Researchers at the Case Western University School of Medicine say they have identified a previously unknown gene and associated protein which could potentially be suppressed to slow the advance of Alzheimer’s disease.
“Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimer’s disease (AD),” said Xinglong Wang, an associate professor of pathology at the School of Medicine. “We also see this as a potential novel therapeutic target for this devastating disease.”
Wang said proving the latter assertion, which has not yet been tested in humans, would require additional research to corroborate the function of the protein they have dubbed “aggregatin.” Eventually, that would someday mean clinical trials with Alzheimer’s patients, he said.
“This protein characteristically accumulates, or aggregates, within the center of plaque in AD patients, like the yolk of an egg–which is part of the reason we named it “aggregatin,” Wang said.
A research team led by Wang and Xiaofeng Zhu, a professor of Population and Quantitative Health Sciences at the School of Medicine, has filed for a patent through the university’s Office of Research and Technology Management for “novel Alzheimer’s disease treatments and diagnosis based on this and related study,” Wang said.
“We’re very excited about this because our study is likely the first systematic work combining the identification from a genome-wide association study of high dimensional brain-imaging data and experimental validation so perfectly in Alzheimer’s disease,” Zhu said.
Their research was published this month by the scientific journal Nature Communications and supported by grants from the National Institutes of Health (NIH) and the Alzheimer’s Association. Genomic and brain imaging data was obtained from the Alzheimer’s Disease Neuroimaging Initiative, which is supported by the NIH.
Alzheimer’s Disease affects millions
More than 5.7 million Americans have Alzheimer’s disease, which is the primary cause of dementia and sixth-leading cause of death in the United States. That population is predicted to reach 14 million by the year 2050, according to the Alzheimer’s Association.
The relationship between Alzheimer’s (and subsequent brain atrophy) and amyloid plaques–the hard accumulations of beta amyloid proteins that clump together between the nerve cells (neurons) in the brains of Alzheimer’s patients–has been well-established among researchers.
Less understood is precisely how that amyloid-beta actually leads to plaque formation–and where this new work appears to have broken new ground, Wang said.
An image of the ‘Aggregatin’ protein. Image is credited to Wang, Zhu and collaborators.
Further, while there has been much research into what genes might influence whether or not someone gets Alzheimer’s, there is less understanding of genes that might be linked to the progression of the disease, meaning the formation of plaque and subsequent atrophy in the brain.
The role of ‘aggregatin’ protein
In the new work, the researchers began by correlating roughly a million genetic markers (called single-nucleotide polymorphisms, or SNPs) with brain images. They were able to identify a specific SNP in the FAM222, a gene linked to different patterns of regional brain atrophy.
Further experiments then suggested that the protein encoded by gene FAM222A is not only associated with AD patient-related beta-amyloid plaques and regional brain atrophy, but that “aggregatin” attaches to amyloid beta peptide–the major component of plaque and facilitates the plaque formation.
So when researchers injected mouse models with the “aggregatin” protein (made from the FAM222A gene), plaque (amyloid deposits) formation accelerated in the brain, resulting in more neuroinflammation and cognitive dysfunction.
This happened, they report, because the protein was found to bind directly the amyloid beta peptide, thus facilitating the aggregation and placque formation, Wang said.
Conversely, when they suppressed the protein, the plaques were reduced and neuroinflammation and cognitive impairment alleviated.
Their findings indicate that reducing levels of this protein and inhibition of its interaction with amyloid beta peptide could p
Dementia is a general term that refers to a decline in cognitive ability severe enough to interfere with activities of daily living. Alzheimer disease (AD) is the most common type of dementia, accounting for at least two-thirds of cases of dementia in people age 65 and older.
Alzheimer disease is a neurodegenerative disease that causes progressive and disabling impairment of cognitive functions including memory, comprehension, language, attention, reasoning, and judgment. It is the sixth leading cause of death in the United States. Alzheimer disease is typically a disease of old age. Onset before 65 years of age (early onset) is unusual and seen in less than 10% of Alzheimer disease patients.
The most common presenting symptom is selective short-term memory loss. The disease is invariably progressive, eventually leading to severe cognitive decline. There is no cure for Alzheimer disease, although there are treatments available that may improve some symptoms.
Symptoms of Alzheimer disease depend on the stage of the disease. Alzheimer disease is classified into preclinical, mild, moderate, and late-stage depending on the degree of cognitive impairment.
