Additional Mechanisms: De Novo Variants Copy Number Variation Epigenetic Modifications And Somatic Variation
In individuals with apparently sporadic EOAD with very early-onset , variants in PSEN1 were identified in 13% of cases in one study, and in the subset of cases for which parental DNA was available, all variants were found to have occurred de novo . These findings suggest that PSEN1 may be an important contributor to apparently sporadic AD cases with very early-onset , either due to de novo variants or because the cases transmitting parent died before the onset of AD . Besides smaller variants in MAPT, a rare duplication encompassing the MAPT locus is known to underlie some cases of early-onset dementia resembling AD clinically . Additional copy number variations and other structural variation have also been found in mEOAD, including duplication of APP , deletion of PSEN1 exon 9 , and other rare CNVs involving additional genes . In addition, work from our group has implicated rare variation in TET2encoding an enzyme that promotes DNA demethylationin EOAD as well as FTD risk . Given that methylation within SORL1, ABCA7, and other loci has been associated with AD risk , the results suggest that epigenetic modifications should be explored further for their contribution to EOAD risk. Finally, further exploration of mosaicism and brain somatic variation for their role in AD represent a promising area for future research.
Latest Advances In Alzheimers Disease Fluid Biomarkers
The past several years have witnessed dramatic advances in the analysis of p-tau species in the CSF and plasma as potential AD biomarkers . Measurements of plasma tau phosphorylated at residues 181 and 217 in particular have shown that these tau species have remarkable accuracy as candidate biomarkers of AD diagnosis and progression, both in CSF and plasma . However, much work remains to be done in determining the validity of these biomarkers in diverse populations that have thus far been underrepresented in these studies.
Problem Solving Or Planning Difficulties
The person may find that they have difficulty following directions, solving problems, and focusing. For example, they may find it difficult to:
- follow a recipe
- follow directions on a product
- keeping track of monthly bills or expenses
Some people often have problems like these, but if they start to happen when they did not happen before, it could indicate early onset Alzheimers disease.
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Living With Early Onset Alzheimers Disease
When younger people reach a stage that requires extra care, this may create the impression that the disease has moved faster. But people with early onset Alzheimers do not progress faster through the phases. It progresses over the course of several years in younger people as it does in adults older than 65.
But its important to plan ahead after receiving a diagnosis. Early onset Alzheimers can impact your financial and legal plans.
Examples of some steps that can help include:
- seeking out a support group for those with Alzheimers
- leaning on friends and family for support
- discussing your role, and disability insurance coverage, with your employer
- going over health insurance to ensure certain medications and treatments are covered
- having disability insurance papers in order before the symptoms appear
- engaging in financial planning for the future if a persons health changes suddenly
Dont be afraid to seek help from others during these steps. Getting personal affairs in order can provide peace of mind as you navigate your next steps.
Theres currently no cure for Alzheimers disease. But there are ways to medically manage the condition and live as healthy a life as possible. Examples of ways you can stay well with early onset Alzheimers disease include:
Researchers are learning more about the disease every day.
What To Do At Work
When you are diagnosed with early-onset Alzheimers, it is important to talk with your employer early. Talk with them about
- If you can switch to a job that better suits your current life
- Learn about any programs that are available through your employer to help.
- Explore other benefits under the Americans with Disability Act, COBRA, and the Family and Medical Leave Act.
- If you are stressed and overwhelmed, consider taking some time off or reducing your hours.
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Structural And Functional Neuroimaging
Given the distinct clinical phenotypes observed in EOAD, it comes as no surprise that there are similarly distinct neuroanatomic signatures localizing to brain regions involved in each clinical syndromes affected cognitive domains . Moreover, patterns of regional cortical atrophy are tightly linked to the distribution of tau neuropathology . Neuroimaging thus facilitates systematic characterization of each EOAD clinical variants distinct radiographic signature, monitoring of disease progression, and quantitative integration of brain structure and function with other biomarkers of disease.
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:
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Risk Factors To Consider
Although AD isnt an expected part of advancing age, youre at increased risk as you get older. More than 32 percent of people over age 85 have Alzheimers.
You may also have an increased risk of developing AD if a parent, sibling, or child has the disease. If more than one family member has AD, your risk increases.
