How Alzheimers Disease Progresses
An individuals abilities deteriorate over time, although the progression varies from person to person.
As Alzheimers disease affects different areas of the brain, specific functions or abilities are lost. Short-term memory is often the first to be affected, but as the disease progresses, long-term memory is also lost. The disease also affects many of the brains other functions and consequently language, attention, judgement and many other aspects of behaviour are affected.
Some abilities remain, although these lessen as Alzheimers disease progresses. People living with advancing dementia may keep their senses of touch and hearing, and also respond to emotion even in the advanced stages of the condition.
At the end stages of Alzheimers disease many people become immobile and dependent, requiring extensive care.
Section Iv Application And Submission Information
1. Requesting an Application Package
The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
2. Content and Form of Application Submission
It is critical that applicants follow the Multi-Project Instructions in the SF424 Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIA staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Nina B. Silverberg, Ph.D.National Institute on Aging Telephone: 301-496-9350Email:
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Overall Component
Clinical And Neuropsychological Features Of Eoad
Patients with EOAD can present with a variety of clinical signs, symptoms, and syndromes that do not always resemble the typical amnestic syndrome most often described in LOAD. EOAD is associated with less salient memory deficits and greater likelihood of impairment of other functions, including language, visuospatial, executive, and motor functions, and behavioral dysregulation. This clinical heterogeneity is partly responsible for the misdiagnosis and delay in diagnosis for patients with EOAD . However, non-amnestic presentations of AD have gained better recognition in the last decadewhile progressive memory worsening was one of the mandatory features of probable AD in the 1984 clinical criteria , this requirement was dropped in the 2011 revision of the diagnostic guidelines .
The heterogeneity of clinical presentations of EOAD can be seen as a spectrum based on patients relative impairment in various cognitive and clinical domains. Some patients at extreme ends of this spectrum fulfill criteria for specific non-amnestic syndromes which are also referred to as focal cortical presentations or atypical phenotypes . These presentations are associated with insidious onset and gradual progression of clinical deficits.
In addition to a high degree of variability in the domains of cognitive impairment, EOAD is usually associated with a more aggressive clinical course than LOAD as cognitive and clinical function tends to decline more rapidly in younger patients .
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Genetic Findings Categorized Based On Clinical Actionability
We evaluated the impact of the different genetic components for each family. The cumulative genetic evidence and potential relationships between variant carrier status , APOE burden, and PRS were assessed, leading to categorization of the families as follows: genetic cause identified, sufficient to be reported back to patients one or more genetic risk factors identified suggesting potential polygenic etiology no genetic risk factors identified after evaluation of variants in dementia-related genes, APOE, and PRS, suggesting the presence of additional, yet undiscovered genetic risk factors.
Health Environmental And Lifestyle Factors
Research suggests that a host of factors beyond genetics may play a role in the development and course of Alzheimers. 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 diseases, 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 Alzheimers.
A nutritious diet, physical activity, social engagement, 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 Alzheimers. Researchers are testing some of these possibilities in clinical trials.
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Dementia is a cognitive condition that affects an estimated 900,000 people across the UK.
The term dementia does not refer to a single specific ailment but rather a collection of symptoms occurring as a result of a disease like Alzheimers causing damage to the nerve cells that transmit messages from the brain.
It is particularly common among the elderly, with one person in 14 people aged over 65 experiencing the condition and one in six aged over 80, with women statistically more likely to suffer than men.
Everyone experiences the condition differently but common symptoms of dementia fall under three categories memory problems, cognitive ability and communication.
Section V Application Review Information
1. Criteria
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan will not be evaluated at time of review.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field involved, in consideration of the following review criteria and additional review criteria .
Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
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Who Gets Alzheimers Disease
Anyone can develop Alzheimers disease, but it is more common in older age.
Genetics, lifestyle and health factors are associated with an increased risk of developing dementia.
In a few cases, Alzheimers disease is inherited, caused by a genetic mutation. This is called familial Alzheimers disease, with symptoms occurring at a relatively young age. This is usually when someone is in their 50s, but sometimes younger.
