Alzheimer's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Alzheimer’s disease is the most common cause of dementia among older people. Dementia is a loss of thinking, remembering, and reasoning skills that interferes with a person’s daily life and activities. Other causes of dementia include blood vessel disease in the brain (called vascular dementia), Parkinson’s disease, frontotemporal dementia, and Lewy body dementia. The first case of Alzheimer’s disease was described by a German psychiatrist named Alöis Alzheimer in the year 1901. For many decades after Alzheimer’s original description, there was little progress in defining the pathogenesis of AD occurred. In the mid 1970’s, it was found that the levels of acetylcholine decrease in brains of individuals undergoing neurodegeneration due to Alzheimer’s disease. In early 1980’s major advances in biochemistry and molecular genetics allowed the use of compositional analyses and immunocytochemistry to explain the structure of tangles and plaques found in the brains of Alzheimer patients. The term Alzheimer’s disease was subsequently formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology. Alzheimer’s disease may be classified according to severity into mild, moderate and severe dementia. It may also be classified based on age of onset into early onset and late onset Alzheimer’s disease. Another method of classification of Alzheimer’s disease is based on the course of disease into pre-dementia, early dementia, moderate dementia and advanced dementia. Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. The microscopic histopathological features of alzheimer’s disease consist of neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy. Alzheimer’s disease may be caused by trisomy of chromosome 21, familial inheritance of mutations in either presenilin 1 gene, presenilin 2 gene or APOE4 gene. Presenilin mutations are associated with early onset Alzheimer’s disease, whereas APOE mutations are associated with late onset disease. Environmental factors, such as aging, low level of education and head trauma may also contribute to the development of Alzheimer’s disease. An estimated 5.5 million Americans of all ages have Alzheimer’s disease. An estimated 10,000 per 100,000 individuals aged greater than 65 years have been known to be living with Alzheimer’s disease in the United States. The diagnosis of Alzheimer’s disease (AD) is made on the basis of clinical criteria described by either the National Institute on Aging and the Alzheimer’s Association (NIA-AA) or DSM-V (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Histopathologic examination for diagnosis of Alzheimer’s disease is rarely done. Elderly patients presenting with progressive decline in memory and other cognitive impairments such as aphasia, agnosia or apraxia should be suspected for Alzheimer’s disease. In these patients, mental status examination (MSE) and neuropsychological testing should be performed to further evaluate the status of cognitive abilities. Diagnostic tools for the examination of the patient include mini- mental status examination (MMSE), Montreal Cognitive Assesment (MOCA) and instruments of activities of dailing living (IADL). Characteristic findings on MRI suggestive of Alzheimer’s disease include reduced hippocampal volume and medial temporal lobe atrophy. There is no known cure for Alzheimer’s disease (AD). Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmacological, psychosocial, and caregiving. Acetylcholine esterase inhibitors increase the amount of acetylcholine in the brain and are a major part of pharmacotherapy for Alzheimer’s disease. Major drugs include, donepezil, rivastigmine and galantamine, these drugs help with the cognitive symptoms of the disease. Associated psychosis and depression may be managed with antipsychotics and selective serotonin reuptake inhibitors (SSRIs). Caregiving plays a pivotal role in the management of patients suffering from Alzheimer’s disease.

The first case of Alzheimer’s disease was described by a German psychiatrist named Alöis Alzheimer in the year 1901. For many decades after Alzheimer’s original description, there was little progress in defining the pathogenesis of AD occurred. In the mid 1970’s, it was found that the levels of acetylcholine decrease in brains of individuals undergoing neurodegeneration due to Alzheimer’s disease. In early 1980’s major advances in biochemistry and molecular genetics allowed the use of compositional analyses and immunocytochemistry to explain the structure of tangles and plaques found in the brains of Alzheimer patients. The term Alzheimer’s disease was subsequently formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.

Alzheimer’s disease may be classified according to severity into mild, moderate and severe dementia. It may also be classified based on age of onset into early onset and late onset Alzheimer’s disease. Another method of classification of Alzheimer’s disease is based on the course of disease into pre-dementia, early dementia, moderate dementia and advanced dementia.

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD. On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer’s disease. The microscopic histopathological features of alzheimer’s disease consist neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy.

