Nervous System

Prevalence of Alzheimer disease rises with each decade of age.

- 6 percent in people older than 65 years - 20 percent in people older than 80 years - More than 95 percent in those older than 95 years

Nervous System and Aging - Structural Changes

- Decreased brain weight and size, especially frontal regions - Narrowing of gyri and widening of sulci - Increase in size of ventricles - Fibrosis and thickening of the meninges

Late-onset Alzheimer disease:

- Most cases of Alzheimer's are the late-onset form, which develops after age 60. - Causes of late-onset Alzheimer's are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that influence a person's risk for developing the disease.

normal signs of aging other symptoms

- Normal sense of smell - No weight changes in men or women

Aging and injury may result in changes that contribute to the development and progression of the disease including:

- Oxidative stress and neuro-inflammation - Decreased oxygen and glucose transport - Molecular changes in vascular smooth muscle and in the blood-brain barrier - Mitochondrial defects that alter cell metabolism and processing of proteins including amyloid (APOE4).

Normal Signs of Aging (memory and concentration)

- Periodic minor memory lapses or forgetfulness of part of an experience. - Occasional lapses in attention or lapses in attention or concentration

examples of inherited genetic disorders:

- Sickle cell anemia, - cystic fibrosis, - early-onset familial Alzheimer's disease

Formation of neurofibrillary tangles:

- Tau protein is a microtubule binding protein that normally stabilizes the microtubular transport system in neurons. - In Alzheimer disease, the tau protein detaches from the microtubule and forms an insoluble helical filament called a neurofibrillary tangle. Tangles are flame shaped. - Cortical nerve cell processes become twisted and dilated because of accumulation of the same filaments that form tangles.

Mood and Behavior normal signs of aging

- Temporary sadness or anxiety based on appropriate and specific cause - Changing interests - Increasingly cautious behavior

Mood and behavior Alzheimer Disease

- Unpredictable mood changes - Increasing loss of outside interests - Depression, confusion, or anger in response to change - Denial of symptoms

Movement and coordination Alzheimers Disease

- Visibly impaired movement or coordination including slowing of movements, halting gait, and reduced sense of balance

Level of education may be a risk factor for Alzheimer disease. Highly educated (or highly intelligent) people may have

- a larger cognitive reserve, allowing longer and more effective adaptation to declining brain function. - People with less education (often less wealthy) may be at higher risk because of exposure to malnutrition or noxious substances early in life.

Early-onset Alzheimer's disease: Each of the mutations play a role in the breakdown of

- amyloid precursor protein, a protein whose function is not yet known. - Breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of Alzheimer disease.

(Pathologic Alterations in the Brain with Alzheimer Disease) Amyloid is also deposited in the cerebral arteries causing ....

- an amyloid angiopathy and disturbance in blood flow. ** Neuro-inflammation occurs but the exact mechanisms are unknown.

language and speech normal signs of aging

Unimpaired language skills

Using a relatively new approach called genome-wide association study, researchers have identified

a number of genes in addition to APOE4 that may increase a person's risk for late-onset Alzheimer disease including BIN1, CLU, PICALM, and CR1.

Cerebral amyloid angioplasty may

predispose an individual to develop Alzheimer disease. - Amyloid angioplasty is a common feature of senile dementia and Alzheimer disease, along with neuritic plaques, neurofibrillary tangles, neutrophil threads, and synapse loss. - Amyloid causes atrophy of smooth muscle cells of the arteries of the brain. Weakens them, causing predisposition to hemorrhage. - Relationship between cerebral vascular infarct and Alzheimer disease.

Alterations in intracellular calcium levels are functionally linked to

presenilin mutations, APOE4 expression, neuritic plaques, neurofibrillary tangles, and synaptic dysfunction.

Nervous System and Aging - Cerebrovascular Changes

- Arterial atherosclerosis (may cause infarcts and scars) - Increased permeability of the blood-brain barrier - Decreased vascular density

Alzheimer Disease: Possible Risk Factors

- Head injury - Depression - Progression of Parkinson-like signs in older adults - Lower thyroid-stimulating hormone within normal range - Hyperhomocysteinemia - Folate deficiency - Hyperinsulinemia - Low educational attainment

In people with one copy of the APOE4 allele, the risk is

25-60 percent.