The initial presenting symptom is usually recent memory loss with relative sparing of long-term memory and can be elicited in most patients even when not the presenting symptom. Short-term memory impairment is followed by impairment in problem-solving, judgment, executive functioning, lack of motivation and disorganization, leading to problems with multitasking and abstract thinking. In the early stages, impairment in executive functioning may be subtle.
This is followed by language disorder and impairment of visuospatial skills. Neuropsychiatric symptoms like apathy, social withdrawal, disinhibition, agitation, psychosis, and wandering are also common in the mid to late stages. Difficulty performing learned motor tasks (dyspraxia), olfactory dysfunction, sleep disturbances, extrapyramidal motor signs like dystonia, akathisia, and parkinsonian symptoms occur late in the disease. This is followed by primitive reflexes, incontinence, and total dependence on caregivers.[1],[2],[3]
Etiology
Alzheimer disease is a gradual and progressive neurodegenerative disease caused by neuronal cell death. It typically starts in the entorhinal cortex in the hippocampus. There is a genetic role identified for both early and late-onset Alzheimer disease. Several risk factors have been associated with Alzheimer disease. Increasing age is the most important risk factor for Alzheimer disease.
Traumatic head injury, depression, cardiovascular and cerebrovascular disease, higher parental age, smoking, family history of dementia, and presence of APOE e4 allele are known to increase the risk of Alzheimer disease. Higher education, use of estrogen by women, use of anti-inflammatory agents, and regular aerobic exercise is known to decrease the risk of Alzheimer disease. Having a first-degree relative with Alzheimer disease increases the risk of developing Alzheimer disease by 10% to 30%. Individuals with 2 or more siblings with late-onset Alzheimer disease increases their risk of getting Alzheimer disease by 3-fold as compared to the general population.[4],[5],[6]
Epidemiology
Alzheimer disease is typically a disease of old age. The global prevalence of dementia is reported to be as high as 24 million and is predicted to increase 4 times by the year 2050. Estimated health care cost of Alzheimer disease is $172 billion per year in the United States alone. In 2011, the United States had an estimated 4.5 million people age sixty-five and above, living with clinical Alzheimer disease. The incidence of dementia is predicted to double every 10 years after 60 years of age. Age-specific incidence increases significantly from less than 1% per year before 65 years of age to 6% per year after 85 years of age. Incidence rates of Alzheimer disease are slightly higher for women, especially after 85 years of age.Go to:
Pathophysiology
Alzheimer disease is characterized by an accumulation of abnormal neuritic plaques and neurofibrillary tangles.
Plaques are spherical microscopic lesions that have a core of extracellular amyloid beta peptide surrounded by enlarged axonal endings. Beta-amyloid peptide is derived from a transmembrane protein known as an amyloid precursor protein (APP). The beta-amyloid peptide is cleaved from APP by the action of proteases named alpha, beta, and gamma-secretase. Usually, APP is cleaved by either alpha or beta-secretase and the tiny fragments formed by them are not toxic to neurons. However, sequential cleavage by beta and then gamma-secretase results in 40 and 42 amino acid peptides (beta-amyloid 40 and beta-amyloid 42). Elevation in levels of beta-amyloid 42 leads to aggregation of amyloid that causes neuronal toxicity. Beta-amyloid 42 favors formation of aggregated fibrillary amyloid protein over normal APP degradation. APP gene is located on chromosome 21, one of the regions linked to the familial Alzheimer disease. Amyloid deposition occurs around meningeal and cerebral vessels and gray matter in Alzheimer disease. Gray matter deposits are multifocal and coalesce to form milliary structures called plaques.
Neurofibrillary tangles are fibrillary intracytoplasmic structures in neurons formed by a protein called tau. The primary function of tau protein is to stabilize axonal microtubules. Microtubules run along neuronal axons and are essential for intracellular transport. Microtubule assembly is held together by tau protein. In Alzheimer disease, due to aggregation of extracellular beta-amyloid, there is hyper-phosphorylation of tau which then causes the formation of tau aggregates. Tau aggregates form twisted paired helical filaments known as neurofibrillary tangles. They occur first in the hippocampus and then may be seen throughout the cerebral cortex. There is a staging system developed by Braak and Braak based on topographical staging of neurofibrillary tangles into 6 stages, and this Braak staging is an integral part of the National Institute on Aging and Reagan Institute neuropathological criteria for the diagnosis of Alzheimer disease.