What Happens After A Diagnosis Of Younger Onset Dementia
A diagnosis of younger onset dementia can come as a shock. The person affected, and their family and friends may all feel angry or sad. They might not believe it. There can be a huge sense of loss. These feelings are normal.
But help and support is available, and it is better to get it earlier than later.
Younger people with dementia need to think about several issues.
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How Is Alzheimers Disease Diagnosed
Doctors use several methods and tools to help determine whether a person who is having memory problems has Alzheimers disease.
To diagnose Alzheimers, doctors may:
- Ask the person and a family member or friend questions about overall health, use of prescription and over-the-counter medicines, diet, past medical problems, ability to carry out daily activities, and changes in behavior and personality.
- Conduct tests of memory, problem solving, attention, counting, and language.
- Carry out standard medical tests, such as blood and urine tests, to identify other possible causes of the problem.
- Perform brain scans, such as computed tomography , magnetic resonance imaging , or positron emission tomography , to support an Alzheimers diagnosis or to rule out other possible causes for symptoms.
These tests may be repeated to give doctors information about how the persons memory and other cognitive functions are changing over time.
People with memory and thinking concerns should talk to their doctor to find out whether their symptoms are due to Alzheimers or another cause, such as stroke, tumor, Parkinsons disease, sleep disturbances, side effects of medication, an infection, or another type of dementia. Some of these conditions may be treatable and possibly reversible.
In addition, an early diagnosis provides people with more opportunities to participate in clinical trials or other research studies testing possible new treatments for Alzheimers.
The Same Genes May Underlie Cardiometabolic Diseases And Dementia
Being affected by several cardiometabolic diseases such as diabetes, heart disease and stroke, is linked to a greatly increased risk of dementia and Alzheimer’s disease. A new twin study by researchers from Karolinska Institutet suggests that the same genes may be behind the risk of both cardiometabolic diseases and dementia. The findings have been published in European Heart Journal.
Cardiometabolic diseases such as type 2 diabetes, heart disease and stroke are a growing challenge in society. With an aging population and improved health care, people are living longer with cardiometabolic diseases more likely to get two or more of these conditions in a lifetime, known as cardiometabolic multimorbidity. It affects an estimated 30% of older adults and leads to increased mortality.
“We know that type 2 diabetes, heart disease and stroke are well-established individual risk factors for dementia. As the population ages, more and more people are affected by several co-morbid cardiometabolic diseases, but few studies have dealt with the effect of this multimorbidity on dementia risk and whether genetic factors affect the relationship,” says Abigail Dove, Ph.D. student at the Aging Research Center, Karolinska Institutet and the study’s first author.
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Replication Of Candidate Variants
To replicate the association of our candidate variants with AD, we used exome sequencing data available from Dutch studies contributing to the Alzheimer Disease European Sequencing consortium and from the Amsterdam Human Genetics department consisting of 833 EOAD patients, 521 LOAD patients, and 6949 healthy controls. The set of samples was pruned such that no family relations remained. Only variants with a MAF < 0.1% were selected and results were categorized based on CADD score . Population structure was corrected for with 10 PCA components. Only genes with 10 carriers were considered for subsequent analysis. Quality control and burden tests were performed using ordinal logistic regression with an EOAD > LOAD > controls labeling as recently described . This method exploits the assumption that the genetic risk will be enriched towards EOAD patients, as can be expected for the candidate variants and genes in this study. Variant-specific analyses were performed with the same approach . P-values were adjusted for multiple testing using the FDR approach , with FDR < 0.05 considered as suggestively associated with AD.
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.
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Additional File : Table S1
. List of dementia related genes and loci that were analyzed in the exome sequencing data for each family separately. Table S2. List of variants and genes that were excluded following manual evaluation using the Integrative Genomics Viewer . Table S3. List of variants included to compute the Polygenic Risk Score . Table S4. Clinical and genetic findings of all affected individuals and unaffected relatives . Table S5. Selection of genes shared by two families with possible connection to dementia based on literature search. Table S6. Total list of candidate genes and variants occurring in 2 families selected for replication analysis. Table S7. Replication analysis of candidate genes. Table S8. Replication analysis of candidate variants.
