<Emphasis Type="Bold">Personal Genomic Testing,Genetic Inheritance,and Uncertainty</Emphasis>

The case outlined below is the basis for the In That Case section of the “Ethics and Epistemology of Big Data” symposium. Jordan receives reports from two separate personal genomic tests that provide intriguing data about ancestry and worrying but ambiguous data about the potential risk of developing Alzheimer’s disease. What began as a personal curiosity about genetic inheritance turns into an alarming situation of medical uncertainty. Questions about Jordan’s family tree are overshadowed by even more questions about Alzheimer’s disease and healthy ageing. As a parent, Jordan is unsure whether to share these results and what it would mean for their children to learn about their genetic inheritance and potential future health. Furthermore, Jordan is unsure how to make sense of these reports in light of current knowledge of the risk factors for Alzheimer’s disease and in the absence of effective treatments or robust preventative guidelines.     

Controlling futures? Online Genetic Testing and Neurodegenerative Disease

Online personalized genetic testing services offer accessible and convenient options for satisfying personal curiosity about health and obtaining answers about one’s genetic provenance. They are especially attractive to healthy people who wish to learn about their future risk of disease, as Paul Mason’s (2017) case study of “Jordan” illustrates. In this response, we consider how online genetic testing services are used by people diagnosed with a common neurodegenerative disease, Parkinson’s disease, to gain a sense of certainty regarding the future.     

Alzheimer’s Disease is an Important Risk Factor of Fractures: a Meta-analysis of Cohort Studies

The risk of fracture in individuals with Alzheimer’s disease had not been fully quantified. A systematic review and meta-analysis of cohort studies was performed to estimate the impact of Alzheimer’s disease on risk of fractures. Pubmed and Embase were searched for eligible cohort studies assessing the association between Alzheimer’s disease and risk of fractures. The overall relative risks (RRs) with 95% CIs were calculated using a random-effects model to evaluate the association. Six cohort studies with a total of 137,986 participants were included into the meta-analysis. Meta-analysis of a total of six studies showed that Alzheimer’s disease was significantly associated with two-fold increased risk of fractures (RR?=?2.18, 95 % CI 1.64–2.90, P?<?0.001; I ²?=?91.4 %). Meta-regression analysis showed that type of fractures was a source of heterogeneity (P?=?0.003). Meta-analysis of five studies on hip fracture showed that Alzheimer’s disease was significantly associated with 2.5-fold increased risk of hip fracture (RR?=?2.52, 95 % CI 2.26–2.81, P?<?0.001; I ²?=?25.2 %). There was no risk of publication bias observed in the funnel plot. There is strong evidence that Alzheimer’s disease is a risk factor of hip fracture.     

Toepassing van stemmingsvragenlijsten bij ouderen met alzheimerdementie (met of zonder taalstoornis) en hun informanten

Introduction

Alzheimer’s Dementia (AD) may be associated with symptoms of depression. In AD, problems of language expression or understanding will arise sooner or later. The aim of this study was to determine whether elderly persons with AD, with or without a language disorder, experience difficulties understanding and answering mood related questions. In addition to this, it was our object to test the validity of the answers of nurses as informants, on the mood of an elderly client.

Methods

53 elderly persons, living in care homes, and their nurses, took part in the study. 25 participants had been diagnosed with Alzheimer’s disease, 28 participants had no cognitive impairment. Language skills were tested using the SAN-test (Stichting Afasie Nederland) and subtests of the Aachen Aphasia Test (AAT). Mood was assessed with the Beck Depression Inventory-second edition (BDI-II-NL) and the Geriatric Depression Scale (GDS-30).

Results

There were no significant differences in scores on the mood related questionnaires between participants without cognitive impairment and participants with Alzheimer’s disease, with or without a language disorder. The correlation between self- and informant-rating was very limited. In general, nurses reported more depressive symptoms than the elderly persons did themselves. Disparities between self- and informant-ratings varied from informant scores overestimating low self-ratings of depression to informant scores underestimating high self-ratings.

