Establishment Of The Ad Panel Quality Assessment And Variant Calling Strategy
The overall study design and documented in vivo pathology biomarkers are represented in Fig. a, b. The clinical and demographic characteristics of the 557 participants are described in Supplementary Table S. The mean age of the participants is 67.4years, and 57.8% are women. The frequency of the APOE4 allele in each diagnostic group indicated a strong disease association . The mean coverage depth of the AD target sequencing runs was 436.8×, and 97.8% of the targeted bases were covered more than 20×, ensuring high variant sensitivity .
Fig. 1
Study design and variant profile of the cohort. a Flowchart of the study design. b Phenotyping strategies of in vivo AD pathology. c Principal component analysis of the KBASE cohort with individuals from the 1000 Genomes Project individuals across different populations. d Distribution of variants in the KBASE cohort by population frequency. e Distribution of variants by genetic regions
Clinical Features Of Ad
In 1906, the German psychiatrist Alois Alzheimer first described the clinical features of an early-onset case of AD with its pathognomonic hallmarksextracellular amyloid plaques and intracellular neurofibrillary tangles . Patients typically show an insidious onset and continuous cognitive decline, which typically starts with an amnestic presentation with impaired ability to remember new information. The cognitive decline may further affect language, reasoning, executive function, visuospatial abilities, and the illness is often accompanied by personality and behavioral changes that affect the social function of the patient. In an advanced disease stage, patients are completely dependent on their caregivers for daily functioning such as getting dressed, toileting, mobility, and eating. The NINCDS-ADRDA criteria for diagnosing possible and probable AD are being widely used and have a sensitivity and specificity of ~70% for distinguishing between AD patients and people without dementia. However, they were less accurate distinguishing between different types of dementias . The median survival time of patients from the symptom onset is reported to be 9 years .
What Is Early Onset Familial Alzheimer Disease
Definition: What Is eFAD?
Early onset familial Alzheimer disease is hereditary and marked by Alzheimer disease symptoms that appear at an unusually early age. Symptoms can start in a person’s thirties, forties, and fifties . Generally, if you are diagnosed with eFAD, then one of your parents will also have had it if he or she lived long enough, and your siblings and your children may have a 50-50 chance of having inherited it. Very rarely, eFAD can make a first-time appearance in a family through a new genetic mutation.
Genetics researchers studied eFAD families to discover the three known genes that cause familial AD: amyloid precursor protein , presenilin-1 , and presenilin-2 . Of these, PS1 mutations account for most eFAD, while APP and PS2 are more rare. Having a pathogenic mutation in one of these three genes virtually guarantees that one will develop early onset Alzheimer disease. Tests can determine which gene is at fauly . There are also cases of eFAD that cannot be linked to one of these three genes. There may be additional genes waiting to be discovered, if only researchers could connect with more eFAD families.
Prognosis: Is eFAD Different from LOAD?
How Common Is Early Onset Familial Alzheimer Disease?
For practical and research purposes, doctors and scientists need defined populations for study and the numbers change based on the definitions. The definition would seem to rest on two criteria:
| Early onset sporadic | Late-onset sporadic |
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Causes Of Alzheimers: Is It Hereditary
Increasing cases of Alzheimers disease
The Alzheimers Association states that Alzheimers disease is the sixth leading cause of death in the United States, and that more than 5 million Americans are affected by the condition. Additionally, one out of three seniors dies of Alzheimers or some other type of dementia. That number will likely increase as the aging population increases.
Scientists have been researching Alzheimers for decades, but still there is no cure. Learn more about how genes are related to the development of Alzheimers, as well as other potential causes of the condition.
Current State Of Development Of Treatment For Ad And Future Outlook
Currently, no disease modifying treatment is available for AD. The only treatments available are treating symptoms, but not the causes of the disease and its progression . This statement holds despite the stunning fact that between 2002 and 2014, more than 400 drug trials for AD have been performed but subsequently failed . More recently, several large drug trials aiming at reducing the amyloid burden had failed to show efficacy. Attempts to reduce A production as well as immunotherapeutic approaches to clear amyloid plaques from the brain did not show efficacy in slowing down or halting the course of AD . Biogens immunotherapeutic drug Aducanumab reported positive Phase 1 results on removing brain A plaques and clinical benefits . The result of a larger phase 3 trial is still pending.
Explanations of the failure of so many drug trials targeting A argue for possible flaws in the amyloid hypothesis, or the possibility that the disease being too advanced at the time of intervention . Drug trials in presymptomatic mutation carriers of autosomal dominant AD may shed light on whether targeting amyloid will yield any therapeutic effect . Ongoing drug trials include targeting anti-amyloid, anti-tau, anti-inflammatory, neuroprotection, stem cell therapy, and metabolism .
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How Can Genes Cause Dementia
Most often, dementia is caused by a complex disease in which genes are only one factor. When this happens, the dementia develops as a result of many different factors. In these cases, genes do not directly cause it to develop.
It is not possible to directly inherit dementia when it is caused by a complex disease.