Another feature of Alzheimer disease is granulovacuolar degeneration of hippocampal pyramidal cells by amyloid angiopathy. Some reports indicate that cognitive decline correlates more with a decrease in density of presynaptic boutons from pyramidal neurons in laminae III and IV, rather than an increase in the number of plaques.
Vascular contribution to the neurodegenerative process of Alzheimer disease is not fully determined. Risk of dementia is increased fourfold with subcortical infarcts. Cerebrovascular disease also exaggerates the degree of dementia and its rate of progression.[7],[8],[9]
Genetic Basis of Alzheimer Disease
Alzheimer disease can be inherited as an autosomal dominant disorder with nearly complete penetrance. The autosomal dominant form of the disease is linked to mutations in 3 genes: AAP gene on chromosome 21, Presenilin1 (PSEN1) on chromosome 14, and Presenilin 2 (PSEN2) on chromosome 1. APP mutations may lead to increased generation and aggregation of beta-amyloid peptide. PSEN1 and PSEN2 mutations lead to aggregation of beta-amyloid by interfering with the processing of gamma-secretase. Mutations in these 3 genes account for about half of the familial forms of early-onset Alzheimer disease.
Apolipoprotein E is a regulator of lipid metabolism that has an affinity for beta-amyloid protein and is another genetic marker that increases the risk of Alzheimer disease. Isoform e4 of APOE gene (located on chromosome 19) has been associated with more sporadic and familial forms of Alzheimer disease that present after age 65. Presence of APOEe4 allele does not always lead to Alzheimer disease, but one APOE- e4 allele increase the risk by 2- to 3-fold and 2 copies by 5-fold. Each APOE e4 allele also lowers the age of disease onset. Presence of APOE e4 allele is an important risk factor for Alzheimer disease.
Variants in the gene for the sortilin receptor, SORT1, which is essential for transporting APP from cell surface to Golgi-endoplasmic reticulum complex, have been found in familial and sporadic forms of Alzheimer disease.[4]
History and Physical
A good history and physical examination are the keys to diagnosis. It is also essential to take a history from the family and caregivers as some patients may lack insight into their disease. It is vital to characterize onset and early symptoms to differentiate from other types of dementia. It is important to obtain a good assessment of functional abilities like basic and individual activities of daily living.
A complete physical examination with a detailed neurological exam and mental status examination is needed to evaluate disease stage and rule out other conditions. Comprehensive clinical assessment can provide reasonable diagnostic accuracy in most patients. A detailed neurological examination is essential to rule out other conditions. In Alzheimer disease, the neurological exam is usually normal. A mental status examination should assess concentration, attention, recent and remote memory, language, visuospatial functioning, praxis, and executive functioning.
Brief standard examinations like the mini-mental status examination are less sensitive and specific, although they can be used for screening.
All follow-up visits should include a full mental status examination to evaluate disease progression and development of neuropsychiatric symptoms.
Evaluation
Routine laboratory tests show no specific abnormality. Complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), B12 are usually checked to rule out other causes.[10],[11],[12]
Brain imaging may help in the diagnosis and monitor the clinical course of the disease. MRI or CT brain can help exclude other causes of dementia like stroke or tumors. Dilated lateral ventricles and widened cortical sulci, especially in the temporal area are typical for Alzheimer disease.
Cerebrospinal fluid (CSF) is usually normal, but total protein may be mildly elevated. Measurements of total-tau, beta-amyloid, and phosphorylated tau protein are sometimes helpful for differential diagnosis. Alzheimer disease is strongly predicted if CSF has decreased beta-amyloid 42 and increased tau protein.
EEG typically shows a generalized slowing with no focal features.
The most reliable method to detect mild cognitive impairment in early disease is neuropsychological testing.
More recently, volumetric MRI is being used to precisely measure volumetric changes in the brain. In Alzheimer disease, volumetric MRI shows shrinkage in the medial temporal lobe. However, hippocampal atrophy is also linked to normal age-related memory decline, so the use of volumetric MRI for early detection of Alzheimer disease is questionable. A definite role for volumetric MRI to aid diagnosis of Alzheimer disease is not fully established yet.
