1. Presented by Akpan Edidiong Anieti 5th Course Lugansk State Medical University

2. Defination Alzheimer disease (AD) is an acquired disorder ofcognitive and behavioral impairment that markedly interferes with social and occupational functioning. It is an incurable disease with a long and progressive course. 3. ETIOLOGY The cause of AD is unknown. Several investigatorsnow believe that converging environmental and genetic risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia. 4. The following risk factors for Alzheimer-typedementia have been identified: Advancing age Family history 5. APOE 4 genotype: APOE The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to increased risk for AD, principally late-onset but also some early-onset cases. The gene is inherited as an autosomal codominant trait with 3 alleles. The APOE E2 allele, the least prevalent of the 3 common APOE alleles, is associated with the lowest risk of developing AD,with a lower rate of annual hippocampal atrophy and higher cerebrospinal fluid A and lower phosphotau, suggesting less AD pathology. 6. The E3 allele confers intermediate risk of developing AD,with less risk than the E4 allele. The E3 allele, which is more common than the E2 allele, may protect tau from hyperphosphorylation, and the E2 alleles effect on tau phosphorylation is complex. APOE E4 gene dose is correlated with increased risk and earlier onset of AD.Individuals who are genetically predisposed to AD are advised to closely control their blood pressure closely. Hypertension has been shown to interact with APOE E4 genotype to increase amyloid deposition in cognitively healthy middle-aged and older adults; controlling hypertension may significantly decrease the risk of developing amyloid deposits, even in those with genetic risk. 7. Persons with 2 copies of the APOE E4 allele (4/4 genotype)have a significantly greater risk of developing AD than persons with other APOE subtypes. Mean age at onset is significantly lower in the presence of 2 APOE E4 copies. A collaborative study has suggested that APOE E4 exerts its maximal effect before the age of 70 years. Many APOE E4 carriers do not develop AD, and many patients with AD do not have this allele. Therefore, the presence of an APOE E4 allele does not secure the diagnosis of AD, but instead, the APOE E4 allele acts as a biologic risk factor for the disease, especially in those younger than 70 years. 8. Obesity Infection: Treponemas and Borrelia burgdorferi, as wellas pathogens such as herpes simplex virus type 1 9. Insulin resistance Vascular factors Dyslipidemia Hypertension Inflammatory markers Down syndrome Traumatic brain injury 10. Midlife hypertension is an established risk factor forlate-life dementia, of which AD is the most common type. A brain autopsy study evaluating the link between hypertension and AD found that patients using beta-blockers to control blood pressure had fewer Alzheimer's-type brain lesions on autopsy compared to patients taking no drug therapy or those taking other medications. 11. In addition, epidemiologic studies have suggestedsome possible risk factors (eg, aluminum, previous depression) and some protective factors (eg, education,long-term use of nonsteroidal antiinflammatory drugs ). 12. Genetic causes Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist. Autosomal dominant AD, which accounts for less than 5% of cases, is almost exclusively early onset AD; cases occur in at least 3 individuals in 2 or more generations, with 2 of the individuals being first-degree relatives. Mutations in the following genes unequivocally cause early-onset autosomal dominant AD: The amyloid precursor protein (APP) gene on chromosome 21 The presenilin-1 (PS1) gene on chromosome 14 The presenilin-2 (PS2) gene on chromosome 1 13. PATHOPHYSIOLOGY A continuum exists between the pathophysiology of normal aging and that ofAD. Pathologic hallmarks of AD have been identified; however, these features also occur in the brains of cognitively intact persons. For example, in a study in which neuropathologists were blinded to clinical data, they identified 76% of brains of cognitively intact elderly patients as demonstrating AD. AD affects the 3 processes that keep neurons healthy: communication, metabolism, and repair. Certain nerve cells in the brain stop working, lose connections with other nerve cells, and finally die. The destruction and death of these nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease. The accumulation of SPs primarily precedes the clinical onset of AD. NFTs, loss of neurons, and loss of synapses accompany the progression of cognitive decline. 14. Amyloid, or senile, plaques are dense, insolubledeposits of amyloid-beta proteins, which are fragments of amyloid precursor proteins (APP), a transmembrane neuronal protein. As these proteins are enzymatically broken down, they clump together, forming the dense structures identifiable as amyloid plaques. These plaques primarily accumulate in the association cortices and hippocampus. 