As the title suggests, this presentation is a survey of current structural and behavioral Alzmeimers Disease (AD) signs, causes

and treatments. Structural issues concern effects of the disease on brain structures such as nerve cells and brain tissue. Behavioral issues include effects on memory and personality. First, it describes AD itself in general terms and the scope of the impact the disease has on global society. These impacts are financially, emotionally, and biologically substantial. Next, I show the genetic and non-genetic risk factors for developingAD. Then, it examines AD pathophysiology, including the mechanisms by which AD inflicts its terrible toll. After delineating the stages of AD, it presents two case studies of afflicted indivuduals. Are you able to note the behavioral issues? Finally, it surveys and analyzes the currently approved drug therapies, including psychotropic drugs for psychotic symptoms. In addition, it examines and looks forward to potential immunotherapies. And, lastly, it critiques some of the non-approved drug treatments and trials.

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the accrual of neuritic plaques and neurofibrillary tangles that result in a disruption of neuronal function and which causes cognitive and behavioral dysfunction (Braak & Braak, 1991). AD causes an insidious and progressive loss of cognitive function and independence, taking a heavy personal and financial toll on the patient and the family. Alzheimer's disease, Pick's disease, and other organic forms of dementia are generally considered irreversible, progressive, and incurable. AD is the most common cause of dementia among older people. Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.
Dementia is a group of symptoms caused by gradual death of brain cells. The loss of cognitive abilities that occurs with dementia leads to impairments in memory, reasoning, planning, and behavior. While the overwhelming number of people with dementia are elderly, dementia is not an inevitable part of aging; instead, dementia is caused by specific brain diseases.

In 2010, an estimated 36 million people worldwide were living with dementiaa number that is projected to increase to 66 million in 2030, and 115 million in 2050. 1 to 3 percent of people older than 65 who have normal cognition will develop AD in any one year. According to the World Alzheimer Report, the worldwide cost of dementia is estimated at USD $604 billion for 2010, and according to one model, this cost has increased by 34% between 2005 and 2009. Alzheimers disease is the 6th leading cause of death in the United States and the 5th leading cause of death for those aged 65 and older. And, Alzheimers is the only cause of death among the top 10 in America without a way to prevent, cure or even slow its progression. Approximately 5% of all persons over age 70 have AD; this proportion raises to 25%45% in oldest old (>85 years) individuals. About 10% of AD patients develop symptoms before age 65, more often in their 40 s or 50 s.

Deaths from Alzheimers increased 66 percent between 2000 and 2008, while deaths from other major diseases, including the number one cause of death (heart disease), decreased.

Due to the physical and emotional toll of caregiving on their own health, Alzheimers and dementia caregivers had $8.7 billion in additional health care costs in 2011.

An estimated 800,000 individuals with Alzheimers (more than one in seven) live alone. Of those who live alone, up to half of them do not have an identifiable caregiver. People with Alzheimers and other dementias who live alone are exposed to higher risks including inadequate self-care, malnutrition, untreated medical conditions, falls, wandering from home unattended, and accidental deaths compared to those who do not live alone.

Age: Mitochondria become more susceptible to damage; Inflammation (swelling) increases, which can injure nerve cells, such as after a head injury; Oxidative stress, which is caused by the release of molecules called free radicals from normal cellular processes, increases. Education level: Research suggests the more years of formal education one has, the less likely one is to develop Alzheimer's. Some experts theorize that longer education may produce a denser network of synapses. This may create a kind of "neural reserve" that enables people to compensate longer for the early brain changes. Race and Ethnicity: African-Americans and Hispanics are about twice as likely to develop Alzheimers as white Americans of the same age. While the reasons for this are unclear, there is some speculation that it may have to do with the fact that these groups have a higher incidence of high blood pressure and diabetes. High blood pressure and high cholesterol: There is growing evidence that many of the well-established risk factors for cardiovascular disease, including high cholesterol and high blood pressure, may also be risk factors for Alzheimer's disease.

Diabetes: Diabetes has been implicated as a risk factor for eventually developing Alzheimer's disease. There are many ongoing studies attempting to understand the connection, and some diabetes drugs appear to slow the cognitive decline associated with Alzheimer's disease. Head trauma: Some studies have found that Alzheimer's occurs more often in people who have suffered traumatic brain injury earlier in life. A history of head injury is clearly a risk factor for Alzheimer's in people who carry the APOE-4 Alzheimer's gene. Diet: Obesisty doubled the risk of developing AD; Foods high in fat and sugar, as well as larger amounts of red and processed meats increased risk versus lean meats (fish and poultry) and more fruits and vegetables.

The cause of AD is not clear. Your genes and environmental factors seem to play a role. Aluminum, lead, and mercury in the brain is no longer believed to be a cause of AD.

