Polymorphic Genetic Markers of the GABA Catabolism Pathway in Alzheimer’s Disease

2020 ◽  
Vol 77 (1) ◽  
pp. 301-311
Author(s):  
Bianca Maria Ciminelli ◽  
Giovanna Menduti ◽  
Luisa Benussi ◽  
Roberta Ghidoni ◽  
Giuliano Binetti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age At Onset ◽  
Apoe Genotype ◽  
Degradation Pathway ◽  
Research Field ◽  
Genetic Modifiers ◽  
Phenotype Analysis ◽  
The Individual ◽  
Catabolism Pathway

Background: The compilation of a list of genetic modifiers in Alzheimer’s disease (AD) is an open research field. The GABAergic system is affected in several neurological disorders but its role in AD is largely understudied. Objective/Methods: As an explorative study, we considered variants in genes of GABA catabolism (ABAT, ALDH5A1, AKR7A2), and APOE in 300 Italian patients and 299 controls. We introduce a recent multivariate method to take into account the individual APOE genotype, thus controlling for the effect of the discrepant allele distributions in cases versus controls. We add a genotype-phenotype analysis based on age at onset and the Mini-Mental State Evaluation score. Results: On the background of strongly divergent APOE allele distributions in AD versus controls, two genotypic interactions that represented a subtle but significant peculiarity of the AD cohort emerged. The first is between ABAT and APOE, and the second between some ALDH5A1 genotypes and APOE. Decreased SSADH activity is predicted in AD carriers of APOE ɛ4, representing an additional suggestion for increased oxidative damage. Conclusion: We identified a difference between AD and controls, not in a shift of the allele frequencies at genes of the GABA catabolism pathway, but rather in gene interactions peculiar of the AD cohort. The emerging view is that of a multifactorial contribution to the disease, with a main risk factor (APOE), and additional contributions by the variants here considered. We consider genes of the GABA degradation pathway good candidates as modifiers of AD, contributing to energy impairment in AD brain.

scholarly journals The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

2019 ◽  
Vol 11 (505) ◽  
pp. eaau2291 ◽  
Author(s):  
Yuetiva Deming ◽  
Fabia Filipello ◽  
Francesca Cignarella ◽  
Claudia Cantoni ◽  
Simon Hsu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Critical Role ◽  
Age At Onset ◽  
Mechanistic Explanation ◽  
Genetic Modifiers ◽  
A Genome

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer’s Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10−15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

scholarly journals The National Institute on Aging Late Onset Alzheimer's Disease Family Based Study: A Critical Component of the International Effort to Understand Alzheimer's Disease

2021 ◽  
Author(s):  
Dolly Reyes-Dumeyer ◽  
Kelley Faber ◽  
Badri N. Vardarajan ◽  
Alison Goate ◽  
Alan Renton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Age At Onset ◽  
Apoe Genotype ◽  
Alzheimers Disease ◽  
Genetic Etiology ◽  
Wide Range ◽  
Family Based ◽  
Disease Family

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimers Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimers disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained as was neuropathology, when possible. APOE genotypes, genome-wide SNP arrays and sequencing was completed in the majority of families. RESULTS: A wide range in the age-at-onset in many large families was related to APOE genotype, but not in all. Variants typically associated with early-onset AD and frontotemporal dementia were also found. DISCUSSION: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 126 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.

Most rapid cognitive decline in APOE ε4 negative Alzheimer's disease with early onset

2009 ◽  
Vol 39 (11) ◽  
pp. 1907-1911 ◽  
Author(s):  
A. E. van der Vlies ◽  
E. L. G. E. Koedam ◽  
Y. A. L. Pijnenburg ◽  
J. W. R. Twisk ◽  
P. Scheltens ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Early Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Apoe Genotype ◽  
Apoe Ε4 ◽  
Rapid Cognitive Decline ◽  
State Examination