Alzheimer’s disease may be caused by trisomy of chromosome 21, familial inheritance of mutations in either presenilin 1 gene, presenilin 2 gene or APOE4 gene. Presenilin mutations are associated with early onset Alzheimer’s disease, whereas APOE mutations are associated with late onset disease. Environmental factors, such as aging, low level of education and head trauma may also contribute to the development of Alzheimer’s disease.

Alzheimer’s disease must be differentiated from other causes of dementia which may share common characteristics of cognitive impairment. The differentials include, vascular dementia, Lewy body dementia and frontotemporal dementia.

Alzheimer’s disease is the most frequently observed form of dementia, and it typically develops in elderly patients. An estimated 5.5 million Americans of all ages have Alzheimer’s disease. An estimated 10,000 per 100,000 individuals aged greater than 65 years have been known to be living with Alzheimer’s disease in the United States. Alzheimer’s disease has been known to affect females more than males. African Americans and Hispanics are more likely to develop Alzheimer’s disease than older whites. AD is diagnosed in people over 65 years of age, although the less prevalent early-onset Alzheimer’s can occur much earlier.

The most potent risk factors for the development of Alzheimer’s disease (AD) are age and genetic mutations. Females are more prone to development of Alzheimer’s disease. Inhabitants of Central African Republic, East Africa, Southern Africa, Malaysia, Australia, and Papua New Guinea are more predisposed to the development of Alzheimer’s disease. Stroke increases the risk of Alzheimer’s dementia.

Alzheimer’s disease (AD) is a slow-progressing condition that involves complications such as the inability to take care of oneself. If left untreated, Alzheimer’s disease progresses from pre-clinical stage to advanced dementia. Common complications of Alzheimer’s disease include anosmia, bedsores, psychosis, malnutrition and dehydration. There is no cure for Alzheimer’s disease currently and the treatment focuses on symptomatic management of the disease.

The diagnosis of Alzheimer’s disease (AD) is made on the basis of clinical criteria described by either the National Institute on Aging and the Alzheimer’s Association (NIA-AA) or DSM-V (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Histopathologic examination for diagnosis of Alzheimer’s disease is rarely done. Elderly patients presenting with progressive decline in memory and other cognitive impairments such as aphasia, agnosia or apraxia should be suspected for Alzheimer’s disease. In these patients, mental status examination (MSE) and neuropsychological testing should be performed to further evaluate the status of cognitive abilities. Laboratory investigation are not required to diagnose Alzheimer’s and are done to exclude other conditions which may present with similar symptoms as seen in Alzheimer’s disease (such as vit B12 deficiency, syphilis, or tuberculosis). Patients with atypical clinical presentation may also be tested for biomarkers such as Aβ and total and phosphorylated tau protein.

Obtaining patient’s history is an important aspect of making a diagnosis of Alzheimer’s disease. Alzheimer’s disease patients may be disoriented and therefore the patient interview may be difficult. In such cases history from the care givers or the family members may need to be obtained. Specific histories about the symptoms (duration, onset, progression), associated symptoms, drug usage have to be obtained.

Patients with Alzheimer’s disease usually appear disoriented and disorganized. When a doctor or physician has been notified, and AD is suspected, the diagnosis is usually further supported by behavioral assessments and cognitive tests, often followed by a brain scan if available. Physical examination of Alzheimer’s disease consists of a thorough neurological assessment of the patient. Patient may be disoriented to time, place and person. Diagnostic tools for the examination of the patient include mini- mental status examination (MMSE), Montreal Cognitive Assesment (MOCA) and instruments of activities of dailing living (IADL).

There are no specific diagnostic laboratory findings associated with Alzheimer’s disease. However, laboratory findings are done to rule out other conditions which may mimic Alzheimer’s disease symptoms. These include CSF analysisfor Aβ 2 and tau protein, 14-3-3 protein, vitamin B12 levels, thyroid hormones, electrolytes, HIV serology, complete blood count, blood glucose, renal function test, liver function test, and urine screen for drug abuse.

ECG has minimal diagnostic value in diagnosing Alzheimer’s disease but plays a role in diagnosing concurrent conduction abnormalities and monitoring side effects of medications. Electrocardiogram of a patient with Alzheimer’s disease may show QT dispersion and heart rate variability abnormalities.

There are no x-ray findings associated with Alzheimer’s disease.

Focused ultrasound is a non-invasive, therapeutic technology aiming to improve the quality of life at lower costs for patients with Alzheimer’s disease.

