing of Turkish Alzheimer patients. Results. According to the results, Turkish Alzheimer patients use short and simple sentences composed of fewer words in their speech. It was determined that these patients performed better in Picnic Picture Description test, which is thought to be easy to describe. In Cookie Theft Picture Description test, which is a complex one, and in the Subject-based Narration test, it was found that the speech amounts of AD patients were less. It was revealed that early-onset AD patients used shorter sentences including fewer words compared to late-onset AD patients. Conclusion. In the light of the data obtained, it can be said that AD patients have different sentence processing than normal individuals because of the problems in the language and memory areas of the disease. The fact that sentence processing is different means that these patients do not prefer the types of sentences that normal individuals prefer in their speeches, and use less words and simpler sentences.

Estimating the X chromosome-mediated risk for developing Alzheimer's disease.

Parental lineage has been shown to increase the risk of Alzheimer's disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci have been linked to the risk of developing AD, none has been found on the X chromosome. We propose a new method to estimate the risk for developing AD mediated by the X chromosome in a subgroup of late-onset AD (LOAD) patients with amnestic mild cognitive impairment (aMCI) or early AD and unilateral ancestral history of AD or dementia, and pilot-test it on our clinic data. Records of patients aged 55-80years presenting to our Memory Disorders Clinic with aMCI or early AD between May 2015 and September 2020, were reviewed, counting patients with a family history of AD or dementia and unilateral ancestral lineage. The X chromosome-attributable relative risk was estimated by calculating the following odds ratio (OR): (women with paternal lineage:women with maternal lineage)/(men with paternal lineage:men with maternal lineage). The proportion of genetic risk borne by the X chromosome is equal to (OR-1)/OR. 40 women aged 66.1 ± 5.1years (mean ± standard deviation) and 31 men aged 68.1 ± 6.5 were identified. The OR was (18:22)/(6:25) = 3.4 (95% confidence interval 1.1-10.1; p = 0.027). The estimated proportion of genetic risk borne by the X chromosome in this population is 70% (95% CI 12-90%). This paper presents the first application of a new method. The numbers are small, the confidence intervals wide. The findings need to be replicated. The method may be generalizable to other diseases.

Premature termination codon mutations in ABCA7 contribute to Alzheimer's disease risk in Belgian patients

The ATP-Binding Cassette Subfamily A Member 7 gene (ABCA7) was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies of large cohorts of late-onset AD (LOAD) patients. Extended resequencing of the ABCA7 coding regions identified mutations that lead to premature termination codons (PTC) and loss of function of ABCA7. PTC mutations were enriched in LOAD patients and were frequently present in patients with early-onset AD (EOAD). We aimed at assessing the contribution of ABCA7 PTC mutations to AD in the Belgian population by screening the ABCA7 coding region in a Belgian AD cohort of 1376 patients, including LOAD and EOAD patients, and in a Belgian control cohort of 976 individuals. We identified a PTC mutation in 67 AD patients (4.9%) and in 18 control individuals (1.8%) confirming the enrichment of ABCA7 PTC mutations in Belgian AD patients. The patient carriers had a mean onset age of 69.7 ± 9.8 years with a wide onset age range of 42 years (48–90 years). In 77.3% of the families of ABCA7 carriers, there were AD patients present suggestive of a positive family history of disease, but a Mendelian co-segregation of ABCA7 PTC mutations with disease is not clear. Overall, our genetic data predict that PTC mutations in ABCA7 are common in the Belgian population and are present in LOAD and EOAD patients.

Effects of APOE, ACE, PICALM, and CYP2D6 Gene Variants on Alzheimer's Disease

Background: Alzheimer’s disease is a multifactorial, neurodegenerative disease which is considered the most common cause of dementia. It is divided into two subtypes based on the age of onset: Early-Onset Alzheimer’s Disease (EOAD) and Late-Onset Alzheimer’s Disease (LOAD). Objective: In this study, we aimed to analyse the polymorphisms of APOE2/E3/E4, ACE I/D, PICALM rs3851179, which are thought to increase the risk of disease, and CYP2D6 rs1080985, that affects the therapy response. Methods: 102 early onset and 99 late onset Alzheimer's patients diagnosed according to DSM-IV and NINCDS-ADRDA diagnostic criteria were included in the study. MMSE test was applied at the time of diagnosis and the control examination was performed after 6 months. We analysed the polymorphisms of APOE2/E3/E4 by fragment analysis and ACE I/D, PICALM rs3851179, CYP2D6 rs1080985 by Real Time- PCR. The response of the therapy and effects on prognosis were compared between groups by Mini-Mental State Exam test scores. Results: The score differences of the women were significantly lower than men’s score differences. The score differences of the EOAD group were significantly lower than the LOAD group in women. Family history situation was higher in men compared to women. The score differences were higher at CC genotype for PICALM rs3851179 in the EOAD group; the score differences were higher at E3/E4 genotype than E2/E2 genotype in LOAD. Also, the score differences were significantly higher at PICALM rs3851179 in the acetylcholinesterase inhibitor+antidepressant therapy group. Conclusions: The relationship between the treatment groups and related gene regions was investigated extensively for the first time in the literature. As a result, it will be a guide in the clinic in light of the findings of the prognosis and pharmacogenetic interactions of the disease obtained from the study.

Genetic effect of MTHFR C677T, A1298C, and A1793G polymorphisms on the age at onset, plasma homocysteine, and white matter lesions in Alzheimer's disease in the Chinese population.

Background: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population.Method: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients.Results: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls (P = 0.040), while no statistical difference was observed in A1298C and A1793G (P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls (P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers (P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers (P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level (P = 0.036) and higher Fazekas score (P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score (P = 0.013).Conclusions: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.