Conclusion

Alzheimer’s disease, whether or not it is complicated by a language disorder, does not disturb the normal score distribution on either test (BDI or GDS). This means that elderly persons with Alzheimer’s disease are capable of adequately answering questions related to their own mood. However, considerable discrepancies were found between observer- and self-ratings of emotional wellbeing. Therefore it is important to not only take into account the information of an informant when testing for depression, but also the elderly person’s own assessment of their mood.

     

Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography

Late-onset Alzheimer’s disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer’s disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD’s genetic etiology. Subsets of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid–calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.     

老年痴呆的遗传机制研究进展

老年痴呆症,又称阿尔茨海默病(Alzheimer’s disease,AD),是威胁老年人健康的主要疾病之一。根据发病年龄,AD可分为早发性(early-onset Alzheimer’s disease,EOAD)和迟发性(late-onset Alzheimer’s disease,LOAD)两种,两者均受到遗传因素的影响。目前已知3个致病基因导致家族性EOAD的发病:淀粉样前体蛋白基因(β-amyloid precursor protein,APP)、早老素1基因(presenilin 1,PSEN1)和早老素2基因(presenilin 2,PSEN2)。而近年来在全基因组关联分析(genome-wide association study,GWAS)等新技术的支持下,研究者相继发现并报道了一系列影响LOAD易感性的风险基因多态性位点。试对上述AD相关致病基因和主要风险基因加以简要介绍,深入探索这些基因的功能有助于对AD病理生理机制的认知。     

SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer’s disease

Background

Synaptic degeneration is an early pathogenic event in Alzheimer’s disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples.

Results

We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer’s disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer’s disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer’s disease from controls with area under the curve of 0.901 (P?<?0.0001).

Conclusions

We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.

     

Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila

Alzheimer’s disease (AD) pathogenesis is characterized by senile plaques in the brain and evidence of oxidative damage. Oxidative stress may precede plaque formation in AD; however, the link between oxidative damage and plaque formation remains unknown. Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation and early-onset familial Alzheimer’s disease. Presenilins physically interact with two antioxidant enzymes thiol-specific antioxidant (TSA) and proliferation-associated gene (PAG) of the peroxiredoxin family. The functional consequences of these interactions are unclear. In the current study we expressed a presenilin transgene in Drosophila wing and sensory organ precursors of the fly. This caused phenotypes typical of Notch signaling loss-of-function mutations. We found that while expression of TSA or PAG alone produced no phenotype, co-expression of TSA and PAG with presenilin led to an enhanced Notch loss-of-function phenotype. This phenotype was more severe and more penetrant than that caused by the expression of Psn alone. In order to determine whether these phenotypes were indeed affecting Notch signaling, this experiment was performed in a genetic background carrying an activated Notch (Abruptex) allele. The phenotypes were almost completely rescued by this activated Notch allele. These results link peroxiredoxins with the in vivo function of Presenilin, which ultimately connects two key pathogenetic mechanisms in AD, namely, antioxidant activity and plaque formation, and raises the possibility of a role for peroxiredoxin family members in Alzheimer’s pathogenesis.     

Optimising multistage dairy cattle breeding schemes including genomic selection using decorrelated or optimum selection indices

Background

The prediction of the outcomes from multistage breeding schemes is especially important for the introduction of genomic selection in dairy cattle. Decorrelated selection indices can be used for the optimisation of such breeding schemes. However, they decrease the accuracy of estimated breeding values and, therefore, the genetic gain to an unforeseeable extent and have not been applied to breeding schemes with different generation intervals and selection intensities in each selection path.

Methods

A grid search was applied in order to identify optimum breeding plans to maximise the genetic gain per year in a multistage, multipath dairy cattle breeding program. In this program, different values of the accuracy of estimated genomic breeding values and of their costs per individual were applied, whereby the total breeding costs were restricted. Both decorrelated indices and optimum selection indices were used together with fast multidimensional integration algorithms to produce results.

