Genetic And Hereditary Risk Factors For Alzheimer’s Disease
Alzheimers disease is an incurable condition, involving the loss of memory and cognitive skills. As the incidence of Alzheimers continues to rise, so too does the push for medical science to discover the cause of the disease. Is it genetic? If so, what are the hereditary risk factors of Alzheimers disease?
Synaptic Dysfunction And Endocytosis
In AD the disease process itself probably reflects, in part, an aberration of normal physiological processes at or near the synapse. Amyloid precursor protein is normally proteolytically processed during synaptic activity. Its amino-terminal, soluble APP fragment has neurotrophic properties, and the intracellular domain released by gamma-secretase is thought to enter the nucleus and regulate gene expression events. While A- was thought by many simply to be a waste byproduct of these sequential proteolytic events, recent studies suggest that A- is normally produced during synaptic activity and may function to provide a negative feedback signal on excess synaptic activity. In other words, A- production may normally help to maintain synaptic homeostasis. As such, the inevitable day-to-day production of A- at highly active synapses can lead to its accumulation and eventual oligomerization. Maybe this is why the basal brain activity pattern known as the default pathway aligns closely with the initial sites of amyloid deposition in AD. While the critical toxic species formed by A- remains uncertain, recent studies suggest that dimers or slightly larger oligomers are the key toxic species., Since oligomerization is a concentration-dependent process, excess A- at or just outside the neuronal membrane will favor oligomerization and eventual plaque formation.
The Trem2 Mutations That Lead To Changes In Microglial Phagocytosis And Increased Ad Risk
As microglial phagocytosis has been shown to significantly reduce the plaque load observed in mouse models of AD, researchers investigated whether the TREM2 mutations associated with AD conferred a loss of receptor function, finding that the rare TREM2 variants caused impairment of phagocytosis . The missense mutation R47H of TREM2 is associated with AD risk by dysregulating neuroinflammation and increasing AD pathology . Mazaheri and colleagues showed that TREM2 knockout reduced microglial reactivity and consequently blocked essential defense functions of microglia during disease progression . They further showed that TREM2 knockout mice had impaired microglial migration and process outgrowth, likely due to dysregulation of genes associated with chemotactic motility. Recently, a TREM2R47H mouse model has been produced, which displays abnormal macrophage apoptosis and necrosis . Interestingly, these mice also failed to mount a pro-inflammatory response to challenges, including LPS, demonstrating a failure to produce pro-inflammatory cytokines. This further suggests that the R47H mutation of TREM2 renders it inactive. In support of these findings, it has also been shown that the uptake of ApoE-A complexes is reduced in macrophages from human subjects carrying the R47H TREM2 variant however, whether ApoE isoforms affect TREM2-mediated neuroinflammation response in an isoform-specific manner in the pathogenesis of AD is still unknown.
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The Complexity Of Pro
Targeting of anti-inflammatory and pro-resolution mediators has also produced mixed results, with the activation of IL-10 anti-inflammatory signaling in AD mouse models resulting in impairment in A phagocytosis and exacerbated AD neuropathology . On the other hand, stimulation of anti-inflammatory LXA4 or prostaglandin EP4 receptor signaling facilitates microglia-mediated A clearance and reduces AD-like pathology in mice. Notably, whereas IL-10 is increased , the levels of LXA4 and EP4 are reduced in human AD, indicating that targeting missing inflammatory mediators may be a better approach to restore the balance between pro- and anti-inflammatory signals in the immune responses during aging and AD.
Taken altogether, these studies illustrate the complexity of targeting distinct inflammatory mediators in AD, but also clearly demonstrate that the phagocytic activity of microglia is highly important in the clearance of A deposits. Consequently, one of the current challenges in the field is to identify the underlying molecular mechanisms that regulate the phenotype of microglia or distinct microglial populations in order to develop strategies that stimulate the protective phagocytic phenotype while inhibiting the detrimental pro-inflammatory phenotype.
Other Genes Linked With Late
According to Mayo Clinic, several other genes in addition to the APOE4 gene have been linked with an increased risk of late-onset Alzheimers. These include:
- ABCA7: the exact way it is involved in an increased risk of AD is not well known, but this gene is thought to play a role in how the body utilizes cholesterol
- CLU: plays a role in helping to clear beta-amyloid from the brain. The bodys normal ability to clear amyloid is vital to the prevention of Alzheimers.
- CR1: this gene produces a deficiency of protein, which may contribute to inflammation of the brain
- PICALM: this gene is involved in the method that neurons communicate with each other, promoting healthy brain cell functioning and effective formation of memories
- PLD3: the role of this gene is not well understood, but it has been linked with a significant increase in the risk of AD
- TREM2: this gene plays a role in regulating the brains response to inflammation. Variants of TREM2 are thought to increase the risk of AD.