What Is Younger Onset Dementia
Younger onset dementia is used to describe any form of dementia that develops in people under the age of 65. Dementia has been diagnosed in people in their 50s, 40s and even in their 30s. It is sometimes called early onset dementia.
Younger onset dementia is similar to other types of dementia in many ways. The same problems generally occur, but the disease can have a different impact on a younger person because they are more likely to be employed full time, raising a family or financially responsible for a family.
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Evaluating The Risk Imposed By Apoe And Rare Vus
We identified a substantial burden of APOE, with heterozygous 4-allele carriers in 67% of the families and homozygosity in 50%. Although the risk conferred by two APOE-4 alleles can cause semi-dominant inheritance with AD lifetime risk estimates of 30% by 75 years of age , we cannot be sure if APOE might be the sole genetic factor in these families, or whether some carry additional factors genetic and/or environmental to trigger disease initiation.
Following the relatively low burden of APOE and PRS in families with a known pathogenic variant, we anticipated a similar low burden in families with a VUS, if these are pathogenic. However, six out of eight families with a VUS showed a high occurrence of APOE-4 homozygosity. Moreover, we did not observe a difference in PRS across families with and without a VUS. It suggests that the identified VUS are insufficient by themselves to cause disease and that the genetic burden for AD in these families is multifactorial, although individual families might have a high burden of APOE or PRS by chance, on top of a monogenic cause.
Stages Of Alzheimers Disease
Some features of Alzheimers disease are commonly classified into three stages, or phases. Not all these features will be present in every person, and they might occur at different stages.
Mild Alzheimers disease
Sometimes this stage is only apparent in hindsight. The onset of Alzheimers disease is usually gradual and it is often impossible to identify exactly when it began.
Someone might:
- have difficulty shopping or preparing meals.
Moderate Alzheimers disease
At this stage, the impacts of the condition are more apparent and prevalent. A person may experience significant challenges to their independence and require daily support.
Someone might:
- be forgetful of current and recent events, although generally remember the distant past, even if details may be forgotten or confused
- often be confused regarding time and place
- become lost more easily
- forget the names of family or friends, or confuse family members
- forget saucepans or kettles left heating on the stove
- be less able to perform simple calculations
- show poor judgement and make poor decisions
- see or hear things that are not there or become suspicious of others
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Clinical Characteristics Of Eoad And Load
The typical clinical presentation of AD is characterized by predominant impairment of anterograde episodic memory that, as the disease progresses, is accompanied by dysfunction in additional cognitive domains such as visuospatial, language, and executive function, eventually resulting in global cognitive decline, complete dependency, and death. This typical memory-predominant phenotype is observed in most LOAD cases and a large subset of EOAD cases. However, roughly 25% of all subjects with EOAD show an atypical clinical presentation that is characterized by preserved episodic memory but focal cortical symptoms, in particular apraxia, visual dysfunction, aphasia, or executive dysfunction.,,
Symptoms Of Mild Cognitive Impairment
Some people have a condition called mild cognitive impairment , which can be an early sign of Alzheimers. However, not everyone with MCI will develop Alzheimers. People with MCI can still take care of themselves and perform their normal activities. MCI memory problems may include:
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Risk Factors For Alzheimer’s Disease
Early-onset AD is infrequent, making up approximately 10% of AD cases seen in clinical practice. Most cases of early-onset AD are familial they have been linked to specific identifiable mutations and have an autosomal-dominant pattern of inheritance with nearly full penetrance. Mutations in the Alzheimer precursor protein gene on chromosome 21, the Presenilin-1 gene on chromosome 14, and the Presenilin-2 gene on chromosome 1 have been identified, and they account for approximately 50% of all cases of early-onset familial AD. Also, most individuals who have trisomy-21 , and therefore three APP genes instead of two, develop AD at relatively early ages, supporting the theory that the overexpression of the APP protein may be involved in causing AD.
Jose A. Soria Lopez, … Gabriel C. Léger, in, 2019