15. a structure deep in the brain that helps to encodememories, and in other areas of the cerebral cortex that are used in thinking and making decisions. Plaques may begin to develop as early as the fifth decade of life. Whether Ab plaques themselves cause AD or whether they are a by-product of the AD process is still unknown. It is known that changes in APP structure can cause a rare, inherited form of AD. 16. Neurofibrillary tangles develop when microtubule tau (a protein thatbinds to and regulates the assembly and stability of neuronal microtubules and that is found in an abnormal form as the major component of neurofibrillary tanglescalled also tau protein) proteins become hyperphosphorylated and aggregate within the neuronal cells. These tangles break down the neurons' ability to transport molecules along the axon. Neurofibrillary tangles initially form in the medial aspect and pole of the temporal lobe, especially the hippocampus. With increasing disease progression, they spread throughout the cortex, beginning in the high-order association regions and less commonly in the primary motor and sensory regions. 17. Tangles are insoluble twisted fibers that build upinside the nerve cell. Although many older people develop some plaques and tangles, the brains of people with AD have them to a greater extent, especially in certain regions of the brain that are important in memory. There are likely to be significant age-related differences in the extent to which the presence of plaques and tangles are indicative of the presence of dementia. 18. In addition to NFTs and SPs, many other lesions of ADhave been recognized since Alzheimers original papers were published. These include the granulovacuolar degeneration of Shimkowicz; the neuropil threads of Braak et al ; and neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder 19. Inflammatory reactions Inflammatory and immune mechanisms may play a role in the degenerative process in AD. Reactive microglia are embedded in neuritic plaques. Increased cytokine levels are seen in the serum, cortical plaques, and neurons of patients with AD, as compared with aged-matched control patients. Interestingly, transforming growth factor beta 1 (TGF-1), which is an anti-inflammatory cytokine, has been found to promote or accelerate the deposition of amyloid. Classical complement pathway fragments are also found in the brains of patients with AD, and amyloid may directly activate the classical complement pathway in an antibody-independent fashion. 20. Whether markers of immune and inflammatory processesactively participate in the neurodegenerative process or instead represent an epiphenomenon remains unclear. Brain specimens from elderly patients with arthritis treated with nonsteroidal anti-inflammatory drugs (NSAIDs) have similar numbers of senile plaques as do control brains. However, less microglial activation is seen in the brains of the patients with arthritis. This suggests that although NSAIDs may not impede senile plaque formation, they may delay or prevent clinical symptoms by limiting the associated inflammation. 21. As mentioned above, RAGE has been shown to mediate theinteraction of amyloid and glial cells, producing cellular activation and an inflammatory response with cytokine production, chemotaxis, and haptotaxis. The expression of this receptor appears to be upregulated in neurons, vasculature, and microglia in affected regions of AD brains. The unrelated class A scavenger receptor (class A SR) also mediates the adhesion of microglial cells to amyloid fibrils. SPs contain high concentrations of microglia that express class A SRs. RAGE and class A SRs may represent novel pharmacologic targets for diminishing the inflammatory a 22. CLINICAL SYMPTOMS AND DEGREES Preclinical Alzheimer disease A patient with preclinical AD may appear completely normal on physical examination and mental status testing. Specific regions of the brain (eg, entorhinal cortex, hippocampus) probably begin to be affected 1020 years before any visible symptoms appear. 23. Mild Alzheimer disease Signs of mild AD can include the following: Memory loss Confusion about the location of familiar places Taking longer to accomplish normal, daily tasks Trouble handling money and paying bills Compromised judgment, often leading to bad decisions Loss of spontaneity and sense of initiative Mood and personality changes; increased anxiety 24. Moderate Alzheimer disease The symptoms of this stage can include the following: Increasing memory loss and confusion Shortened attention span Problems recognizing friends and family members Difficulty with language; problems with reading, writing, working with numbers Difficulty organizing thoughts and thinking logically 25. Inability to learn new things or to cope with new or unexpected situations Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night Repetitive statements or movement; occasional muscle twitches Hallucinations, delusions, suspiciousness or paranoia, irritability Loss of impulse control: Shown through behavior such as undressing at inappropriate times or places or vulgar language Perceptual-motor problems: Such as trouble getting out of a chair or setting the table 26. Severe Alzheimer disease Patients with severe AD cannot recognize family or loved ones and cannot communicate in any way. They are completely dependent on others for care, and all sense of self seems to vanish. Other symptoms of severe AD can include the following: Weight loss Seizures, skin infections, difficulty swallowing Groaning, moaning, or grunting Increased sleeping