In people with two copies of the APOE4 allele, the risk is

50-90 percent. ** Only 2 percent of the population carries two copies of the APOE4 allele.

People without APOE4 have an estimated risk of

9-20 percent for developing Alzheimer disease by age 85 years.

Gene—

A basic unit of heredity. Genes direct cells to make proteins and guide almost every aspect of cells' construction, operation, and repair.

Genetic mutation-

A permanent change in a gene that can be passed on to children. The rare, early-onset familial form of Alzheimer's disease is associated with mutations in genes on chromosomes 1, 14, or 21.

Protein kinase R accumulates in the brains of patients with

Alzheimer disease and can indirectly induce the phosphorylation of tau, and induce the death of neurons. ** Protein kinase R levels in the cerebral spinal fluid and its activity in the brain are highly elevated in patients with Alzheimer disease.

Early-onset Alzheimer's disease occurs in people

age 30 to 60. It is rare, representing less than 5 percent

Research also indicates that people who inherit one or two APOE4 alleles tend to develop the disease

at an earlier age than those who do not have any APOE4 alleles.

Synaptic loss is the

best pathologic corollary of cognitive design decline. Synaptic dysfunction is evident long before synapses and neurons are lost. One synaptic function stops, there may be little chance of changing the disease process.

APOE proteins normally remove beta amyloid. Studies report the greatest deposits of

beta amyloid in people with APOE4. APOE4 allele removes beta amyloid less efficiently than other APOE types.

Loss of acetylcholine and other neurotransmitters contributes to the

decline of memory and attention, as well as the decline of other cognitive functions associated with Alzheimer disease

Protein kinase R (PKR) is an

enzyme that plays a role in recognizing and signaling viral infection. It is altered in several neurologic disorders where it negatively modulates memory, and can become toxic.

Glutaminergic neurons are prone to

formation of neurofibrillary tangles. Most vulnerable group of cortical neurons are the pyramidal cells with corticocortical and hippocampal projections.

Alzheimer Disease: Possible Protective Factors

- APOE2 allele - Regular fish consumption - Regular consumption of omega-3 fatty acids - High educational level - Regular exercise - NSAID therapy - Moderate alcohol intake - Adequate intake of vitamins C, E, B6, and B12, and folate

Alzheimers Disease other symptoms

- Impaired sense of smell - Severe weight loss, especially in women

Alzheimer Disease - Incidence and Prevalence

25 million people with Alzheimer disease worldwide, 5 million in the United States.

Amyloid cascade is considered by many researchers as a key contributor to the pathogenesis of Alzheimer disease

However, some researchers believe that beta amyloid occurs secondary to neuron stress, and functions as a protective adaptation to the disease, rather than causing cell death.

Epigenetics: Nature Meets Nurture

Scientists have long thought that genetic and environmental factors interact to influence a person's biological makeup, including the predisposition to different diseases.

Defective genes appear to

accelerate beta amyloid plaque formation and apoptosis (natural process by which cells self-destruct).

Familial Alzheimer's disease is caused by any one of a number of different single-gene mutations on

chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed.

In Alzheimer disease, certain enzymes (i.e. gamma secretases) snip the amyloid precursor protein (APP) into beta amyloid pieces. Process is controlled by presenilin proteins.

- Amyloid precursor protein undergoes proteolysis to form beta-amyloid peptide pieces (i.e. beta-amyloid 30 through beta-amyloid 46). - Beta-amyloid 40 and beta-amyloid 42 are the most abundant isoforms produced, and have a strong tendency to form clusters of fibrils, especially beta-amyloid 42.

Nervous System and Aging

- Central nervous system mechanisms involved in the aging process are complex. -Some of the identified mechanisms are pathologic. Distinction between these mechanisms and those that are part of normal aging is ambiguous.

Pathogenesis of Alzheimer Disease - Neuritic Plaques

- Contain a core of amyloid beta protein. Failure to process and clear amyloid precursor protein results in the accumulation of toxic fragments of amyloid beta protein. - Leads to the formation of diffuse neuritic plaques, disruption of nerve impulse transmission, and death of neurons.

Nervous System and Aging - Cellular Changes

- Decreased number of neurons, not consistently related to changes in mental function. - Decreased amount of myelin. - Decreased number of dendritic processes and synaptic connections. - Imbalance in the amount and distribution of neurotransmitters.