The Role Of Genetics In Advancing Precision Medicine For Alzheimers Diseasea Narrative Review
- 1Litwin-Zucker Center for the study of Alzheimers Disease, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- 2Division of Geriatric Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, United States
- 3Robert S Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
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Dementia And Down Syndrome
People with Down syndrome are born with an extra piece of DNA. This means they also have an extra copy of the APP gene. This leads to the build-up of amyloid plaques in the brain, which play a role in the development of Alzheimers disease. While not everyone with Down syndrome will go on to develop symptoms of Alzheimers, most people with the condition over the age of 40 will have amyloid build-up. It is estimated that about 50% of people with Down syndrome develop symptoms like memory loss, usually in their 50s and 60s.
To find out more about Down syndrome and dementia you can contact Downs Syndrome Association helpline on 0333 1212 300 or visit their website www.downs-syndrome.org.uk.
Can Genes Cause Dementia
Around 1 in 4 people aged 55 years and over has a close birth relative with dementia. Find out what part genes play in dementia and how genetics can affect the risk of developing the condition.
It is well known that children can take after their parents for example, in the way they look. This is partly because many of the key characteristics of a person are passed down from parents to children in their genes.
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Lexeo Therapeutics Announces Positive Initial Data From Ongoing Phase 1/2 Clinical Trial Of Aav
In the initial clinical data from low-dose cohort of the ongoing trial, we observed that LX1001 expressedthe protective APOE2 protein in the CNS and decreased core Alzheimers disease-related biomarkers
No serious adverse events reported to date, indicating an emerging favorable tolerability profile
Initial data from mid-dose cohort, with additional 12-month follow-up data from low-dose cohort,expected in the second half of 2022
NEW YORK March 2, 2022 LEXEO Therapeutics , a clinical-stage gene therapy company advancing a deep and diverse pipeline of adeno-associated virus -based gene therapy candidates for genetically defined cardiovascular and central nervous system diseases, announced today positive initial expression and biomarker data from the low-dose cohort of its ongoing Phase 1/2 clinical trial of LX1001. LX1001 is an AAV-based investigational gene therapy designed to deliver the protective apolipoprotein E2 gene into the CNS of APOE4 homozygous Alzheimers disease patients to halt or slow disease progression.
LX1001 is the lead program in our Alzheimers disease gene therapy portfolio. These encouraging data support our unique approach to target the genetics of Alzheimers disease with multiple gene therapy candidates, said R. Nolan Townsend, Chief Executive Officer of LEXEO. We will continue to advance this clinical stage program and others at the preclinical stage which are on the cutting edge of todays Alzheimers disease research.
Patients Carrying One Or Two Apoe4 Alleles
The by far largest single genetic risk factor for LOAD is apolipoprotein E , which has been known since 1993. There are three common isoforms of APOE , which result from polymorphic variation in the gene. APOE4 is associated with higher risk of AD . However, APOE4 cannot be regarded as causal in the development of AD, since it is neither sufficient nor necessary to cause AD. This means, individuals carrying one or two of the APOE4 risk alleles will not certainly develop AD and individuals without APOE4 are not protected. However, its high importance can be explained by its relatively high frequency in the population combined with a relatively high effect strength, which is also illustrated in Fig. . Other known genetic variants either occur many times less frequently or have only minor effect on disease development.
The APOE4 allele has been described to promote amyloid deposition starting already in middle age. PET studies in cognitively healthy individuals in various age groups have shown that APOE4-positive individuals exhibit amyloid deposition significantly earlier than APOE4-negative individuals . Although APOE4 has been known as a risk factor for a very long time, there remains disagreement over the specific mechanisms by which the APOE4 allele increases the risk of AD and age-related cognitive decline.
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Behind A Good Mutation: How A Gene Variant Protects Against Alzheimer’s
by University of California, Irvine
While the word “mutation” may conjure up alarming notions, a mutation in brain immune cells serves a positive role in protecting people against Alzheimer’s disease. Now University of California, Irvine biologists have discovered the mechanisms behind this crucial process. Their paper appears in the journal Alzheimer’s and Dementia.
The investigation centered on a variant of the PLCG2 gene, which makes the instructions for producing an enzyme important to brain immune cells called microglia. “Recently the mutation, which is known as P522R, was shown to lower the risk of developing late-onset Alzheimer’s,” said Hayk Davtyan, Ph.D., senior researcher in the laboratory of Mathew Blurton-Jones, professor of neurobiology & behavior, where the study was conducted. The project was led by assistant project scientist Christel Claes, Ph.D., the paper’s first author.
The scientists used CRISPR gene-editing technology to generate the protective mutation in human stem cells and then implanted microglia derived from those stem cells into humanized rodent models of Alzheimer’s disease.
“Our research showed for the first time that the P522R variant increased expression levels of several microglial genes that are reduced in people with Alzheimer’s. This provides some of the first evidence to explain how this protective mutation might reduce Alzheimer’s risk,” Davtyan said.