CT scan of the brain may be helpful in the diagnosis of Alzheimer’s disease. Findings include enlargement of cerebral sulci, loss of gyral volume and mild dilation of the ventricular system.

Structural MRI of the brain may be helpful in the diagnosis of Alzheimer’s disease. Characteristic finding on MRI suggestive of Alzheimer’s disease include reduced hippocampal volume and medial temporal lobe atrophy.

Other imaging studies in Alzheimer’s include positron emission tomography (PET) and single photon emission computed tomography (SPECT) scan. PET and SPECT scan are not routinely done in Alzheimer’s disease. However, patients with atypical presentation may be evaluated with either a PET or SPECT scan to assess for any underlying condition. In these patients, use of amyloid β PET scan will reveal lower FDG (fluorine-18 fluorodeoxyglucose) metabolism and higher PiB ([11 C]Pittsburgh compound B) deposition in areas of the brain affected by Alzheimer’s disease. On SPECT scan patients with Alzheimer’s disease have low relative regional cerebral blood flow (rCBF) in the parietal and prefrontal cortices.

Genotyping for Apolipoprotein (APOE) ε-4, APOE ε-3, amyloid precursor protein (APP), presenilin PSEN1 and PSEN 2 genes may be helpful in the diagnosis of Alzheimer’s disease (AD), although it is not routinely recommended. They may be helpful in the diagnosis of Alzheimer’s dementia. However, genetic study is reserved for research purposes or for those who have presenile dementia.

There is no known cure for Alzheimer’s disease (AD). Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmacological, psychosocial, and caregiving. Acetylcholine esterase inhibitors increase the amount of acetylcholine in the brain and are a major part of pharmacotherapy for Alzheimer’s disease. Major drugs include, donepezil, rivastigmine and galantamine, these drugs help with the cognitive symptoms of the disease. Associated psychosis and depression may be managed with antipsychotics and selective serotonin reuptake inhibitors (SSRIs). Caregiving plays a pivotal role in the management of patients suffering from Alzheimer’s disease.

Surgical intervention is not recommended for the management of Alzheimer’s disease.

Primary prevention of Alzheimer’s disease includes mental stimulation, exercise, and the maintenance of a balanced diet are often recommended as both a possible prevention and a sensible way of managing the disease.

Secondary prevention of Alzheimer’s disease is similar to primary prevention.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The first case of Alzheimer’s disease was described by a German psychiatrist named Alöis Alzheimer in the year 1901. For many decades after Alzheimer’s original description, there was little progress in defining the pathogenesis of AD occurred. In the mid 1970’s, it was found that the levels of acetylcholine decrease in brains of individuals undergoing neurodegeneration due to Alzheimer’s disease. In early 1980’s major advances in biochemistry and molecular genetics allowed the use of compositional analyses and immunocytochemistry to explain the structure of tangles and plaques found in the brains of Alzheimer patients. The term Alzheimer’s disease was subsequently formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.

• In 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer’s disease in a fifty-year-old woman whom he referred to as Auguste D.
• Alöis Alzheimer followed her until she died in 1906, at which point he reported the case publicly for the first time^[1]
• In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer’s disease.^[2]
• In 1910, Emil Kraepelin recognized Alzheimer’s dementia as a separate entity in the eighth edition of his ‘Textbook of Psychiatry’, which was later published^[3]
• In the 1960’s, Alzheimer’s disease became one of the most common causes of senile dementia
• For many decades after Alzheimer’s original description, there was little progress in defining the pathogenesis of AD occurred. The diagnosis of Alzheimer’s disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia
• In late 1960s, with the advent of electron microscopy, Michael Kidd in England and Robert Terry in the United States deciphered the microscopic changes underlying senile (neuritic) plaques and neurofibrillary tangles
• In the mid 1970’s, it was found that the levels of acetylcholine decrease in brains of individuals undergoing neurodegeneration due to Alzheimer’s disease. As a result, pharmacological therapy became more focused on increasing the levels of acetylcholine across the synaptic clefts of Alzheimer patients
• In the late 1970’s and early 1980s, it was identified that the levels of neurotransmitters other than acetylcholine were also changed in affected patients
• In early 1980’s major advances in biochemistry and molecular genetics allowed the use of compositional analyses and immunocytochemistry to explain the structure of tangles and plaques. This eventually led to the use of Alzheimer’s disease independently of the age of onset of the disease^[4][5]
• The term Alzheimer’s disease was subsequently formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Aravind Reddy Kothagadi M.B.B.S[3], Haleigh Williams, B.S.

