Alzheimer's disease (AD)Under supervision of:

Prof. Dr. Seham Abo Shosha

Presented by:Sara Ahmed Youssry

Alzheimer's disease (AD)

Is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in planning, language, and perception.

Results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.

The likelihood of having Alzheimer's disease increases after the age of 70 and may affect around 50% of persons over the age of 85 .

However, Alzheimer's disease is not a normal part of aging.

Epidemiology

Risk factors: •Increased age. The biggest risk factor for Alzheimer's disease

•Genetic risk factors

-The best-studied "risk" gene is the one that encodes apolipoprotein E (apoE) .

The apoE4 form of the gene has been associated with increased risk of Alzheimer's disease .

Persons with one copy of the E4 gene usually have 2-3fold increased risk .

Persons with two copies of the E4 gene have about 9-fold increase in risk .

-Mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2

•Traumatic head injuries earlier in life, particularly among those with the apoE 4 gene.

•limited formal education usually less than eight years . It is not known whether this reflects a decreased "cognitive reserve"

or other factors associated with a lower educational level.

•women have a higher risk for Alzheimer's disease than men.

- women live longer than men- The role of estrogen in Alzheimer's disease

remains an area of research focus .

Symptoms of Alzheimer's disease 

The course of Alzheimer's disease is not the same in every person, but symptoms seem to develop over 3 stages.

 Very early signs and symptomsMemory problems are typically one of the first signs of AD.

A) Mild Alzheimer's disease

As the disease progresses, memory loss worsens, and changes in other cognitive abilities are evident. Problems can include:

Getting lostTrouble handling money and paying billsRepeating questionsPoor judgmentMood and personality changes

Alzheimer's disease is often diagnosed at this stage

B) Moderate Alzheimer's diseaseIn this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Symptoms may include:

Increased memory loss and confusionproblems recognizing family and friendsinability to learn new thingsHallucinations.

impulsive behavior

C) Severe Alzheimer's diseasePeople with severe Alzheimer's are completely dependent on others for their care. Near the end, the person may be in bed most or all of the time. Their symptoms often include:

Inability to communicateWeight lossSkin infectionsDifficulty swallowingIncreased sleepinglack of control of bowel and bladder

What causes Alzheimer's disease?

It is a neurodegenerative disease, caused by progressive brain cell death that happens over a course of time.

The total brain size shrinks with Alzheimer's - the tissue has progressively fewer nerve cells and connections.

Postmortem/autopsy will always show tiny inclusions in the nerve tissue, called plaques and tangles:•Plaques are found between the dying cells in the brain - from the build-up of a protein called beta-amyloid (amyloid plaques).•The tangles are within the brain neurons - from a disintegration of another protein, called tau.

Several competing hypotheses exist trying to explain the cause of the disease:

-Genetics:( Amyloid hypothesis ) : The most important one

Mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2 increase the production of a small protein called AB42, which is the main component of senile plaques ( Familial type of AD )APOE4, is a major genetic risk factor for AD leading to excess amyloid buildup in the brain ( Sporadic type of AD )

Tau hypothesis

Tau protein abnormalities initiate the disease cascade. Hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells

Other hypotheses

-Age-related myelin breakdown in the brain. Iron released during myelin breakdown cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau. -Oxidative stress may be significant in the formation of the pathology

The amyloid hypothesis points to the accumulation of beta-amyloid peptides ( the toxic form of the protein ) as the central event triggering neuron degeneration “cascade” that results in neuron death (apoptosis) and cognitive impairments

Aß resulted in increased p53 levels, which were sufficient to increase Bax protein and nuclear fragmentation

In vitro Aß induces expression of pro-apoptotic Bcl-2 proteins, including Bax, and down regulation of anti-apoptotic

members such as Bcl-2, Bcl-xL and Bcl-w .

Mechanisms linking AD pathogenesis to apoptosis.

Aß has been shown to destabilize neuronal calcium homeostasis, generally leading to an increase in cytosolic calcium which can then trigger neuronal apoptosis

Aβ associated mitochondrial dysfunction leading to cognitive decline in AD:•Decreased mitochondrial motility resulting in disorganized synaptic mitochondrial distribution•Decreased mitochondrial ATP provision and respiratory function•Decreased cytochrome oxidase activity•Elevated mitochondria-associated oxidative stress•Increased mitochondrial permeability•Decreased mitochondrial Ca2+ modulating capacity and Ca2+ accumulation•Release of pro-apoptogenic factors from mitochondria•Membrane potential collapse•Increased free radical production

Increased mitochondrial fragmentation (important event early in apoptosis

Impact of tau on toxicity,

that tau becomes more hyperphosphorylated with disease progression and leads to greater dendritic toxicity.

Increased amounts of cell injury or death of neurons can occur when the inflammatory response is chronic and uncontrolled in nature

Aβ can have toxic effects via direct and indirect mechanisms including inducing local inflammation.Eg. interleukins (IL), TNFα, and TNFβ

In parallel, tumor necrosis factor alpha (TNF ), tumor necrosis factor receptor 1 (TNF-R1)and TNF-R1-associated death domain protein (TRADD) have allbeen found to be increased in AD.

In particular, FasL appears to play an important role in Aβ-mediated neurotoxicity. Exposure of cortical neurons to Aß activates c-Jun N-terminal kinase (JNK). JNK is required for the activation of the c-Jun transcription factor, which in turn stimulates the transcription of several key target genes, including the death inducer FasL. The binding of FasL to its receptor Fas then induces a cascade of events, leading to caspase activation and, ultimately, apoptosis .

Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD

Initiate apoptosis

How is AD Diagnosed?• Asking questions about the person’s general health, any past

medical problems, and the ability to do daily activities• Memory tests, problem solving strategies, attention, counting• Tests of blood, urine, or spinal fluid• Brain scans

Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain.

In the early stages of dementia, brain image scans may be normal .

In later stages, an MRI may show a decrease in the size of different areas of the brain.

While the scans do not confirm the diagnosis of AD, they do exclude other causes of dementia (such as stroke and tumor).

However, the only way to know for certain that someone has AD is to examine a sample of their brain tissue after death .

TreatmentThere is no cure for AD. The goals of treatment are:

-Slow the progression of the disease.-Manage symptoms, such as behavior problems, confusion, and sleep

problems-Change home environment so you can better perform daily activities

-Support family members and other caregivers

a) DRUG TREATMENTMedicines are used to help slow down the rate at which symptoms

become worse. The benefit from these drugs is usually small .

Modulate neurotransmitters, either acetylcholine or glutamate. (reduction in the activity of cholinergic neurons is a feature of AD) .

Eg.cholinesterase inhibitors (ChEIs) and a partial N-methyl-D-aspartate (NMDA) antagonist.

Psychotropic medications have been used to treat behavioral symptoms:

-Antidepressants-Anxiolytics

-Antiparkinsonian agents-Beta-blockers

-Antiepileptic drugs (for their effects on behavior)-Neuroleptics

b) Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD.

c) If the patient becomes a danger to him/herself or others, short-term hospitalization may be indicated 

Thank You