Language and Speech Alzheimers disease

- Difficulty completing sentences or finding the right words - Inability to understand the meaning of words - Reduced and/or irrelevant conversation

Movement and coordination normal signs of aging

- Increasing caution in movement - Slower reaction times

Nervous System and Aging - Cellular Changes

- Lipofuscin deposition (pigment resulting from cellular autodigestion). - Formation of intracellular neurofibrillary tangles - significant accumulation in cortex is associated with Alzheimer disease.

Alzheimer Disease - Risk Factors

- No evidence exists that mutations play a role in the more common, sporadic, non-familial form of late onset Alzheimer disease. - However, there is a subtype of early onset Alzheimer disease seen in families with histories of late onset disease. Exact genetic abnormality and transmission are unclear.

Early-onset Alzheimer's disease:

- Occurs in people age 30 to 60. Rare, represents less than 5 percent of all people who have Alzheimer disease. - Some cases of early-onset Alzheimer's have no known cause, but most cases are inherited, a type known as familial Alzheimer's disease (FAD). - Children whose mother or father carry a genetic mutation for FAD have a 50/50 chance of inheriting the mutation. If the mutation is inherited, the children will develop the disease.

No specific gene has been identified that causes

- late-onset Alzheimer disease. However, one genetic risk factor does appear to increase the risk of developing the disease. - Increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. - APOE comes in several different forms or alleles. Three forms that occur most frequently are APOE2, APOE3, and APOE4.

Genetic variant—

A change in a gene that may increase or decrease a person's risk of developing a disease or condition. is a gene change that can sometimes cause a disease directly. More often, it acts to increase or decrease a person's risk of developing a disease or condition.

Chromosome

A compact structure containing DNA and proteins present in nearly all cells of the body. Chromosomes carry genes, which direct the cell to make proteins and direct a cell's construction, operation, and repair. Normally, each cell has 46 chromosomes in 23 pairs. Each biological parent contributes one of each pair of chromosomes.

Epigenetics

Genetic and environmental factors interact to influence a person's biological makeup, including the predisposition to different diseases. Expression of genes (when particular genes are "switched" on or off) can be affected - positively and negatively - by environmental factors such as exercise, diet, chemicals, or smoking, to which an individual may be exposed, even in the womb.

DNA (deoxyribonucleic acid)—

The hereditary material in humans and almost all other organisms. Almost all cells in a person's body have the same DNA. Most DNA is located in the cell nucleus.

Same genes may have different effects depending on ethnic population. Dietary and cultural factors that increase the risk for hypertension and unhealthy cholesterol levels may also play a role. For example,

a study of Japanese men showed that their risk increased if they emigrated to America. Disease is less common in West Africa than in African-Americans, whose risk is the same or higher than that of white Americans.

Alzheimer disease

brain disease characterized by plaques, tangles, and neuronal loss.

Age-associated memory impairment or benign senescent forgetfulness, is a decline in

short-term memory that does not progress to other mental intellectual impairments.

Alzheimer disease is not inevitable, even in people with

two copies of the APOE4 allele.

Inheriting an APOE4 allele does not mean that a person

will definitely develop Alzheimer's. Some people with one or two APOE4 alleles never get the disease, and others who develop Alzheimer disease do not have any APOE4 alleles.

Nervous System and Aging - Functional Changes Functional changes and nervous system aging have significant individual variation.

- Decreased tendon reflexes - Skeletal muscle atrophy - Decrease in neuromuscular control with change in gait and posture - Progressive deficit in taste and smell - Decreased vibratory sense - Decreased accommodation and color vision - Sleep disturbances - Memory impairments - Cognitive alterations associated with chronic disease

Alzheimer Disease (memory and concentration)

- Misplacement of important items - Confusion of how to perform simple tasks - Trouble with simple arithmetic problems - Difficulty making routine decisions - Confusion about month or season

Early-onset Alzheimer's disease: Caused by single-gene mutations on chromosomes

21, 14, or 1. These mutations cause formation of abnormal proteins. - Mutation on chromosome 21 causes the formation of abnormal amyloid precursor protein (APP). - Mutation on chromosome 14 causes the formation of abnormal presenilin 1. - Mutation on chromosome 1 leads to abnormal presenilin 2.

Genetic risk factor—

A change in a gene that increases a person's risk of developing a disease. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.