Alzheimer’s disease may be classified according to severity into mild, moderate and severe dementia. It may also be classified based on age of onset into early onset and late onset Alzheimer’s disease. Another method of classification of Alzheimer’s disease is based on the course of disease into pre-dementia, early dementia, moderate dementia and advanced dementia.

Alzheimer’s disease may be classified based on the clinical dementia rating criteria into minimal, intermediate, mild, moderate and severe:^{[1][2][3][4][5]}

Alzheimer’s disease may be classified into early onset and late onset based on age of onset:^{[6][7][8][9][10]}

Alzheimer’s disease may be classified into the following stages based on course of disease:^{[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][19][27][28][29][30][31][32][33][34][35]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Aravind Reddy Kothagadi M.B.B.S[3]

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD. On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer’s disease. The microscopic histopathological features of alzheimer’s disease consist neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy.

Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of Aβ peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. There is also an accumulation of intracellular neurofibrillary tangles that consist of hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus, and the neocortex.

Triggers

The following factors lead to the development of Alzheimer’s dementia:

• Genetic factors
• Environmental factors
• Chromosomal factors

Pathogenesis

The pathogenesis of Alzheimer’s dementia (AD) can be explained by four pathological processes. The processes involved in the development of AD and their molecular basis is as follows:^[1][2]

(i) Neuronal loss

• Neurogenesis is a complex process characterized by several progressive steps, including neural progenitor cell (NPC) proliferation, migration, differentiation (cell fate commitment) and maturation, including growth and synapse formation
• Initial synaptic injury is followed by neuronal loss accompanied by astrogliosis and microglial cell proliferation.^[3][3]
• Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system^[4][5]
• Increase in neurogenesis in the brains of AD patients may be related to glial and vasculature-associated changes as suggested by an increase in neurogenic markers^[6]
• Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD

(ii) Aggregation of extra-cellular amyloid β (Aβ)

• Amyloid precursor protein (APP) is physiologically present in normal brains
• It is proteolytically processed by α-, β-, and γ-secretases^[7][8]
• In familial forms of AD, mutations result in an increased Aβ production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role
• Aβ oligomers are responsible for the synapto-toxic effects of Aβ^[9]

Constitutive (nonamyloidogenic) pathway

• In the constitutive pathway, proteolysis of APP by α- and γ-secretases results in nonpathogenic fragments (sAPPα and α-C-terminal fragment)

Amyloidogenic pathway

• In the amyloidogenic pathway, proteolysis of APP by β-secretase and γ-secretase gives rise to a mixture of Aβ peptides with different lengths. There are two major Aβ species: Aβ1–40 (90%) and Aβ1–42 (10%). The Aβ1–42 fragments are more aggregation-prone and are predominantly present in amyloid plaques in brains of AD patients.^[10]
• Abnormal accumulation of Aβ is the result of an imbalance between the levels of Aβ production, aggregation and clearance.
• Aβ clearance is mediated by proteolytic enzymes such as neprilysin, chaperone molecules such as apoE, lysosomal (e.g. autophagy) and non-lysosomal pathways (e.g. proteasome)^[11]
• Nerve damage as described under ‘neuronal loss’, might result from the conversion of normally non-toxic monomers to toxic oligomers of Aβ peptides^[9][12][13]
• Changes in glutamate receptors and increased excitability; mitochondrial dysfunction; lysosomal failure and alterations in signaling pathways related to synaptic plasticity, neuronal cell death and neurogenesis have been proposed as the molecular mechanisms leading to the development of Alzeimer’s dementia (AD)^[14][15][16]

(iii) CDK5 pathway

• CDK5 is the predominant CDK found in the brain, is expressed heavily in neurons and plays a key part in synaptic integrity and neuronal development
• Increased activation of CDK5/p35/p25 has been linked to the pathogenesis of neurodegenerative diseases such as AD
• CDK5 may mediate changes in neurogenesis in AD via aberrant phosphorylation of CDK5 substrates, which include cytoskeletal (neurofilaments, nestin), synaptic proteins (synapsin)^[17]

(iv) Formation of intraneuronal neurofibrillary tangles (tau protein accumulation)

