what is alzheimer disease and the two pathological changes that contributes to neuronal death?

Alzheimer affliction causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical grey affair. Diagnosis is clinical; laboratory and imaging tests are ordinarily done to expect for specific findings that suggest Alzheimer affliction and to identify other treatable causes of dementia. Handling is supportive. Cholinesterase inhibitors can sometimes temporarily improve cognitive function.

• Age 65 to 74: 3%

• Age 75 to 84: 17%

• Age ≥ 85: 32%

The illness is twice equally common amidst women as amongst men, partly because women have a longer life expectancy. Prevalence in industrialized countries is expected to increase equally the proportion of older people increases.

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• 1. Alzheimer'southward Association: 2020 Alzheimer's Disease Facts and Figures. Alzheimers Dement xvi (3):391–460, 2020. https://doi.org/10.1002/alz.12068

Nearly cases of Alzheimer disease are sporadic, with late onset (≥ 65 years) and unclear etiology. Risk of developing the disease is best predicted by age. Nonetheless, about 5 to xv% of cases are familial; one-half of these cases have an early on (presenile) onset (< 65 years) and are typically related to specific genetic mutations.

At least 5 distinct genetic loci, located on chromosomes 1, 12, fourteen, 19, and 21, influence initiation and progression of Alzheimer affliction.

Mutations in genes for the amyloid precursor poly peptide, presenilin I, and presenilin II may lead to autosomal dominant forms of Alzheimer illness, typically with presenile onset. In afflicted patients, the processing of amyloid precursor protein is altered, leading to deposition and fibrillar aggregation of beta-amyloid; beta-amyloid is the master component of senile plaques, which consist of degenerated axonal or dendritic processes, astrocytes, and glial cells around an amyloid core. Beta-amyloid may too change kinase and phosphatase activities in ways that eventually lead to hyperphosphorylation of tau (a poly peptide that stabilizes microtubules) and formation of neurofibrillary tangles.

Other genetic determinants include the apolipoprotein (apo) E (epsilon) alleles. Apo E proteins influence beta-amyloid deposition, cytoskeletal integrity, and efficiency of neuronal repair. Risk of Alzheimer affliction is substantially increased in people with two epsilon-4 alleles and may be decreased in those who have the epsilon-2 allele. For people with two epsilon-4 alleles, take chances of developing Alzheimer affliction by historic period 75 is most 10 to xxx times that for people without the allele.

Vascular take chances factors, such as hypertension, diabetes, dyslipidemia, and smoking, tin increase the risk of Alzheimer disease. Growing evidence suggests that aggressive treatment of these risk factors equally early as midlife can attenuate the risk of developing cerebral impairment in older age.

The relationship of other factors, such as depression hormone levels and metal exposure, to Alzheimer illness has not been established.

The two pathologic hallmarks of Alzheimer disease are

• Extracellular beta-amyloid deposits (in senile plaques)

• Intracellular neurofibrillary tangles (paired helical filaments)

The beta-amyloid deposition and neurofibrillary tangles lead to loss of synapses and neurons, which results in gross cloudburst of the affected areas of the brain, typically starting at the mesial temporal lobe.

The mechanism by which beta-amyloid peptide and neurofibrillary tangles cause such impairment is incompletely understood. There are several theories.

The amyloid hypothesis posits that progressive aggregating of beta-amyloid in the encephalon triggers a circuitous cascade of events ending in neuronal jail cell death, loss of neuronal synapses, and progressive neurotransmitter deficits; all of these furnishings contribute to the clinical symptoms of dementia.

• 1. Kinney JW, Bemiller SM, Murtishaw AS, et al: Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (NY) 4:575–590, 2018. doi: 10.1016/j.trci.2018.06.014

Symptoms and Signs of Alzheimer Disease

The well-nigh common first manifestation of Alzheimer disease is

• Loss of brusque-term memory (eg, asking repetitive questions, oftentimes misplacing objects or forgetting appointments)

Other cognitive deficits tend to involve multiple functions, including the following:

• Impaired reasoning, difficulty treatment complex tasks, and poor judgment (eg, being unable to manage banking company account, making poor financial decisions)

• Language dysfunction (eg, difficulty thinking of common words, errors speaking and/or writing)

• Visuospatial dysfunction (eg, inability to recognize faces or mutual objects)

Alzheimer disease progresses gradually simply may plateau for periods of fourth dimension.