Results

In comparison to optimum indices, the genetic gain with decorrelated indices was up to 40% less and the proportion of individuals undergoing genomic selection was different. Additionally, the interaction between selection paths was counter-intuitive and difficult to interpret. Independent of using decorrelated or optimum selection indices, genomic selection replaced traditional progeny testing when maximising the genetic gain per year, as long as the accuracy of estimated genomic breeding values was ≥ 0.45. Overall breeding costs were mainly generated in the path "dam-sire". Selecting males was still the main source of genetic gain per year.

Conclusion

Decorrelated selection indices should not be used because of misleading results and the availability of accurate and fast algorithms for exact multidimensional integration. Genomic selection is the method of choice when maximising the genetic gain per year but genotyping females may not allow for a reduction in overall breeding costs. Furthermore, the economic justification of genotyping females remains questionable.     

Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy

Background

Biotin-thiamine responsive basal ganglia disease is a severe, but potentially treatable disorder caused by mutations in the SLC19A3 gene. Although the disease is inherited in an autosomal recessive manner, patients with typical phenotypes carrying single heterozygous mutations have been reported. This makes the diagnosis uncertain and may delay treatment.

Methods and Results

In two siblings with early-onset encephalopathy dystonia and epilepsy, whole-exome sequencing revealed a novel single heterozygous SLC19A3 mutation (c.337T>C). Although Sanger-sequencing and copy-number analysis revealed no other aberrations, RNA-sequencing in brain tissue suggested the second allele was silenced. Whole-genome sequencing resolved the genetic defect by revealing a novel 45,049 bp deletion in the 5’-UTR region of the gene abolishing the promoter. High dose thiamine and biotin therapy was started in the surviving sibling who remains stable. In another patient two novel compound heterozygous SLC19A3 mutations were found. He improved substantially on thiamine and biotin therapy.

Conclusions

We show that large genomic deletions occur in the regulatory region of SLC19A3 and should be considered in genetic testing. Moreover, our study highlights the power of whole-genome sequencing as a diagnostic tool for rare genetic disorders across a wide spectrum of mutations including non-coding large genomic rearrangements.     

PICALM rs3851179 Variant Confers Susceptibility to Alzheimer’s Disease in Chinese Population

The association between PICALM rs3851179 variant and Alzheimer’s disease (AD) has been well established by previous genome-wide association studies (GWAS) and candidate gene studies in European population. Recent studies investigated the association between PICALM rs3851179 and AD susceptibility in Chinese population. However, these studies reported consistent and inconsistent results. Here, we selected 9435 samples including 3704 AD cases and 5731 controls from previous studies and evaluated this association using a meta-analysis method for additive model. We did not observe significant genetic heterogeneity in Chinese population. Our results indicate significant association between PICALM rs3851179 and AD in Chinese population. The sensitivity analysis indicates that the association between rs3851179 and AD did not vary substantially. The regression analysis suggests no significant publication bias. In summary, this updated meta-analysis highlights the involvement of PICALM rs3851179 variant in Alzheimer’s disease susceptibility in Chinese population.     

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease

Background

Neuronal Ca²⁺ dyshomeostasis and hyperactivity play a central role in Alzheimer’s disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer’s disease contributes to increased Ca²⁺ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca²⁺ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential.

Methods

Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca²⁺ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer’s disease.

Results

The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca²⁺ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders.

Conclusion

Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer’s disease.

     

The DRD2 <Emphasis Type="Italic">Taq1A A1</Emphasis> Allele May Magnify the Risk of Alzheimer’s in Aging African-Americans

Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer’s; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer’s disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer’s in aging African-Americans. Research linking this high risk for Alzheimer’s in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.     