• Aβ is involved in tau deposition in AD pathogenesis and leads to the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau increases Aβ toxicity via a positive feedback loop
• A protein that functionally links Aβ to tau is fyn. This cytosolic tyrosine kinase positively regulates N-methyl-D-aspartate (NMDA) receptor activity and has been shown to be targeted to postsynaptic sites in dendrites by tau, which binds fyn^[18]
• In response to Aβ, tau is relocated from axons and dendrites into the somatodendritic compartment^[19]
• Excess fyn accompanies the excess tau in AD dendrites and upregulates NMDA receptor activity in those areas, causing an increased calcium influx. This calcium-driven excitotoxicity can damage postsynaptic sites and cause neurodegeneration

Genetics

Genetic origin of Alzheimer’s dementia (AD) demonstrates an autosomal dominant pattern of inheritance. Alzheimer’s dementia arising from genetic alterations may lead to early onset (<60 years) of disease. The following mutations are implicated in the development of AD are:^[20]

Common genes

Early onset (Alzheimer’s dementia-AD 1, 3 and 4)

30-50 percent of early-onset Alzheimer’s dementia (AD) is associated with an autosomal dominant inheritance and consists of mutations in the following genes:^[21][22]

• Presenilin1 (PS1) gene, also called PSEN1 gene on chromosome 14 (AD3- 20 to 30 percent cases)
• Presenilin 2 (PS2) gene, also called PSEN2 gene on chromosome 1 (AD4- rare)

• Point mutations in amyloid beta A4 protein gene, also called amyloid precursor protein (APP) gene on chromosome 21 are associated in some cases of early onset (< 65 yr) familial AD cases

Late onset (Alzheimer’s dementia -AD2)

• Apolipoprotein 4 gene (APOE4) mutation is associated with late onset (>60 years) Alzheimer’s dementia (AD)^[23]
• p.Arg47His allelic variant in TREM2 gene^[24]

Less common genes

Less common genes associated with the development of AD are:

• A2M on chromosome 12
• ABCA7; when suppressed, results in an elevation of amyloid production
• AKAP9, a kinase anchor protein 9 (PRKA) that regulates NMDA channel activity

• There is evidence both for and against ADAM10
• BIN1, a tumor suppressor protein
• CALHM1 on chromosome 10q24; CALHM1 influences calcium homeostchaperon has a single nucleotide polymorphism (SNP) associated with late-onset AD
• CD2AP, an adaptor molecule involved in dynamic actin remodeling and membrane trafficking
• A SNP in CD33
• Clusterin (CLU, APOJ), a molecular chaperon present in senile plaques that has CR1 and PICALM, implicated in two genome-wide association studies (GWAS)
• Dysferlin (encoded by DYSF), associated with several limb-girdle muscular dystrophies; accumulates in Alzheimer patients
• EPHA1 (encoding a protein that belongs to the ephrin receptor subfamily); plays part in synaptic plasticity
• GAB2 on chromosome 11q14 interacting with the APOE e4 allele
• GST01 and GST02 on chromosome 10
• PAX1P1, which encodes for a nuclear protein that may function in DNA repair pathways
• PLD3 on chromosome 19q13.2
• SORL1 on chromosome 11q23, a protein involved with APP protein trafficking
• TOMM40, located on chromosome 19q very close to the APOE locus,TOMM40 has been implicated in late-onset AD both by linkage analysis and by the presence of a variable length poly-T repeat within the gene
• UNC5C is enriched in neurons of the hippocampal pyramidal layer
• In a large GWAS meta-analysis, the following genes have been identified as rare causes of Alzheimer’s disease:
  • HLA-DRB5/HLA-DRB1
  • SLC24A4
  • SORL1
  • PTK2B
  • ZCWPW1
  • CELF1
  • FERMT2
  • CASS4
  • INPP5D
  • MEF2C
  • NME8
• Several other potential loci under investigation on the following chromosomes:
  • Chromosome 12
  • Chromosome 10
  • Chromosome 2q
  • Chromosome 9p
  • Chromosome 15q
  • Chromosome 19p13
  • Chromosome 7q36
  • Chromosome 9q22 (UBQLN1)
  • Chromosome 1q22
  • Chromosome 3q23
  • Chromosome 10q22
  • Chromosome 11q25

Associated Conditions

• Cerebral amyloid angiopathy
• Down’s Syndrome
• Reccurent respiratory infections (pneumonia)

Gross Pathology

• On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer’s disease.