The only identified deterministic factors for the development of AD are the presence of mutations in one of three genes amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) or duplication of APP.

Even if only one of these genes that are inherited from a parent contains a mutation, the person will almost inevitably develop early-onset AD. (100%)

You are more likely to get Alzheimer's disease (AD) if you: Have a close blood relative, such as a brother, sister, or parent with AD. Have certain genes linked to AD, such as APOE epsilon4 allele
This gene, called APOE, produces a protein called apolipoprotein E. APOE comes in several forms, or alleles2, 3, and 4. APOE 4 occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the population.

Notably, the cognitive declines and functional changes in APOE 4 carriers tend to become most evident after age 65 (Jorm et al., 2007; Mondadori et al., 2006b), suggesting that the negative effects of the APOE 4 allele accelerate with age. The genetics of late-onset Alzheimers disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of betaamyloid precursor, and autophagy of damaged organelles. Further analysis highlights the role of inflammatory response in AD pathogenesis.

The brains of people with AD have an abundance of two abnormal structuresamyloid plaques and neurofibrillary tanglesthat are made of misfolded proteins . The third main feature of AD is the loss of connections between cells. This leads to diminished cell function and cell death.

Accumulation of toxic beta amyloid with the formation of extracellular betaamyloidcontaining plaques: We still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process. However, genetic mutations can increase production of beta-amyloid and can cause rare, inherited forms of AD. Development of intracellular neurofibrillary tangles: Tangles are abnormal collections of twisted protein threads found inside nerve cells. The chief component of tangles is a protein called tau.

Neuronal degeneration: The AD process not only inhibits communication between neurons but can also damage neurons to the point that they cannot function properly and eventually die. As neurons die throughout the brain, affected regions begin to shrink in a process called brain atrophy.

Amyloid precursor protein (APP) becomes embedded in cell surface Specific enzymes snip, or cleave, APP into discrete fragments, some are Beta-amyloid (A) peptides Aggregates of two, three, four, or even up to a dozen beta-amyloid peptides are called oligomers. As the process continues, oligomers grow larger, becoming entities called protofibrils and fibrils. Eventually, other proteins and cellular material are added, and these increasingly insoluble entities combine to become the wellknown plaques that are characteristic of AD.

Multiple lines of evidence now suggest that it is not just the presence of A but the production and/or deposition of toxic forms of beta amyloid, along with the slowing of A clearance, that act as the central and primary events in AD pathogenesis, while neurofibrillary tangle formation and neuronal cell death occur downstream in this amyloid cascade.

Elevated levels of tau protein in the cerebrospinal fluid (CSF) are markers of active neuronal degeneration, while levels of abnormally phosphorylated tau (P-tau) appear to correlate with the quantity of neurofibrillary tangles in the brain, suggesting that CSF Ptau may serve as an in vivo biomarker of the neurofibrillary pathology of AD.

Cells and compounds known to be involved in inflammation are found in AD plaques. Some researchers think that components of the inflammatory process may play a role in AD. Other players in the aging process that may be important in AD are free radicals, oxygen or nitrogen molecules that combine easily with other molecules.
Betaamyloid deposition within the CNS would bring about the activation of microglia and thus initiate a proinflammatory cascade leading to release potentially neurotoxic substances (cytokines; chemokines; reactive oxygen andnitrogen species; proteolytic enzymes) and to amplify neural damage.

Healthy neurons are internally supported in part by structures called microtubules, which help transport nutrients and other cellular components, from the cell body down the axon. As a result of hyperphosphorylation, tau disengages from the microtubules and begins to come together with other tau threads.

These tau threads form structures called paired helical filaments, which can become enmeshed with one another, forming tangles within the cell.
The microtubules can disintegrate in the process, collapsing the neurons internal transport network. This collapse damages the ability of neurons to communicate with each other.

On this slice, the atrophic hippocampus and amygdala can be seen. These structures subserve memory function, and are the sites of major damage in Alzheimer's disease.

Here is a mid-ventricular slice which demonstrates the commonest finding in functional imaging of Alzheimer's disease. The dark blue regions in the parietal lobes represent areas of decreased blood flow or perfusion. This reduction in blood flow is due in part to the underlying atrophy, in part to the presence of diseased brain, and in part to the functional "disconnection" of this from other brain regions affected by the disease.

The association cortex of the parietal lobes is often severely affected, as illustrated in this case.

MRI and PET scan image overlay for corresponding slice showing perfusion and atrophy in the associated areas of reduced blood flow.