The exact cause of early onset AD hasnt been fully determined. Many researchers believe that this disease develops as the result of multiple factors rather than one specific cause.
Researchers have discovered rare genes that may directly cause or contribute to AD. These genes may be carried from one generation to the next within a family. Carrying this gene can result in adults younger than age 65 developing symptoms much earlier than expected.
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|
A Team Of Scientists Have Discovered A Genetic Mutation That Causes An Early
Although Alzheimers disease most commonly occurs in those aged 65 years and above, a rare, early-onset form of the disease also exists. Early-onset Alzheimers disease usually shows up by age 40 or 50. Symptoms include forgetfulness, inability to perform complex but familiar tasks, trouble recalling certain words, difficulty with normal work or household activities, and behavioural changes. The buildup of proteins amyloid and tau are often considered the cause of the disease. However, why this protein buildup occurs is still uncertain.
Now, a team of international scientists, led by neurobiologists in Sweden, have discovered a genetic mutation that can cause an extremely rare and aggressive form of the disease. The mutation, the Uppsala APP deletion, has so far only been found in one family. Moreover, according to researchers, the resultant form of Alzheimers is aggressive, rapid and starts at a much younger age.
Affected individuals have an age at symptom onset in their early forties, and suffer from a rapidly progressing disease course.
Dr. María Pagnon de la Vega, study author
The family involved in the study had several members affected by memory loss and cognitive decline. Physicians at Uppsala University Hospital had treated several of the family members for nearly identical symptoms and diagnosed them with early-onset Alzheimers disease.
Science Translational Medicine
Confusion About Location And Time
The person may experience confusion about places or times. They may have difficulty keeping track of seasons, months, or times of day.
They may become confused in an unfamiliar place. As Alzheimers disease progresses, they may feel confused in familiar places or wonder how they got there. They may also start to wander and get lost.
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Take Care Of Yourself
- Follow your doctors advice about diet and exercise. If you take medicine, be sure to take the right amount at the right time. Visit or talk with your doctor if you have questions about your health or treatment.
- Consider joining a support group. To find one near you, contact your local Alzheimers Association chapter.
Difficulty Determining Time Or Place
Losing track of dates and misunderstanding the passage of time as it occurs are also two common symptoms. Planning for future events can become difficult since they arent immediately occurring.
As symptoms progress, people with AD can become increasingly forgetful about where they are, how they got there, or why theyre there.
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What Are The Causes Of Young
The causes of young-onset dementia are similar to the diseases that usually cause dementia in older people. However, some causes, such as frontotemporal dementia , are more common in younger people. Dementia in younger people often has different symptoms, even when its caused by the same diseases as in older people.There is more information about some common causes of dementia, and how they can affect younger people, below.
Legal And Financial Planning
Advance planning ideally takes place soon after a diagnosis of early-stage Alzheimers disease, while the person can still think clearly and make decisions. This web page explains the basics of legal and financial planning and links to helpful NIA publications. A Spanish-language version is provided.
Published by the NIA Alzheimers and related Dementias Education and Referral Center. Phone: 1-800-438-4380. Email: .
This program allows people with designated serious diseases and disorders, including early-onset Alzheimers, to have their applications for Social Security disability benefits reviewed quickly. See the Compassionate Allowances information on early-onset Alzheimers disease.
Published by the Social Security Administration. Phone: 1-800-772-1213. Email: .
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Limitations And Interpretation Of Genetic Studies Of Early
In the sections that follow, we highlight associations of several genes with clinical EOAD that are better known for their role in other neurodegenerative diseases. When interpreting the results of genetic studies of EOAD, it is important to ask several questions. First, is the phenotype in question clinically diagnosed EOAD or pathologically confirmed EOAD? If the former, is there good reason to believe the underlying neuropathology is AD? If such evidence is not presented, interpretation of the results should be shaped by the possibility that any identified variants may actually contribute to clinical EOAD via non-AD pathology. The importance of these questions is further highlighted by the broad spectrum of clinical EOADand particularly the atypical syndromeswhich may overlap with that of etiologically distinct neurodegenerative disorders. Finally, it is important to remain cognizant of the fact that many genetic studies have focused, for reasons of cost and practicality, on genes already known to be implicated in AD and other forms of dementia or neurodegeneration. The above factors and biases have cumulatively played an important role in shaping our current knowledge regarding the genetics of EOAD.