Common Medications Used in Alzheimer Disease Donepezil (Aricept)

cholinergic stimulant (cholinesterase inhibitor). Modest benefits, helps slow loss of function and reduce caregiver burden. Works equally in patients with or without APOE4. May have some advantage in patients with moderate to severe disease.

Dementia

clinical syndrome consisting of global cognitive decline, memory deficits plus one other area of cognition, and significant effect on day-to-day function. Not delirium.

Alzheimer dementia

dementia syndrome that has gradual onset and slow progression and is best explained as caused by Alzheimer disease.

Epigenetic changes, whether protective, benign, or harmful, may help explain,

for example, why one family member develops the disease and another does not.

When a genetic variant increases disease risk but does not directly cause a disease, it is called a

genetic risk factor

Dozens of studies have confirmed that the APOE4 allele increases the risk of developing Alzheimer disease, but

how that happens is not yet understood.

APOE4 allele

is associated with increased risk of developing the disease. people who inherit one or two APOE e4 alleles tend to develop the disease at an earlier age than those who do not have any APOE e4 alleles. - APOE e4 is called a risk-factor gene because it increases a person's risk of developing the disease. However, inheriting an APOE e4 allele does not mean that a person will definitely develop Alzheimer's.

APOE2 allele

may be protective. ** is relatively rare and may provide some protection against the disease. If Alzheimer's disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE e4 gene.

Mutations in the presenilin 1 presenilin 2 genes account for

most cases of early onset inherited Alzheimer disease.

Underlying mechanism through which APOE influences Alzheimer disease risk has

not been determined. ** Scientists have explored several possibilities, including the idea that APOE may play a role in cholesterol transport, neuronal integrity, and amyloid deposition.

Mutations on chromosome 21 cause

the formation of abnormal amyloid precursor protein (APP)

Pathogenesis of Alzheimer Disease Summary

- Abnormal amounts of beta-amyloid are cleaved from amyloid precursor protein (APP) and released into the circulation. The beta-amyloid fragments come together in clumps to form plaques that attach to the neuron. Microglial cells react to the plaques and an inflammatory response occurs. - Tau proteins provide structural support for the neuron microtubules. Chemical changes in the neuron produce structural changes in tau proteins. This results in twisting and tangling (neurofibrillary tangles).

Alzheimer Disease: Primary Risk Factors

- Age - Family history - Genetic markers such as APOE4 allele, trisomy 21, mutations in presenilins 1 and 2 - Female gender after age 80 - Cardiovascular risk factors such as hypertension, diabetes, obesity, and hypercholesterolemia

Alzheimer Disease - Overview

- Alzheimer disease is the most common cause of dementia. One of the principal causes of disability and decreased quality of life among older adults. - Progress in clinical knowledge of Alzheimer disease has led to more reliable diagnostic criteria and accuracy. The earliest manifestations and pre-symptomatic phases of the disease may soon be identifiable.

Pathologic Alterations in the Brain with Alzheimer Disease

- Formation of neuritic plaques containing a core of amyloid beta protein - Failure to process and clear amyloid precursor protein (APP) results in the accumulation of toxic fragments of amyloid beta protein. - Leads to the formation of diffuse neuritic plaques, disruption of nerve impulse transmission, and death of neurons.

Alzheimer disease has no single identifiable cause. Loss of neurons is thought to be a consequence of the breakdown of several processes necessary for sustaining brain cells. Theories include:

- Mutation for encoding amyloid precursor protein (APP) - Alteration in apolipoprotein E, which binds amyloid-beta - Pathologic activation of N-methyl-d-aspartate receptors resulting in an influx of excess calcium - Loss of neurotransmitter stimulation by choline acetyltransferase

Pathology of Alzheimer Disease

- Some diseases are caused by a genetic mutation, or permanent change in one or more specific genes. - If a person inherits a genetic mutation that causes a certain disease, then they will generally get the disease. - For example, sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer's.

Asymptomatic APOE4 carriers are more likely to display subtle abnormalities in brain scans such as

- positron emission tomography (PET) or magnetic resonance imaging (MRI) scans. - Combining information on APOE4 carrier status with other informative biologic marker data is a promising research strategy for detecting people who might be candidates for Alzheimer disease prevention strategies.