Functional brain imaging techniques like PET, fMRI, and SPECT are being used to map patterns of dysfunction in smaller brain areas of the medial temporal and parietal lobe. These studies may be helpful in early detection and monitoring clinical course; however, their role in the diagnosis of Alzheimer disease is not fully established yet.
Most recently, there have been developments in brain imaging techniques to detect core histological features of Alzheimer disease, that is amyloid plaques and neurofibrillary tangles. The utility of these techniques is still being investigated.
Genetic testing is usually not recommended for Alzheimer disease. It may sometimes be used in families with rare early-onset forms of Alzheimer disease.
It is important to understand that diagnosing the type of dementia with all certainty may not be entirely possible despite excellent clinical history, physical examination and relevant testing. Some patients will complain of cognitive impairment that can be verified objectively, but is not severe enough to impair activities of daily life and thus does not meet criteria for dementia, and is usually just classified as mild cognitive impairment. However, a significant proportion of people with mild cognitive impairment will develop dementia of some type in 5 to 7 years.
Treatment / Management
There is no cure for Alzheimer disease. Only symptomatic treatment is available.[13][14][15]
Two categories of drugs are approved for the treatment of Alzheimer disease: cholinesterase inhibitors and partial N-methyl D-aspartate (NMDA) antagonists.
Cholinesterase Inhibitors
Cholinesterase inhibitors act by increasing the level of acetylcholine; a chemical used by nerve cells to communicate with each other and is important for learning, memory and cognitive functions. Of this category, 3 drugs: donepezil, rivastigmine, and galantamine are FDA-approved for the treatment of Alzheimer disease.
Donepezil can be used in all stages of Alzheimer disease. Galantamine and rivastigmine are approved for treatment in mild to moderate Alzheimer disease only. Donepezil and galantamine are rapid, reversible inhibitors of acetylcholinesterase. Rivastigmine is a slow, reversible inhibitor of acetylcholinesterase and butyrylcholinesterase. Donepezil is usually preferred of all because of once-daily dosing. Galantamine is available as a twice daily tablet or as a once-daily extended-release capsule. It cannot be used in end-stage renal disease or severe liver dysfunction. Rivastigmine is available in an oral and transdermal formulation. Most common side effects of cholinesterase inhibitors are gastrointestinal-like nausea, vomiting, and diarrhea. Sleep disturbances are more common with donepezil. Due to increased vagal tone, bradycardia, cardiac conduction defects, and syncope can occur, and these medications are contraindicated in patients with severe cardiac conduction abnormalities.
Partial N-Methyl D-Aspartate (NMDA) Memantine
Partial N-Methyl D-aspartate (NMDA) antagonist memantine blocks NMDA receptors and slows intracellular calcium accumulation. It is approved by the FDA for treating moderate to severe Alzheimer disease. Dizziness, body aches, headache, and constipation are common side effects. It can be taken in combination with cholinesterase inhibitors.[16]
It is also important to treat anxiety, depression, and psychosis, which is often found in the mid to late stages of Alzheimer disease.
Environmental and behavioral approaches are beneficial especially in managing behavioral problems. Simple approaches such as maintaining a familiar environment, monitoring personal comfort, providing security object, redirecting attention, and avoiding confrontation can be very helpful in managing behavioral issues.
The expected benefits of the treatment are modest. Treatment should be stopped or modified if no significant benefits or if intolerable side effects.
Regular aerobic exercise has been shown to slow the progression of Alzheimer disease.Go to:
Differential Diagnosis
Differential diagnosis of Alzheimer dementia includes- Mild cognitive decline, Pseudodementia, Depression, Lewy body dementia, Vascular dementia, Mixed dementia, and frontotemporal lobar degeneration. Other disorders to consider and rule out when evaluating for Alzheimer disease include age-associated memory impairment, alcohol or drug abuse, depression, vitamin-B12 deficiency, hearing or visual impairment, electrolyte imbalance, thyroid problems, normal pressure hydrocephalus, Parkinson disease with dementia, polypharmacy, Wernicke-Korsakoff syndrome.
Some atypical presentations of Alzheimer disease include:
- The multidomain amnestic syndrome affects multiple areas of cognition especially language and spatial orientation with relative sparing of memory in early stages.
- Posterior cortical atrophy manifests as progressive cortical visual impairment with features such as simultagnosia, object, and space perception deficits, acalculia, alexia, and oculomotor apraxia, with relative sparing of anterograde memory, non-visual language function, behavior, and personality. Neuroimaging shows occipitoparietal or occipitotemporal atrophy.