Types Of Alzheimer’s Disease
Nearly everyone with Alzheimerâs disease will eventually have the same symptoms — memory loss, confusion, trouble with once-familiar tasks, and making decisions. While the manner of the disease development remains unclear, all forms of Alzheimer’s appear to share overproduction and/or decreased clearance of a type of protein called amyloid beta peptides. Though the effects of the disease are similar, there are two main types.
- Early-onset Alzheimer’s. This type happens to people who are younger than age 65. Often, theyâre in their 40s or 50s when theyâre diagnosed with the disease. Itâs rare — up to 5% of all people with Alzheimer’s have early-onset. People with Down syndrome have a higher risk for it.Scientists have found a few ways in which early-onset Alzheimerâs is different from other types of the disease. People who have it tend to have more of the brain changes that are linked with Alzheimerâs. The early-onset form also appears to be linked with a defect in a specific part of a personâs DNA: chromosome 14. A form of muscle twitching and spasm, called myoclonus, is also more common in early-onset Alzheimer’s.
- Late-onset Alzheimer’s. This is the most common form of the disease, which happens to people age 65 and older. It may or may not run in families. So far, researchers havenât found a particular gene that causes it. No one knows for sure why some people get it and others donât.
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Getting The Right Diagnosis
Getting an early-onset Alzheimers diagnosis can be difficult because doctors dont typically look for the disease in younger people.
Instead, healthcare professionals may blame symptoms on stress, menopause, depression, or other conditions.
As a result, patients grappling with confusing symptoms may not get the treatment they need.
Younger people with atypical Alzheimers face an even bigger challenge in getting an accurate diagnosis.
To understand whats causing symptoms, a doctor should conduct a thorough investigation that includes a detailed family history, physical and neurological tests, a cognitive assessment, and possibly a brain-imaging scan to rule out conditions like a stroke or brain tumor.
Physicians may also use genetic testing to help diagnose early-onset Alzheimers disease.
Difficulty Completing Everyday Tasks
The person may have difficulty completing an otherwise familiar task. For example, they may find it hard to:
- get to a grocery store, restaurant, or place of employment
- follow the rules of a familiar game
- prepare a simple meal
Sometimes, people need help with new or unfamiliar things as they get older, such as the settings on a new phone. However, this does not necessarily indicate a problem.
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Common Types Of Dementia In Younger People
There are differences in the types of dementia commonly diagnosed in younger people with dementia compared to those of an older age.
- Alzheimers disease is the most common form of dementia in younger people, accounting for around a third of younger people with dementia, in comparison to about 60% in the older age group
- Vascular dementia is the second most common form of dementia in young people. Around 20% of younger people with dementia have vascular dementia
- Around 12% of younger people with dementia have frontotemporal dementia, compared with just 2% in older people. It most commonly occurs between the ages of 45-65. In about 40% of cases there is a family history of the condition
- Korsakoffs syndrome around 10% of dementias in younger people are caused by a lack of vitamin B1 , most commonly associated with alcohol abuse
The Uppsala App Deletion
The team of researchers conducted genetic analysis, structural biological research, studies of amino acid and protein chemistry, and mass spectrometry to confirm the genetic mutation. Their analysis further revealed that all carriers carried the APP gene deletion in a specific string of amino acids part of the amyloid precursor protein. The gene deletion led to a total of six amino acids missing.
According to researchers, the mutation accelerates the formation of amyloid plaques in the brain, which then destroy neurons. Thus, resulting in neurocognitive decline.
Symptoms and biomarkers are typical of Alzheimers disease, with the exception of normal cerebrospinal fluid.
Dr. María Pagnon de la Vega, study author
Study authors believe this rare form of early-onset Alzheimers disease is autosomal dominant. However, there is no evidence of other families carrying the Uppsala APP deletion. Further research us required to learn more about this rare disease.
María Pagnon de la Vega et al, The Uppsala APP deletion causes early onset autosomal dominant Alzheimers disease by altering APP processing and increasing amyloid fibril formation, Science Translational Medicine . DOI: 10.1126/scitranslmed.abc6184
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