Microscopic Pathology

• The microscopic histopathological features of alzheimer’s disease represent neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy:
  • Neurofibrillary tangles: Consists of tau, location in the hippocampus, cerebral cortex, hypothalamus. Dementia severity correlates better with neurofibrillary tangles number rather than senile plaque number
  • Senile plaques or the neuritic plaques consists of two components which are A-beta amyloid which radiate from the center and the neurites with swollen axons. Senile plaques are considered to be more specific for alzheimer’s than neurofibrillary tangles
  • Loss of neurons
  • With or without cerebral amyloid angiopathy

References

1. ↑ Crews L, Masliah E (2010). “Molecular mechanisms of neurodegeneration in Alzheimer’s disease”. Hum. Mol. Genet. 19 (R1): R12–20. doi:10.1093/hmg/ddq160. PMC 2875049. PMID 20413653.
2. ↑ Weller J, Budson A (2018). “Current understanding of Alzheimer’s disease diagnosis and treatment”. F1000Res. 7. doi:10.12688/f1000research.14506.1. PMC 6073093. PMID 30135715.
3. ↑ ^{3.0 3.1} Beach TG, Walker R, McGeer EG (1989). “Patterns of gliosis in Alzheimer’s disease and aging cerebrum”. Glia. 2 (6): 420–36. doi:10.1002/glia.440020605. PMID 2531723.
4. ↑ DeKosky ST, Scheff SW (1990). “Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity”. Ann. Neurol. 27 (5): 457–64. doi:10.1002/ana.410270502. PMID 2360787.
5. ↑ Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991). “Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment”. Ann. Neurol. 30 (4): 572–80. doi:10.1002/ana.410300410. PMID 1789684.
6. ↑ Boekhoorn K, Joels M, Lucassen PJ (2006). “Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus”. Neurobiol. Dis. 24 (1): 1–14. doi:10.1016/j.nbd.2006.04.017. PMID 16814555.
7. ↑ Selkoe DJ (1989). “Amyloid beta protein precursor and the pathogenesis of Alzheimer’s disease”. Cell. 58 (4): 611–2. PMID 2504495.
8. ↑ Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987). “Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus”. Science. 235 (4791): 880–4. PMID 2949367.
9. ↑ ^{9.0 9.1} Walsh DM, Selkoe DJ (2004). “Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration”. Protein Pept. Lett. 11 (3): 213–28. PMID 15182223.
10. ↑ Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016). “The genetic landscape of Alzheimer disease: clinical implications and perspectives”. Genet. Med. 18 (5): 421–30. doi:10.1038/gim.2015.117. PMC 4857183. PMID 26312828.
11. ↑ Bendiske J, Bahr BA (2003). “Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis–an approach for slowing Alzheimer disease?”. J. Neuropathol. Exp. Neurol. 62 (5): 451–63. PMID 12769185.
12. ↑ Volles MJ, Lansbury PT (2002). “Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism”. Biochemistry. 41 (14): 4595–602. PMID 11926821.
13. ↑ Selkoe DJ (1999). “Translating cell biology into therapeutic advances in Alzheimer’s disease”. Nature. 399 (6738 Suppl): A23–31. PMID 10392577.
14. ↑ Lin H, Bhatia R, Lal R (2001). “Amyloid beta protein forms ion channels: implications for Alzheimer’s disease pathophysiology”. FASEB J. 15 (13): 2433–44. doi:10.1096/fj.01-0377com. PMID 11689468.
15. ↑ Nakamura T, Lipton SA (2010). “Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer’s and Parkinson’s diseases”. Apoptosis. 15 (11): 1354–63. doi:10.1007/s10495-010-0476-x. PMC 2978885. PMID 20177970.
16. ↑ Nixon RA, Cataldo AM (2006). “Lysosomal system pathways: genes to neurodegeneration in Alzheimer’s disease”. J. Alzheimers Dis. 9 (3 Suppl): 277–89. PMID 16914867.
17. ↑ Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H (1996). “Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions”. J. Biol. Chem. 271 (35): 21108–13. PMID 8702879.
18. ↑ Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J (2010). “Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models”. Cell. 142 (3): 387–97. doi:10.1016/j.cell.2010.06.036. PMID 20655099.
19. ↑ Delacourte A, Flament S, Dibe EM, Hublau P, Sablonnière B, Hémon B, Shérrer V, Défossez A (1990). “Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer’s disease. Demonstration with a panel of antibodies against Tau proteins”. Acta Neuropathol. 80 (2): 111–7. PMID 2117840.
20. ↑ “Alzheimer Disease Overview – GeneReviews® – NCBI Bookshelf”.
21. ↑ Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T (1999). “Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum”. Am. J. Hum. Genet. 65 (3): 664–70. doi:10.1086/302553. PMC 1377972. PMID 10441572.
22. ↑ Tsuang D, Larson EB, Bowen J, McCormick W, Teri L, Nochlin D, Leverenz JB, Peskind ER, Lim A, Raskind MA, Thompson ML, Mirra SS, Gearing M, Schellenberg GD, Kukull W (1999). “The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series”. Arch. Neurol. 56 (12): 1489–95. PMID 10593304.
23. ↑ Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC (2004). “Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study”. Arch. Gen. Psychiatry. 61 (5): 518–24. doi:10.1001/archpsyc.61.5.518. PMID 15123497.
24. ↑ Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013). “Variant of TREM2 associated with the risk of Alzheimer’s disease”. N. Engl. J. Med. 368 (2): 107–16. doi:10.1056/NEJMoa1211103. PMC 3677583. PMID 23150908.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Alzheimer’s disease may be caused by trisomy of chromosome 21, familial inheritance of mutations in either presenilin 1 gene, presenilin 2 gene or APOE4 gene. Presenilin mutations are associated with early onset Alzheimer’s disease, whereas APOE mutations are associated with late onset disease. Environmental factors, such as aging, low level of education and head trauma may also contribute to the development of Alzheimer’s disease.