Explore further
What Is A Gene Variant
The same gene can differ between individuals these are known as gene variants. These can help to explain why people are different to each other for instance, why one person has blue eyes and another person has brown eyes.
If a gene variant increases a person’s risk of developing a disease, it is known as a ‘risk variant’ for that disease.
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Whats Next In This Research
Dr. Kofoed: In this study, we used an easily visible reporter gene to explore the potency of gene delivery. The next stage of our research will look to deliver a therapeutic gene to target Alzheimer-related pathology in a preclinical model. These studies will help us determine the therapeutic potential of our delivery strategy.
Dr. Aubert: Gene therapy has tremendous potential for the treatments of brain disorders. The current study and the next stage of our research are required steps to evaluate the safety and efficacy of gene therapy approaches. With colleagues and collaborators at Sunnybrook and other institutions, these approaches could one day be brought to patients to halt degeneration and promote brain health for conditions such as Alzheimers disease.
Key drivers of Sunnybrooks research are funding agencies and philanthropic investment. This study was funded with support from the Alzheimer Society Research Program, the Carlsberg Internationalisation Fellowship, the Canada Research Chairs Program, Canadian Institutes for Health Research , the Weston Brain Institute, the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health and Temerty Chair in Focused Ultrasound Research. Additional funding was received from the FDC Foundation, the WB Family Foundation and Gerald and Carla Connor.
Pathways Implicated By Risk Genes For Ad
The established AD associated genes exert pleiotropic functions across many molecular pathways. Several of these pathways stand out by providing insights for the disease mechanisms that may play a role in the etiology of AD . Major pathways include inflammatory response , lipid metabolism , as well as endocytosis/vesicle-mediated transport . Other functional categories include regulation of cell cycle , oxidative stress response , and axon guidance .
A role of innate immunity and inflammation in AD etiology is independently supported by a large body of functional evidence . Among the risk genes from the immune pathways, TREM2 stands out with its high effect-size of AD risk . TREM2 stands for triggering receptor expressed on myeloid cells 2, a single-transmembrane protein expressed by monocytic myeloid cells. Both ApoE and Clusterin are extracellular chaperons that prevent protein aggregation. In addition, both bind to the microglial receptor TREM2 and thus may promote uptake of A by microglia . Studies on animal and human brains indicated that the TREM2 risk variant p.R47H impairs TREM2 detection of lipid ligands leading to microglia dysfunction . In addition to TREM2, the two newly identified AD risk genes ABI3 and PLCG2 are highly expressed in microglia as well .
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If Familial Alzheimers Disease Is Suspected
Genetic testing can identify specific changes in a persons genes. This test can tell if a person has FAD and if a child has inherited the changed gene from a parent and will develop the disease in the future. It cannot determine when the symptoms will begin. It is essential to ensure that suspected cases in the family have, or have had, Alzheimers disease and not some other form of dementia. This can only be done through a medical examination, or a careful analysis of past medical records if the person is no longer alive.
What About Other Genes That Increase The Risk Of Developing Alzheimers Disease
The diagram below shows a number of genes associated with Alzheimers disease according to how common they are. Mutations in the APP, PSEN-1 and PSEN-2 genes are rare, but having a mutation gives a very high risk of developing Alzheimers disease, so these genes are shown in the top left of the diagram.
Most people who develop Alzheimers dont have familial Alzheimers disease, the particular reason that they develop the disease isnt clear. Its most likely to be due to a combination of factors such as age, environment, lifestyle and genetic risk factors. In these cases, the disease is known as sporadic there isnt one clear cause. Some of the risk factor genes are shown in the diagram above. Having one of these genes means youre more likely to develop Alzheimers disease than someone who doesnt have the gene, but it doesnt mean youll definitely develop Alzheimers. These genes increase your risk slightly, but some people with the genes dont get the disease, and vice versa. There are a number of genes that are very common lots of people have the form of the gene that increases the risk of developing Alzheimers disease, but they dont have a strong effect. These are shown in the bottom right of the diagram . TREM2 on the other hand is fairly rare, but has a greater effect than those more common genes2.
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Heteroduplex Analysis With Surveyor Nuclease
Surveyor Nuclease is a plant endonuclease that cleaves double-stranded DNA at mismatch sites, including SNPs, insertions, and deletions. A novel PCR-based mutation detection method has been developed by Transgenomic. The process has four main steps: 1) amplification of target DNAs from patients and healthy controls 2) hybridization of normal DNA with the DNA of the patient 3) digestion of homo- and heteroduplexes by Surveyor Nuclease and finally, 4) separation of cleavage products by standard gel electrophoresis or high-pressure liquid chromatography . This method may be promising in molecular diagnosis, and it has been successfully used for the identification of genetic-based disorders.
The basic steps of genotyping with Surveyor® Nuclease . After mixing the polymerase chain reaction amplicons of healthy control and patient , hybridization should be performed, resulting in homo- and heteroduplex formation . Treatment with Surveyor Nuclease cleaves the DNA at the mismatch site . Cleavage products can be separated by electrophoresis .
Abbreviation: SNP, single-nucleotide polymorphism.
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