Amyloid-beta peptide decreases expression and function of glutamate transporters in nervous system cells

Glutamate is an essential excitatory neurotransmitter that regulates brain functions, and its activity is tightly regulated by glutamate transporters. Excess glutamate in the synaptic cleft and dysfunction of excitatory amino acid transporters have been shown to be involved in development of Alzheimer’s disease, but the precise regulatory mechanism is poorly understood. Using a D-[³H]-aspartic acid uptake assay, we found that Aβ_1-42 oligomers impaired glutamate uptake in astrocytes and neurons. In astrocytes, this process was accompanied by reduced expression of GLT-1 and GLAST as detected by Western blot and immunocytofluorescence. However, mRNA levels of EAATs detected by qPCR in astrocytes and neurons were not altered, which suggests that this process is post-translational. Co-localization analysis using immunocytofluorescence showed that ubiquitylation of GLT-1 significantly increased. Therefore, we hypothesized that Aβ_1-42 oligomers-induced endocytosis of astrocytic GLT-1 may be involved in ubiquitylation. In addition, Aβ_1-42 oligomers enhanced secretion of IL-1β, TNF-α, and IL-6 into culture supernatant, which may be correlated with an inflammatory response and altered EAATs expression or function in Alzheimer’s disease. These findings support the idea that dysregulation of the glutamatergic system may play a significant role in pathogenesis of Alzheimer’s disease. Furthermore, enhancing expression or function of EAATs in astrocytes and neurons might be a new therapeutic approach in treatment of Alzheimer’s disease.     

Catechol-O-Methyltransferase Val158Met Polymorphism on Striatum Structural Covariance Networks in Alzheimer’s Disease

The catechol-O-methyltransferase enzyme metabolizes dopamine in the prefrontal axis, and its genetic polymorphism (rs4680; Val158Met) is a known determinant of dopamine signaling. In this study, we investigated the possible structural covariance networks that may be modulated by this functional polymorphism in patients with Alzheimer’s disease. Structural covariance networks were constructed by 3D T1 magnetic resonance imaging. The patients were divided into two groups: Met-carriers (n = 91) and Val-homozygotes (n = 101). Seed-based analysis was performed focusing on triple-network models and six striatal networks. Neurobehavioral scores served as the major outcome factors. The role of seed or peak cluster volumes, or a covariance strength showing Met-carriers > Val-homozygotes were tested for the effect on dopamine. Clinically, the Met-carriers had higher mental manipulation and hallucination scores than the Val-homozygotes. The volume-score correlations suggested the significance of the putaminal seed in the Met-carriers and caudate seed in the Val-homozygotes. Only the dorsal-rostral and dorsal-caudal putamen interconnected peak clusters showed covariance strength interactions (Met-carriers > Val-homozygotes), and the peak clusters also correlated with the neurobehavioral scores. Although the triple-network model is important for a diagnosis of Alzheimer’s disease, our results validated the role of the dorsal-putaminal-anchored network by the catechol-O-methyltransferase Val158Met polymorphism in predicting the severity of cognitive and behavior in subjects with Alzheimer’s disease.     

Genetic discoveries and advances in late-onset Alzheimer’s disease

Alzheimer’s disease (AD) is a heterogeneous disorder with multiple patterns of clinical manifestations. Recently, due to the advance of linkage studies, next-generation sequencing and genome-wide association studies, a large number of putative risk genes for AD have been identified using acquired genome mega data. The genetic association between three causal genes, including amyloid precursor protein, presenilin1, and presenilin2 in early-onset AD (EOAD), was discovered over the past few decades. These discoveries showed that there should be additional genetic risk factors for both EOAD and late-onset AD (LOAD) to help fully explain the leading molecular mechanisms in a single pathophysiological entity. This study reviews the clinical features and genetic etiology of LOAD and discusses a variety of AD-mediated genes that are involved in cholesterol and lipid metabolism, endocytosis, and immune response according to their mutations for more efficient selection of functional candidate genes for LOAD. New mechanisms and pathways have been identified as a result.