The following are the causes of Alzheimer’s dementia (AD):^{[1][2][3][4][5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Alzheimer’s disease is the most frequently observed form of dementia, and it typically develops in elderly patients. An estimated 5.5 million Americans of all ages have Alzheimer’s disease. An estimated 10,000 per 100,000 individuals aged greater than 65 years have been known to be living with Alzheimer’s disease in the United States. Alzheimer’s disease has been known to affect females more than males. African Americans and Hispanics are more likely to develop Alzheimer’s disease than older whites. AD is diagnosed in people over 65 years of age, although the less prevalent early-onset Alzheimer’s can occur much earlier.

Alzheimer’s disease (AD) is the most common type of dementia observed in the elderly; it affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for the development of AD.^[1][2]

• An estimated 47 million people worldwide have Alzheimer’s disease according to the World Health Organization (WHO).^[3]
• An estimated 5.5 million Americans of all ages have Alzheimer’s disease^[4]
• An estimated 10,000 per 100,000 individuals aged greater than 65 years have been known to be living with Alzheimer’s disease in the United States^[4]

Trends in United states

• The following table outlines the general prevalence trends according to age in the United States:^[5][6][7]

• Prevalence rates in developing regions are lower^[8]
• Low prevalence of dementia has been reported in India and sub-Saharan Africa

Trends in developing countries

• The following table outlines the general prevalence trends in major developing countries:^{[9][10][11][12][13][14][15][16][17][18][19][20][21]}

Legend: PDD= Parkinson disease dementia, PSD= Post-stroke dementia, FTD= Fronto-temporal dementia, Mixed= Alzheimer’s plus vascular dementia

• The following bar-chart displays the prevalence of Alzheimer’s dementia across different countries based on above data:

• Alzheimer’s disease has been known to affect females more than males

• Out of the 5.5 million people age 65 and older with Alzheimer’s in the United States, 3.5 million are women and 2.0 million are men
• The Framingham Heart Study suggests that because men in middle age have a higher mortality rate from cardiovascular disease than women in middle age, men who survive beyond age 65 may have a healthier cardiovascular risk profile and thus an apparent lower risk for dementia than women of the same age (survival bias)^[22]
• APOE-e4 genotype, has been known to have stronger association with Alzheimer’s dementia in women^[23]

• African Americans and Hispanics are more likely to develop Alzheimer’s disease than older whites^[24]
• Dementia incidence is known to be highest in African-Americans, intermediate in Hispanics and lowest for Asian-Americans
• The prevalence of Alzheimer’s disease and other dementias in the United States based on race has been found to be as follows:
  • 6900 per 100,000 of whites, 9400 per 100,000 of African-Americans and 11500 per 100,000 of Hispanics

The following are the mortality rates for Alzheimer’s dementia between 2001 and 2014:^[25]

• The following scatter-plot shows the above mentioned data:

• Generally, AD is diagnosed in people over 65 years of age,^[26] although the less prevalent early-onset Alzheimer’s can occur much earlier
• The number of people with Alzheimer’s dementia increases with age:
  • 3000 per 100,000 individuals age 65-74
  • 17000 per 100,000 individuals age 75-84
  • 32000 per 100,000 individuals age 85 and older

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The most potent risk factors for the development of Alzheimer’s disease (AD) are age and genetic mutations. Females are more prone to development of Alzheimer’s disease. Inhabitants of Central African Republic, East Africa, Southern Africa, Malaysia, Australia, and Papua New Guinea are more predisposed to the development of Alzheimer’s disease. Stroke increases the risk of Alzheimer’s dementia.

The following risk factors may lead to the development of Alzheimer’s dementia (AD):^[1][2][3]

• Increasing age
• Genetic mutations
• Gender (females > males)
• Early-life negative events and physical attributes
• Literacy and education (low literacy and education increases the chances of developing AD)

• Geographical location (Central African Republic, East Africa, Southern Africa, Malaysia, Australia, and Papua New Guinea, APOE4 is a risk factor for AD among women but not men in Venezuela)
• Stroke
• Vascular disease
• Diet (fruits, vegetables, and fibre decrease risk; Tofu, cycad fruit, salivary phytooestrogens e.g. genistein and daidizein are associated with increased risk)

The following table outlines the comparison of different risk factors among various geographic regions:^{[4][5][6][7][8][9][10][11][12][13][14][15][16][3][17][18]}

Legend:

+ : Positive correlation

– : Negative correlation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Alzheimer’s disease (AD) is a slow-progressing condition that involves complications such as the inability to take care of oneself. If left untreated, Alzheimer’s disease progresses from pre-clinical stage to advanced dementia. Common complications of Alzheimer’s disease include anosmia, bedsores, psychosis, malnutrition and dehydration. There is no cure for Alzheimer’s disease currently and the treatment focuses on symptomatic management of the disease.

If left untreated, Alzheimer’s disease (AD) may progress through three stages:^[1]

• (i) Preclinical stage:
  • The preclinical phase of AD represents asymptomatic individuals with serological evidence of AD associated pathological changes and individuals exhibiting minor cognitive decline, but who do not yet meet the clinical criteria for mild cognitive impairment
• (II) Mild cognitive impairment (MCI) :
  • MCI denotes the period during which there is observable evidence of cognitive impairment, often also reported by an informant; however, the impairment is not enough to limit daily activities
• (III) Alzheimer’s disease dementia:
  • The transition or prodromal stage between normal ageing and dementia or mild cognitive impairment (MCI) is a heterogeneous entity.
  • Advanced dementia may display the following features:
    • Becoming unaware of the time and place
    • Difficulty recognizing relatives and friends
    • Increased need for assisted self-care
    • Difficulty walking
    • Behavioural changes that may escalate and include aggression

Potential complications of Alzheimer’s disease include:^[2][3][4]

• Abuse by an over-stressed caregiver
• Anosmia
• Bedsores, muscle contractures (loss of ability to move joints because of loss of muscle function), infection (particularly urinary tract infections and pneumonia), and other complications related to immobility during the end stages of AD
• Behavioral and psychotic symptoms of dementia (BPSD) or psychosis
• Chronic brain failure
• Falls and bone fractures
• Harmful or violent behavior toward oneself or others
• Hirano body formation
• Loss of ability to function or care for oneself
• Loss of ability to interact with others
• Malnutrition and dehydration

• Individual prognosis is difficult to assess due to the variability of the duration of the disease. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years
• The early stages of Alzheimer’s disease are most difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises everyday activities, although the patient may still be living independently
• People with Alzheimer’s disease progress from mild cognitive problems, such as memory loss, through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living^[3]
• Life expectancy of the population with the disease is reduced^[5][6][7]
• The mean life expectancy following diagnosis is approximately seven years^[8]
• Fewer than 3% of patients live more than fourteen years^[8]
• Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination
• Other coincident diseases such as heart problems, diabetes, or history of alcohol abuse are also related with shortened survival^[6][9][10]
• While the earlier the age of onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger^[7]
• Men have a less favorable survival prognosis than women^[8][11]
• Pneumonia and dehydration are the most frequent immediate causes of death, while cancer is a less frequent cause of death than in the general population.^[5][11]

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