- SORL1: variations of this gene on chromosome 11 may be linked with Alzheimer’s
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Testing For Familial Alzheimers Disease
The decision to undergo testing for FAD is very complex and the advantages and disadvantages must be carefully considered. The test does not produce a relative risk of acquiring the dementia, but is a definitive prediction of whether a person will get a profound and progressive illness in ones middle years. The test can only be completed with the informed consent of the person being tested. No one should ever be pressured to have such a test.
Knowing that you are carrying the gene may help some people plan for the future. It enables them to consider future lifestyle choices and to let their wishes be known to someone they trust. However, given that no cure is available an individual has to consider whether they want to know that they will develop dementia at some time in the future.
To help people consider these issues specialised genetic counselling is essential. The doctor can provide details of this service. In the future, when preventive treatments for Alzheimers disease become available, there may be increased reasons to seek testing.
Genetic Test Protocols For Huntingtons Disease
The goals of counseling are: to inform the individual of his or her options about testing or other alternatives, depending upon personal circumstances, to ensure that the individual is aware of the risks and possible adverse consequences of his or her specific testing circumstances, and to inform the individual of the limitations and level of accuracy of the procedure. Counseling does not try to exclude or discourage persons but tries to insure that the individual is making an informed choice. The protocol used in our New England HD testing program includes telephone intake, two counseling visits, a neurological examination, and in-person delivery of test results.
Neurological examination.
Many programs include a neurological evaluation as part of the pretest evaluation. Many at-risk persons seek testing in the context of concerns for having exhibited symptoms of HD, and the neurological evaluation will answer the question of whether the individual has symptoms of the illness. Not uncommonly, persons who learn that they do not have symptoms decide to postpone the genetic test, because their primary worry for the onset of the disease has been addressed. For those persons who may be symptomatic and who may be diagnosed in the course of the genetic test evaluation, it is important to recognize that the test is no longer presymptomatic and to initiate treatment associated with the onset of the illness.
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Genetics In Diagnosis And Risk Prediction Of Autosomal Dominant Ad
With the advent of high-capacity MPS, genetic diagnostic testing is entering a new era. Multiple genes can now be screened simultaneously using disease-oriented or disease spectrumoriented gene panels, obviating the need of decision trees based on clinical parameters. For AD, a disease-spectrum approach may be particularly relevant. For example, the mutation p.R406W in MAPT, a known causal gene for FTLD, has repeatedly been reported in pedigrees with a clinical presentation of AD. Mutations in two other FTLD genes, GRN and C9orf72, have also been described in clinical AD cohorts., It may be important to include screening of these genes in the genetic diagnostic work-up of high genetic load AD patients, particularly in light of the fact that APP, PSEN1, and PSEN2 account for only a small proportion of autosomal dominant AD.
Health Environmental And Lifestyle Factors That May Contribute To Alzheimer’s Disease
Research suggests that a host of factors beyond genetics may play a role in the development and course of Alzheimer’s disease. There is a great deal of interest, for example, in the relationship between cognitive decline and vascular conditions such as heart disease, stroke, and high blood pressure, as well as metabolic conditions such as diabetes and obesity. Ongoing research will help us understand whether and how reducing risk factors for these conditions may also reduce the risk of Alzheimer’s.
A nutritious diet, physical activity, social engagement, sleep, and mentally stimulating pursuits have all been associated with helping people stay healthy as they age. These factors might also help reduce the risk of cognitive decline and Alzheimer’s disease. Clinical trials are testing some of these possibilities.
Early-life factors may also play a role. For example, studies have linked higher levels of education with a decreased risk of dementia. There are also differences in dementia risk among racial groups and sexesall of which are being studied to better understand the causes of Alzheimers disease and to develop effective treatments and preventions for all people.
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Genetic Testing For Alzheimer’s Disease
A blood test can identify which APOE alleles a person has, but results cannot predict who will or will not develop Alzheimer’s disease. Currently, APOE testing is used primarily in research settings to identify study participants who may have an increased risk of developing Alzheimer’s. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of possible treatments for people with different APOE profiles.
Genetic testing is also used by physicians to help diagnose early-onset Alzheimers disease and to test people with a strong family history of Alzheimers or a related brain disease.
Genetic testing for APOE or other genetic variants cannot determine an individuals likelihood of developing Alzheimers diseasejust which risk factor genes a person has. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy, researchers believe, because too many other factors may influence its development and progression.
Some people learn their APOE status through consumer genetic testing or think about getting this kind of test. They may wish to consult a doctor or genetic counselor to better understand this type of test and their test results. General information about genetic testing can be found at:
Family History By The Numbers
Studies of family history say that if you have a close relative who has been diagnosed with Alzheimer’s diseasethe most common form of dementia in older adultsyour risk increases by about 30%. This is a relative risk increase, meaning a 30% hike in your existing risk.