BackgroundWe aimed to compare the rate of cognitive decline in patients with early and late onset Alzheimer's disease (AD) and to investigate the potentially modifying influence of the apolipoprotein E (APOE) genotype.MethodWe included 99 patients with early onset AD (age ⩽65 years) and 192 patients with late onset AD (age >65 years) who had at least two scores on the Mini-Mental State Examination (MMSE) (range 2–14) obtained at least 1 year apart. Linear mixed models were performed to investigate the rate of cognitive decline dependent on age at onset (AAO) and APOE genotype.ResultsThe mean (s.d.) age for patients with early onset AD was 57.7 (4.5) years, and 74.5 (5.1) years for patients with late onset AD. AAO was not associated with baseline MMSE [β (s.e.)=0.8 (0.5), p=0.14]. However, patients with early onset showed a faster decline on the MMSE [β (s.e.)=2.4 (0.1) points/year] than those with late onset [β (s.e.)=1.7 (0.1) points/year, p=0.00]. After stratification according to APOE genotype, APOE ε4 non-carriers with early onset showed faster cognitive decline than non-carriers with late onset [2.4 (0.3) v. 1.3 (0.3) points/year, p=0.01]. In APOE ε4 carriers, no difference in rate of cognitive decline was found between patients with early and late onset [β (s.e.)=0.2 (0.2), p=0.47].ConclusionPatients with early onset AD show more rapid cognitive decline than patients with late onset, suggesting that early onset AD follows a more aggressive course. Furthermore, this effect seems to be most prominent in patients with early onset who do not carry the genetic APOE ε4 risk factor for AD.

scholarly journals Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures

2021 ◽  
Author(s):  
Sebastian Palmqvist ◽  
Pontus Tideman ◽  
Nicholas Cullen ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apoe Genotype ◽  
Subjective Cognitive Decline ◽  
Cognitive Tests ◽  
Neurofilament Light ◽  
Logistic Regression Models ◽  
Individual Probability ◽  
Lower Accuracy ◽  
The Individual

Abstract A combination of plasma phospho-tau (P-tau) and other accessible biomarkers may provide accurate prediction about the risk of developing Alzheimer’s disease (AD) dementia. We examined this in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) who were consecutively recruited in the BioFINDER study (n=340). The results were validated in SCD/MCI participants in the ADNI study (n=543). Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and MRI (cortical thickness in AD-specific regions) were examined as predictors of progression to AD dementia primarily within 4 years. The accuracy was determined using the area under the ROC curve (AUC) from logistic regression models. Within 4 years, plasma P-tau217 predicted AD dementia accurately (AUC 0.83) in BioFINDER. A model of plasma P-tau217, memory, executive function, and APOE had higher accuracy (AUC 0.91, p<0.001). In ADNI, this model produced a similar AUC (0.90) using plasma P-tau181 instead of P-tau217. A cross-validated version of this model was implemented online for prediction of the individual probability of progressing to AD dementia. Within 2 and 6 years, parsimonious models performed similar in both cohorts (AUCs 0.90-0.91). Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy. The clinical prediction by memory clinic physicians had significantly lower accuracy than all models (4-year AUC 0.71). In summary, plasma P-tau in combination with brief cognitive tests and APOE genotyping may greatly improve the diagnostic prediction of AD dementia and facilitate recruitment for AD trials.

Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021 ◽  
pp. 1-10
Author(s):  
Wei Qin ◽  
Wenwen Li ◽  
Qi Wang ◽  
Min Gong ◽  
Tingting Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Black People ◽  
Late Onset ◽  
Meta Analysis ◽  
Group Analysis ◽  
Apoe Genotype ◽  
Cochrane Library ◽  
Data Sets ◽  
Apoe Genotypes

Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ɛ4 was a risk factor for AD, whereas APOE ɛ2 protected against it. The effects of APOE ɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ɛ4/ɛ4 and lower frequency of APOE ɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

scholarly journals Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

2021 ◽  
Vol 5 (1) ◽  
pp. 49-53
Author(s):  
Steven Lehrer ◽  
Peter H. Rheinstein
Keyword(s):  
Breast Cancer ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apoe Genotype ◽  
Uk Biobank ◽  
Breast Cancer Patients ◽  
Apoe4 Allele ◽  
Significant Difference ◽  
The Uk ◽  
Cognitive Problems

Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.

scholarly journals The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study

2019 ◽  
Vol 216 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Audun Osland Vik-Mo ◽  
Lasse Melvaer Giil ◽  
Miguel Germán Borda ◽  
Clive Ballard ◽  
Dag Aarsland
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuropsychiatric Symptoms ◽  
Personalised Medicine ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Psychotic Symptoms ◽  
Primary Inclusion ◽  
The Individual

IntroductionUnderstanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.MethodPrimary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).ResultsWe found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.ConclusionsWe observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

ApoE genotype and familial Alzheimer's disease: a possible influence on age of onset in APP717 Val → Ile mutated families

1995 ◽  
Vol 183 (1-2) ◽  
pp. 1-3 ◽  
Author(s):  
Benedetta Nacmias ◽  
Stefania Latorraca ◽  
Patrizia Piersanti ◽  
Paolo Forleo ◽  
Silvia Piacentini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Apoe Genotype ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease
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