Lack of bladder and bowel control In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia. 27. APROACH CONSIDERATIONS & DIAGNOSIS Blood Studies Laboratory tests can be performed to rule out other conditions that may cause cognitive impairment. Current recommendations from the American Academy of Neurology (AAN) include measurement of the cobalamin (vitamin B12) level and a thyroid function screening test. Additional investigations are left up to the physician, to be tailored to the particular needs of each patient. Initial test results that require further investigation include the following: Abnormalities in complete blood cell count and cobalamin (vitamin B-12) levels require further workup to rule out hematologic disease Abnormalities found in screening of liver enzyme levels require further workup to rule out hepatic disease 28. Abnormalities in thyroid-stimulating hormone (TSH)levels require further workup to rule out thyroid disease Abnormalities in rapid plasma reagent (RPR) require further workup to rule out syphilis There is a possible link between vitamin D deficiency and cognitive impairment. However, vitamin D deficiency has not been identified as a reversible cause of dementia. 29. Brain MRI or CT Scanning American Academy of Neurology (AAN) recommendations indicate that structural neuroimaging with either a noncontrast computed tomography (CT) scan or magnetic resonance image (MRI) is appropriate in the initial evaluation of patients with dementia, in order to detect lesions that may result in cognitive impairment (eg, stroke, small vessel disease, tumor). 30. In clinical research studies, atrophy of the hippocampi (structuresimportant in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology. Nonetheless, measurement of hippocampal volume is not used in routine clinical care in the diagnosis of AD. A study by Chen et al suggests that resting state functional MRI can help classify patients with AD, patients with amnestic mild cognitive impairment (MCI), and cognitively healthy patients. Default mode network (DMN) imaging appears to distinguish AD, MCI, and controls well, and it may complement positron emission tomography (PET) scanning or prove to be more sensitive. 31. Electroencephalography Electroencephalography (EEG) is valuable when CreutzfeldtJakob disease or other prion-related disease is a likely diagnosis (see EEG in Dementia and Encephalopathy). Periodic high-amplitude sharp waves can eventually be detected in most cases of CreutzfeldtJakob disease. EEG is also useful if pseudodementia is a realistic consideration when a normal EEG in a patient who appears profoundly demented would support that diagnosis. Multiple unwitnessed seizures rarely can present as dementia, and an EEG would be valuable for evaluating such a possibility. 32. Genotyping Genotyping for apolipoprotein E (APOE) alleles is a research tool that has been helpful in determining the risk of AD in populations, but until recently it was of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients. Numerous consensus statements have recommended against using APOE genotyping for predicting AD risk. 33. Investigators from the Copenhagen General Population Study and theCopenhagen City Heart Study have reported that plasma levels of APOE epsilon 4 (APOE 4) are associated with the risk of dementia, independent of the APOE genotype. The risk of Alzheimer disease increased with decreasing levels of APOE levels, with a highly significant 3-fold increased risk for the lowest tertile of APOE levels relative to the highest tertilean association that remained even after adjusting for the APOE genotype. The APOE genotypes with highest risks of Alzheimer disease were 43 and 44, whereas those with the lowest risks were 22, 32, 42, and 33. 34. Lumbar Puncture Perform lumbar puncture in select cases to rule out conditions such as normal-pressure hydrocephalus or central nervous system infection (eg, neurosyphilis, neuroborreliosis, cryptococcosis). CSF levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80%and more often 90%can be achieved. At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD are developed, particularly if the therapies are specific for AD and carry significant morbidity. 35. TREATMENT To date, only symptomatic therapies for Alzheimer disease (AD) areavailable. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors (ChEIs) and a partial N-methyl-Daspartate (NMDA) antagonist. Secondary symptoms of AD (eg, depression, agitation, aggression, hallucinations, delusions, sleep disorders) can be problematic. Behavioral symptoms in particular are common and can exacerbate cognitive and functional impairment. The following classes of psychotropic medications have been used to treat these secondary symptoms: 36. Antidepressants Anxiolytics Antiparkinsonian agents Beta-blockers Antiepileptic drugs (for their effects on behavior) Neuroleptics 37. Treatment of Mild to Moderate Disease Cholinesterase inhibition Numerous lines of evidence suggest that cholinergic systems that modulate information processing in the hippocampus and neocortex are impaired early in the course of AD. These observations have suggested that some of the clinical manifestations of AD are due to loss of cholinergic innervation to the cerebral cortex. Centrally acting