Effect of Alzheimer disease and hippocampal volume equals

- the effect of roughly 17 years of aging, correlates with changes seen in memory behavior and motor skills as the disease progresses. - Distribution of the lesions in the cerebral cortex may be different in Alzheimer disease as compared with other disease processes that cause dementia.

Allele

A form of a gene. Each person receives two alleles of a gene, one from each biological parent. This combination is one factor among many that influence a variety of processes in the body. On chromosome 19, the apolipoprotein E (APOE) gene has three common forms or alleles: e2, e3, and e4.

Apolipoprotein E (APOE) gene—

A gene on chromosome 19 involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. The APOE e4 allele is considered a risk-factor gene for Alzheimer's disease and appears to influence the age at which the disease begins.

Genome-wide association study (GWAS)—

A study approach that involves rapidly scanning complete sets of DNA, or genomes, of many individuals to find genetic variations associated with a particular disease.

Protein—

A substance that determines the physical and chemical characteristics of a cell and therefore of an organism. Proteins are essential to all cell functions and are created using genetic information.

Studies report an association between Alzheimer disease and systolic hypertension.

Lower risk of Alzheimer disease in patients whose blood pressure is reduced. ** Although hypertension is strongly linked to memory and mental difficulties, stronger evidence is needed to prove any causal relationship between hypertension and Alzheimer disease.

A mutation on chromosome 14 causes

abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.

Increased excitotoxicity resulting from increased glutaminergic stimulation of N-methyl-d-aspartate (NMDA) receptors results in

abnormally high levels of intracellular calcium and may ultimately lead to cell death.

APOE e4 is present in

about 10 to 15 percent of the population and in about 40 percent of all people with late-onset Alzheimer's. ** People who develop Alzheimer's are more likely to have an APOE4 allele than people who do not develop the disease.

Family history of dementia, regardless of APOE4 status, can

also increase the risk of developing the disorder. ** Specifically, people with a first-degree relative with dementia have a 10-30 percent increased risk of developing Alzheimer disease.

Pathogenesis of Alzheimer disease is linked to an accumulation of

amyloid-beta peptide in the interstitial fluid between neurons ** In the normal brain, there is a balance between the production and catabolism (involving microglia, macrophages, and bulk flow across the blood brain barrier) of amyloid-beta peptide. ** Altered production and failure of clearance of amyloid from the brain occurs in Alzheimer disease causing accumulation of amyloid-beta peptide.

Alzheimer disease is characterized by the progressive accumulation of insoluble fibrous material, called:

amyloid. ** Neuritic plaques consisting of extracellular amyloid are found in higher concentrations in the brains of patients with Alzheimer disease than in normal aging brains.

Loss of neurons results in

brain atrophy with decreases in weigh and volume. The sulci widen and the gyri thin (especially in the frontal and temporal lobes), and the ventricles enlarge to fill in the space

When amyloid plaque comes in contact with the neuron, it

causes chemical changes that lead to the destruction and destabilization the microtubules, the structural components of the neural cells. - Tau proteins are responsible for holding the microtubules together. One of the functions of the microtubules is axonal transport.

Genetic mutations in the genes that control amyloid precursor protein (APP) are being considered as

causes of early onset Alzheimer disease. Amyloid precursor protein gene is located on chromosome 21.

Amyloid -

chemically diverse proteins that appear microscopically homogenous. Composed of linear non-branching aggregated fibrils arranged in sheets. ** Amyloid deposition is related to beta amyloid protein, a natural substance that is required to maintain fibroblasts and cell function. Components of beta amyloid protein occur as a byproduct of neuron function.

Common Medications Used in Alzheimer Disease Galantamine (Reminyl)

cholinergic stimulant (cholinesterase inhibitor). Not only protects the cholinergic system but also acts on nicotinic receptors, which are also depleted in Alzheimer disease. Improves daily living, behavior, and mental functioning in patients with mild to advanced-moderate Alzheimer disease, and those with a mix of Alzheimer disease and vascular dementia. Effects of medication may persist for a year or longer and may even strengthen over time.

Common Medications Used in Alzheimer Disease Tacrine (Cognex)

cholinergic stimulant (cholinesterase inhibitor). Only modest benefits and has no benefits for patients who carry the APOE4 gene. In high dosages, it can injure the liver. In general, newer cholinergic-protective drugs that do not pose as great a risk for the liver are used for Alzheimer disease.