• Like to that of other dementias

• Formal mental status examination

• History and concrete examination

• Laboratory testing

• Neuroimaging

Traditional diagnostic criteria for Alzheimer disease include all of the following:

• Dementia established clinically and documented by a formal mental condition exam

• Deficits in ≥ 2 areas of cognition

• Gradual onset (ie, over months to years, rather than days or weeks) and progressive worsening of retentiveness and other cognitive functions

• No disturbance of consciousness

• Onset later age 40, most often later on age 65

• No systemic or encephalon disorders (eg, tumor, stroke) that could business relationship for the progressive deficits in memory and cognition

However, deviations from these criteria do not exclude a diagnosis of Alzheimer disease, particularly because patients may have mixed dementia.

• A low level of beta-amyloid in cerebrospinal fluid (CSF)

• Beta-amyloid deposits in the encephalon detected by positron emission tomography (PET) imaging using radioactive tracer that binds specifically to beta-amyloid plaques (eg, Pittsburgh compound B [PiB], florbetapir)

Other biomarkers signal downstream neuronal degeneration or injury:

• Elevated levels of tau poly peptide in CSF or tau deposits in the brain detected by PET imaging using radioactive tracer that binds specifically to tau

• Decreased cerebral metabolism in the temporoparietal cortex measured using PET with fluorine-18 (18F)–labeled deoxyglucose (fluorodeoxyglucose, or FDG)

• Local atrophy in the medial, basal, and lateral temporal lobes and the medial parietal cortex, detected by MRI

Laboratory tests (eg, thyroid-stimulating hormone, vitamin B12 levels) and neuroimaging (MRI or CT) are done to check for other, treatable causes of dementia and disorders that tin can worsen symptoms. If clinical findings suggest some other underlying disorder (eg, HIV, syphilis), tests for those disorders are indicated.

Patients with Alzheimer disease are frequently amend-groomed and neater than patients with other dementias.

• 1. Jack CR Jr, Albert MS, Knopman DS, et al: Introduction to the revised criteria for the diagnosis of Alzheimer's disease: National Institute on Aging and Alzheimer's Association workgroups. Alzheimers Bewilder 7 (iii):257–262, 2011. doi: 10.1016/j.jalz.2011.03.004

• ii. McKhann GM, Knopman DS, Chertkow H, et al: The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Plant on Aging-Alzheimer's Clan workgroups on diagnostic guidelines for Alzheimer'southward disease. Alzheimers Dement 7 (three):263–269, 2011. doi: 10.1016/j.jalz.2011.03.005

• three. Chételat G, Arbizu J, Barthel H, et al: Amyloid-PET and 18 F-FDG-PET in the diagnostic investigation of Alzheimer'due south disease and other dementias. Lancet Neurol 19:951–962, 2020. doi: x.1016/S1474-4422(20)30314-8

Although progression charge per unit varies in patients with Alzheimer disease, cerebral decline is inevitable. Average survival from time of diagnosis is vii years, although this figure is debated. Average survival from the time patients tin no longer walk is well-nigh half dozen months.

• Safety and support measures

• Mayhap cholinesterase inhibitors and memantine

Cholinesterase inhibitors modestly improve cognitive function and memory in some patients. Four are available. Generally, donepezil, rivastigmine, and galantamine are as effective, but tacrine is rarely used considering of its hepatotoxicity.

Donepezil is a first-line drug because information technology has once-a-mean solar day dosing and is well-tolerated. The recommended dose is 5 mg orally once a day for 4 to 6 weeks, then increased to 10 mg one time a mean solar day. Donepezil 23 mg in one case a day may be more constructive than the traditional x mg in one case-a-day dose for moderate to severe Alzheimer disease. Treatment should be continued if functional improvement is credible after several months, only otherwise it should be stopped. The most common adverse furnishings are gastrointestinal (eg, nausea, diarrhea). Rarely, dizziness and cardiac arrhythmias occur. Adverse effects can exist minimized past increasing the dose gradually (see table Drugs for Alzheimer Disease Drugs for Alzheimer Affliction ).

Memantine, an Northward-methyl-d-aspartate (NMDA) receptor antagonist, appears to ameliorate cognition and functional capacity of patients with moderate to astringent Alzheimer disease. The dose is 5 mg orally one time a day, which is increased to x mg orally twice a twenty-four hour period over about 4 weeks. For patients with renal insufficiency, the dose should be reduced or the drug should be avoided. Memantine can be used with a cholinesterase inhibitor.