ChEIs prevent the breakdown of acetylcholine. Four such agents have been approved by the FDA for the treatment of AD, as follows: Tacrine Donepezil (Aricept, Aricept ODT) Rivastigmine (Exelon, Exelon Patch) Galantamine (Razadyne, Razadyne ER) Mental activity to support cognition 38. Treatment of Moderate to Severe Disease The partial N -methyl-D-aspartate (NMDA) antagonist memantine (Namenda, Namenda XR) is believed to work by improving the signalto-noise ratio of glutamatergic transmission at the NMDA receptor. Blockade of NMDA receptors by memantine is thought to slow the intracellular calcium accumulation and thereby help prevent further nerve damage. This agent is approved by the FDA for treating moderate and severe AD. Several studies have demonstrated that memantine can be safely used in combination with ChEIs. The combination of memantine with a ChEI has been shown to significantly delay institutionalization in AD patients. Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD but not in mild to moderate AD.Dizziness, headache, and confusion are some of the most common side effects of memantine. 39. In June 2013, the FDA approved rivastigminetransdermal for severe AD.Approval was based on the ACTION (ACTivities of Daily Living and CognitION in Patients with Severe Dementia of the Alzheimer's Type) study, in which a higher dose of the drug (13.3 mg/24 hr) demonstrated statistically significant improvement in overall cognition and function compared with a lower dose (4.6 mg/24 hr). 40. OTHER TREATMENT:Suppression of Brain Inflammation Many studies have suggested that intense inflammation occurs in the brains of patients with AD. Epidemiologic studies suggest that some patients on long-term anti-inflammatory therapy have a decreased risk of developing AD. Nonetheless, no randomized clinical trial longer than 6 months has demonstrated efficacy of anti-inflammatory drugs in slowing the rate of progression of AD. 41. Experimental Therapies A variety of experimental therapies have been proposed for AD. These include antiamyloid therapy, reversal of excess tau phosphorylation, estrogen therapy, vitamin E therapy, and free-radical scavenger therapy. Studies of these therapies have yielded mostly disappointing results. In the past 10 years, numerous antiamyloid therapy studies have been conducted to decrease toxic amyloid fragments in the brain, including studies of the following: Vaccination with amyloid species Administration of monoclonal antiamyloid antibodies Administration of intravenous immune globulin that may contain amyloid-binding antibodies Selective amyloid-lowering agents Chelating agents to prevent amyloid polymerization Brain shunting to improve removal of amyloid Beta-secretase inhibitors to prevent generation of the A-beta amyloid fragment 42. Dietary Measures There are no special dietary considerations for Alzheimer disease. However, caprylidene (Axona) is a prescription medical food that is metabolized into ketone bodies, and the brain can use these ketone bodies for energy when its ability to process glucose is impaired. Brain-imaging scans of older adults and persons with AD reveal dramatically decreased uptake of glucose. A study of 152 patients with mild to moderate AD found that at day 45, Alzheimers Disease Assessment Scalecognitive subscale (ADAS-Cog) scores stabilized in the caprylidene group but declined in the placebo group. 43. Physical Activity Routine physical activity and exercise may have an impact on AD progression and may perhaps have a protective effect on brain health.[6] Increased cardiorespiratory fitness levels are associated with higher hippocampal volumes in patients with mild AD, suggesting that cardiorespiratory fitness may modify AD-related brain atrophy. The activity of each patient should be individualized. The patients surroundings should be safe and familiar. Too much activity can cause agitation, but too little can cause the patient to withdraw and perhaps become depressed. Maintaining structured routines may be helpful to decrease patient stress in regard to meals, medication, and other therapeutic activities aimed at maintaining cognitive functioning. The patient needs contact with the outside environment. The physician should encourage participation in activities that interest the patient and result in cognitive stimulation but do not stress the patient. The range of possibilities is wide and may include visits to museums, parks, or restaurants. 44. Essential update: FDA approves flutemetamol F18 to evaluate for Alzheimer disease and dementia In October 2013, the FDA approved the radioactive diagnostic drug flutemetamol F18 injection (Vizamyl) for use with positron emission tomography (PET) brain imaging in adults undergoing evaluation for Alzheimer disease (AD) and dementia. This agent attaches to beta amyloid in the brain and produces a PET image that can be used to assess its presence. A positive scan indicates there is likely a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of AD or other dementia. The effectiveness of flutemetamol F18 was established in 2 clinical studies with 384 participants who had a range of cognitive function. This agent is not indicated to predict development of AD or to determine response to treatment for AD. 45. THANK YOU FOR YOUR ATTENTION