Common Medications Used in Alzheimer Disease Rivastigmine (Exelon)

cholinergic stimulant (cholinesterase inhibitor). Targets two enzymes (major one is acetylcholinesterase, also butyrycholinesterase). Beneficial for patients with rapidly progressing disease. Slows or slightly improves disease status in patients with advanced disease. Causes significantly more side effects than donepezil including nausea, vomiting, headache.

Normally, beta amyloid protein dissolves and is reabsorbed by the brain tissue. When beta amyloid protein remains in the interstitial fluid, it

deforms by folding in on itself. Abnormally shaped protein sticks together with other beta amyloid material, forming a sheet of connected proteins or plaque.

In Alzheimer disease, the tau proteins

detach and causes the microtubules to disintegrate. - Process may be caused by an enzyme that escapes its normal restraints and breaks down the tau. - As the microtubule disintegrates, neurofibrillary tangles form and remain in the system. ** Overall effect is decreased cell division and loss of axonal transport of neurotransmitters.

Epigenetics is an

emerging frontier of science focused on how and when particular genes are expressed. Diet and exposure to chemicals in the environment, among other factors, throughout all stages of life can alter a cell's DNA in ways that affect the activity of genes.

An additional protein in the areas of the brain affected by Alzheimer disease is

endoplasmic reticulum-associated binding protein. ** It appears to combine with beta amyloid, which in turn attracts new beta amyloid from outside the cells. - High amounts of endoplasmic reticulum-associated binding protein may also enhance the toxicity of beta amyloid.

Amyloid plaque also includes

fragmented axons, altered glial cells, and cellular debris. - Plaque triggers an inflammatory response, resulting in increased free radicals that cause damage to the nervous system.

Other causes of dementia must be carefully ruled out. There are syndromes that mimic Alzheimer disease in relationship to the dementia, but

have different neurologic causes.

Vascular factors that increase the risk for Alzheimer disease include

hypertension, diabetes, and hyperlipidemia. - Association between high cholesterol levels and Alzheimer disease. Research indicates that statins (cholesterol lowering drugs) may be protective against Alzheimer disease. - APOE genes are linked with atherosclerosis and Alzheimer disease. APOE genotype reflects abnormal cholesterol transport.

Reduction in the number of acetylcholine receptors precedes other pathologic changes. These receptors ae significantly reduced in

late Alzheimer disease, particularly in the basal forebrain. - Selective loss of cholinergic nicotinic receptors in the hippocampus and cortex. - Presynaptic nicotinic receptors control the release of neurotransmitters important for memory and mood, such as acetylcholine, glutamate, serotonin, and norepinephrine.

Common Medications Used in Alzheimer Disease Selegiline (Eldepryl)

monoamine oxidase B inhibitor. Inhibits the monoamine oxidase B enzyme that normally breaks down dopamine in the brain. Used to treat Parkinson disease. Appears to increase the time before advancement to the next stage of Alzheimer disease disability.

Common Medications Used in Alzheimer Disease Memantine (Namenda)

targets the N-methyl-d-aspartate (NMDA) receptors, used for moderate to severe disease. Prevents the pathologic activation of N-methyl-d-aspartate receptors resulting in an influx of excess calcium.

In Down syndrome

the beta-amyloid precursor protein (source of beta amyloid) is overproduced, which almost always leads to early Alzheimer disease.

(Pathologic Alterations in the Brain with Alzheimer Disease) Neuritic plaques and neurofibrillary tangles are more concentrated in .....

the cerebral cortex and hippocampus (important for memory). ** Greater the number of neuritic plaques and neurofibrillary tangles, the more dysfunction associated with Alzheimer disease.

Amyloid precursor protein (APP) is

the large nerve-protecting protein that is the source of beta amyloid.

Apolipoprotein E (APOE) gene on chromosome 19 is

the major genetic source of the common forms of late onset Alzheimer disease

APOE e3,

the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.

Alzheimer disease is characterized by disruptions in multiple major neurotransmitters. Cholinergic abnormalities are

the most prominent. - Acetylcholine is an important neurotransmitter in areas of the brain involved in memory formation. - Loss of acetylcholine activity correlates with the severity of Alzheimer disease.

Other neurons are resistant to the degenerative process, such as

the projections from primary sensory to adjacent secondary sensory areas