If you are age 65, the risk of being diagnosed with Alzheimer’s is 2% per year, although this also means a 98% chance per year of not developing Alzheimer’s. In absolute numbers, a 2% annual risk means that two out of 100 65-year-olds will develop dementia every year.
Family history raises the 2% annual risk by about 30%, to 2.6% per year. That means going from 20 cases in a group of 1,000 to 26 in 1,000, or six additional cases in 1,000. “So the absolute increase is relatively small,” Dr. Marshall says.
Age raises the chance of Alzheimer’s more than family history. People in their 70s have a 5% chance of being diagnosedmore than twice that of people in their 60s. Family history raises this by 30%, from 5% to 6.5%. Again, the absolute change is relatively small.
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Impact Of Genetic Testing On Individuals
Genetic and susceptibility testing brings concerns regarding the impact of test results on individuals. Both survey data and clinical research have shown that the majority of individuals at risk for AD are interested in knowing their genetic profile. Furthermore, since the emergence of personal genomics companies offering direct-to-consumer testing for various neurodegenerative diseases, it is of great importance to examine the possible implications of these test results. Direct-to-consumer companies do not provide genetic counseling or exclude psychologically vulnerable consumers, which increases the potential for inadequately understanding the meaning or implications of test results.
Drug Development And Clinical Trials
Development of disease-modifying and symptomatic therapeutics for AD to date has mostly focused on early insights on the molecular mechanisms and pathways involved in AD and specifically followed three AD hypotheses: the cholinergic, amyloid cascade, and tau hypotheses. Therapeutics based on the enhancement of the cholinergic system show consistent, but modest, clinical effects in late-phase trials. A substantial portion of the field focused its efforts on the amyloid cascade hypothesis, highlighted by the identification of pathogenic mutations in APP, PSEN1, and PSEN2. This approach led to human clinical trials potentially decreasing the production or aggregation of A or enhancing A clearance from the brain. Recent passive and active anti-tau immunization studies in mouse models have been proven effective at preventing and improving tau pathology. The progression of neurofibrillary tangles pathology throughout the brain correlates strongly with synaptic and neuronal loss and cognitive decline, and makes it a potential therapeutic target to interrupt progression of tau pathology early in disease. The spread of tau pathology and neuronal tau release is thought to be a regulated process through active secretion and interneuronal transfer of tau, which could facilitate transneuronal spread of tangle pathology.
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What Are The Early Signs And Symptoms Of Alzheimer’s Disease
Now that we’ve discussed the scientific definitions, let’s turn to the warning signs. According to the experts at the Alzheimer’s Association, there are 10 major early signs and symptoms of Alzheimer’s to watch out for, and they are as follows:
More Information On Genetics
If you would like to learn more about the genetics of all forms of diabetes, the National Institutes of Health has published The Genetic Landscape of Diabetes. This free online book provides an overview of the current knowledge about the genetics of type 1 and type 2 diabetes, as well other less common forms of diabetes. The book is written for health care professionals and for people with diabetes interested in learning more about the disease.
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Dementia With Lewy Bodies
Synucleinopathies include the overlapping spectrum of Parkinsons disease , PD with dementia, and dementia with Lewy bodies . A key hallmark in these related disorders is the intraneuronal cytoplasmic inclusion known as the Lewy body, in which -synuclein is the key aggregated protein. In PD, Lewy bodies are largely confined to the substantia nigra and certain regions of the brainstem. In DLB, however, the Lewy bodies are found widespread in the cerebral cortex and are associated with the various cognitive and psychiatric features of Lewy body dementia . Thus, one can consider the synucleinopathies as a spectrum extending from pure idiopathic PD through PD with dementia to bona fide Lewy body dementia.
Most DLB is not familial. The most strongly implicated gene in familial DLB is the gene encoding -synuclein itself . Triplication of the gene is associated with PD as well as DLB. Rare autosomal dominant mutations in synuclein also can cause familial PD in which dementia is a prominent feature. Glucocerebrosidase mutations implicated in PD also may contribute to DLB.
Presenilin 1 And Presenilin 2
PSEN1 and PSEN2 are highly homologous genes. Mutations in PSEN1 are the most frequent cause of autosomal dominant AD known to date, whereas PSEN2 mutations are least frequent .,,,, Both proteins are essential components of the -secretase complex, which catalyzes the cleavage of membrane proteins, including APP. Mutations in PSEN1 and PSEN2 impair the -secretase mediated cleavage of APP in A fragments, resulting in an increased ratio of A142 to A140, either through an increased A142 production or decreased A140 production, or a combination of both.
PSEN1 mutations cause the most severe forms of AD with complete penetrance, and the onset of disease can occur as early as 25 years of age. The PSEN1 mutations have a wide variability of onset age , rate of progression, and disease severity. Missense mutations in the PSEN2 gene may show incomplete penetrance. In comparison to PSEN1 mutations, PSEN2 mutation carriers show an older age of onset of disease , but the onset age is highly variable among PSEN2-affected family members.,,
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