- Primary progressive aphasia is characterized by progressive language difficulty with relative sparing of memory and other cognitive functions in early disease.
- Dysexecutive or frontal variant patients have impairment in executive functions relative to memory loss.
Staging
Preclinical
Earliest pathological changes begin in the entorhinal cortex, followed by the hippocampus. In this stage, patients present with mild memory loss with no significant functional impairment in their daily activities. At this stage, it is classified as mild cognitive impairment.
Mild Alzheimer Disease
Cognitive impairment starts at this stage as the disease progresses to the cerebral cortex. Along with memory loss, there is an inability to remember new information, forgetting things and appointments, repetitive questions and conversations, confusion, disorientation, personality changes, mood swings, loss of spontaneity, and impairment in reasoning and judgment.
Moderate Alzheimer Disease
At this stage, the disease further spreads to areas of the cerebral cortex responsible for language, reasoning, and sensory processing. There is increasing memory loss and attention, and behavioral problems like wandering off and agitation begin to appear. Patients at this stage have trouble recognizing own family and friends. They have apathy, social withdrawal, and loss of inhibition. They often make repetitive statements and have a loss of impulse control. They also have difficulty with language, reading, and writing.
Severe Alzheimer Disease
The disease progresses to involve the entire cortex at late stages. Patients at this stage of Alzheimer disease, cannot recognize their family and friends at all and are entirely dependent on others for daily activities. Along with other features, they also become incontinent of bladder and bowel and may have difficulty swallowing.
Prognosis
Alzheimer disease is an invariably progressive disease. Average life expectancy for a person age 65 years or older diagnosed with Alzheimer disease is about 4 to 8 years. Some individuals with Alzheimer disease may live up to 20 years after the first signs of disease. The most common cause of death in Alzheimer disease is pneumonia.[17]
Enhancing Healthcare Team Outcomes
Alzheimer disease (AD) is a progressive neurodegenerative disorder marked by behavior and cognitive impairment that eventually interfere with daily functional living activities. The disorder has no cure, and its rate of progression is variable. Further, the diagnosis of Alzheimer disease in the early phase is difficult, and there are no specific laboratory or imaging tests to confirm the diagnosis. The drugs available to treat the condition only work for the mild disease but also have numerous side effects which are not well tolerated. Alzheimer disease is a systemic disorder and creates havoc in the family. These individuals often wander, fall, have significant behavior problems and loss of memory. The majority of patients end up in an institution because they become unmanageable at home. Because of the nature of the disease, an interprofessional team approach to the disorder has been recommended. Many guidelines and recommendations have been made on how to approach, monitor and treat Alzheimer patients. No one measure can prevent or arrest the disease. Given this, the following health care workers have a critical role in ensuring that the patient with Alzheimer disease remains safe and lead a decent quality of life.
- Physical therapy for exercise. There is now ample evidence that exercise can help reduce the progression of the disease.[18] (Level III)
- Nurses to educate the patient and family on medications, lifestyle changes, and performing daily living activities. To educate the partner on self-reporting on the worsening of symptoms.
- Pharmacist to ensure that polypharmacy does not occur and that the patient is not developing adverse effects.
- Clinicians to monitor patient progress and enhance the quality of life
- Caregivers to provide support
- Social workers to ensure that the patient has an adequate support system
- Dietitian to ensure that the patient is eating a healthy diet
- Mental health nurses to ensure that both the patient and caregiver are coping with the disorder
Outcomes
Alzheimer disease is initially associated only with impaired memory, but with time, the individual may develop severe cognitive and behavioral symptoms like depression, anxiety, anger, irritability, insomnia, and paranoia. As the disease progresses most of them will require assistance with daily living activities. Eventually, even walking become difficult and many may not be able to eat or develop swallowing difficulties that lead to aspiration pneumonia.
The time from diagnosis to death is variable; some individuals may die within five years, and others may remain alive for ten years, but overall the quality of life is very poor. While an interprofessional approach to management of Alzheimer patients is recommended, an analysis of several studies reveals that this approach has no impact on the care of his patients. However, because of the heterogeneity in the previous studies, more robust studies will be required to determine what type of approach works best for managing these patients.[19]
Source:
Case Western Reserve