Aducanumab, a human IgG1 anti-amyloid monoclonal antibody specific for beta-amyloid oligomers implicated in the pathophysiology of Alzheimer disease, is at present available as a monthly infusion to treat Alzheimer disease. Although some experts consider aducanumab to be the offset efficacious disease-modifying treatment for Alzheimer disease, its approving by the U.s. Nutrient and Drug Assistants (FDA) was controversial. The drug's accelerated approval was based mainly on its ability to reduce brain beta-amyloid plaques in patients in clinical trials. But evidence of clinical do good (slowing progression of the disease) in these trials was inconsistent; thus, additional trials are needed to confirm clinical benefit.

Anti-amyloid monoclonal antibody therapies, including aducanumab, also have adverse furnishings, including amyloid-related imaging abnormalities (ARIA), which consist of MRI point changes of cerebral edema (ARIA-Eastward) and/or microhemorrhage and superficial hemosiderosis (ARIA-H). ARIA-E adult in 35.ii% of patients receiving a high dose of aducanumab in phase 3 clinical trials; ARIA-E commonly occurred early on in handling and caused no symptoms. Nevertheless, up to 0.9% of patients with ARIA had severe symptoms, including confusion, disorientation, gait disturbance, ataxia, visual disturbance, headache, nausea, and falls (1 Treatment reference Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ).

Other drugs are being studied. Efficacy of high-dose vitamin E (1000 IU orally once or twice a 24-hour interval), selegiline, nonsteroidal anti-inflammatory drugs (NSAIDs), Ginkgo biloba extracts, and statins is unclear. Estrogen therapy does not appear useful in prevention or treatment and may exist harmful.

Because insight and judgment deteriorate in patients with dementia, appointment of a family unit member, guardian, or lawyer to oversee finances may be necessary. Early on in dementia, before the patient is incapacitated, the patient'southward wishes well-nigh care should be clarified, and financial and legal arrangements (eg, durable power of chaser, durable power of chaser for health intendance Durable power of attorney for health care Advance directives are legal documents that extend a person's command over wellness intendance decisions in the event that the person becomes incapacitated. They are called accelerate directives because... read more ) should be made. When these documents are signed, the patient's capacity Capacity (Competence) and Incapacity Historically, "incapacity" was considered primarily a clinical finding, and "incompetency" was considered a legal finding. That distinction, at least in terminology, is no longer firmly recognized... read more should be evaluated, and evaluation results recorded. Decisions about artificial feeding and treatment of acute disorders are best fabricated before the need develops.

• one. Alexander GC, Emerson Southward, Kesselheim AS: Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 325(17):1717-1718, 2021. PMID: 33783469. doi: 10.1001/jama.2021.3854

Preliminary, observational show suggests that run a risk of Alzheimer affliction may be decreased by the following:

• Continuing to exercise challenging mental activities (eg, learning new skills, doing crossword puzzles) well into old age

• Exercising

• Controlling hypertension

• Lowering cholesterol levels

• Consuming a diet rich in omega-3 fatty acids and low in saturated fats

• Drinking alcohol in modest amounts

However, there is no convincing evidence that people who practice not beverage alcohol should start drinking to prevent Alzheimer disease. One time dementia develops, abstaining from booze is usually recommended because alcohol can worsen dementia symptoms.

• Although genetic factors can be involved, most cases of Alzheimer disease are sporadic, with run a risk predicted all-time past patient age.

• Differentiating Alzheimer affliction from other causes of dementia (eg, vascular dementia, dementia with Lewy bodies) tin be difficult merely is often best done using clinical criteria, which are 85% authentic in establishing the diagnosis.

• Treat Alzheimer disease similarly to other dementias.

The following are some English-linguistic communication resources that may exist useful. Please note that THE Manual is non responsible for the content of these resources.

• Alzheimer'south Association: Describes biomarkers for before diagnosis of Alzheimer disease and other diagnostic tools for the diagnosis of Alzheimer disease (eg, neuroimaging, blood and urine tests), equally well every bit links to resources for back up and data about ongoing research

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Source: https://www.msdmanuals.com/professional/neurologic-disorders/delirium-and-dementia/alzheimer-disease

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