 Scientists developed a radiolabeled compound called Pittsburgh Compound B (PiB). PiB binds to beta-amyloid plaques in the brain and can be imaged using PET scans. Initial studies showed that people with AD take up more PiB in their brains than do cognitively healthy older people. Since then, scientists have found high levels of PiB in some cognitively healthy people, suggesting that the damage from beta amyloid may already be underway.
In this PET scan, the red and yellow colors indicate that PiB uptake is higher in the brain of the person with AD than in the cognitively healthy person.

The compensatory hypothesis is an explanation of differential regional (brain regions) activity seen in at-risk groups. The compensatory hypothesis holds that as AD-related degenerative processes progress the brain employs various compensatory measures to overcome these pathologic encroachments until the decline in cognitive abilities becomes apparent and, ultimately, daily functioning is disrupted. Accordingly, increased functional activity has been interpreted as a compensatory process whereby greater cognitive effortusually reflected by increases in BOLD (blood oxygen level)activityis required to perform at an equivalent level compared to healthy control groups. Similarly, decreased activity in healthy functioning has been interpreted as evidence of efficient processing (Mondadori et al., 2006b), whereas decreased activity in neurodegenerative diseases appears to reflect cortical compromise or disconnection.

AD begins deep in the brain, in the entorhinal cortex, a brain region that is near the hippocampus and has direct connections to it. Healthy neurons in this region begin to work less efficiently, lose their ability to communicate, and ultimately die. This process gradually spreads to the hippocampus, the brain region that plays a major role in learning and is involved in converting short-term memories to long-term memories. Affected regions begin to atrophy.

Ventricles, the fluid filled spaces inside the brain, begin to enlarge as the process continues.

Scientists believe that these brain changes begin 10 to 20 years before any clinically detectable signs or symptoms of forgetfulness appear. Thats why they are increasingly interested in the very early stages of the disease process.

As some people grow older, they develop memory problems greater than those expected for their age. But they do not experience the personality changes or other problems that are characteristic of AD. These people may have a condition called mild cognitive impairment (MCI). People with MCI are a critically important group for research because a much higher percentage of them go on to develop AD than do people without these memory problems. About 8 of every 10 people who fit the definition of amnestic MCI go on to develop AD within 7 years. Those with MCI who had lots of trouble moving their legs and feet were more than twice as likely to develop AD as those with good lower body function.

However, researchers are not yet able to say definitively why some people with amnestic MCI do not progress to AD, nor can they say who will or will not go on to develop AD.

As AD spreads through the brain, the number of plaques and tangles grows, shrinkage progresses, and more and more of the cerebral cortex is affected. Memory loss continues and changes in other cognitive abilities begin to emerge. The clinical diagnosis of AD is usually made during this stage. In mild AD, a person may seem to be healthy but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually to the person and his or her family. Signs of mild AD can include: Memory loss Confusion about the location of familiar places (getting lost begins to occur); Taking longer than before to accomplish normal daily tasks; Trouble handling money and paying bills; Loss of spontaneity and sense of initiative; Mood and personality changes, increased anxiety and/or aggression Accepting these signs as something other than normal and deciding to go for diagnostic tests can be a big hurdle for people and families.

By this stage, AD damage has spread to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to shrink, ventricles enlarge, and signs and symptoms of the disease become more pronounced and widespread. Behavioral problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, which can be difficult for many spouses and families. Some of these symptoms may become worse in the evening (a phenomenon called sundowning) or during daily routines, especially bathing. The symptoms of this stage can include: Increasing memory loss and confusion; Inappropriate outbursts of anger; Problems recognizing friends and family members; Difficulty with language; Restlessness, agitation, anxiety, tearfulness, wandering especially in the late afternoon or night. And, Hallucinations, delusions, suspiciousness or paranoia, irritability; Loss of impulse control (shown through undressing at inappropriate times or places or vulgar language); An inability to carry out activities that involve multiple steps in sequence, such as dressing, making a pot of coffee, or setting the table.

People with severe AD cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care.

Symptoms can include: Weight loss; Seizures; Skin infections; Difficulty swallowing; Groaning, moaning or grunting; Increased sleeping; Loss of bladder or bowel control.

Near the end, the person may be in bed much or all of the time. The most frequent cause of death for people with AD is aspiration pneumonia. This type of pneumonia develops when a person is not able to swallow properly and takes food or liquids into the lungs instead of air.

To qualify for hospice benefits under Medicare, a physician must diagnosis the person with Alzheimers disease as having less than six months to live.

This diagram reveals the neuropathological hallmarks of AD that include neuritic (also senile) plaques, neurofibrillary tangles (NFTs), and amyloid angiopathy.

Neuritic plaques are extracellular aggregates of beta()amyloid protein in a milieu of reactive astrocytes and activated microglia.

NFTs are intraneuronal cytoplasmatic filaments composed of hyperphosphorylated tau, frequently conjugated with ubiquitin.

One type is the rare, early-onset Alzheimers disease. It usually affects people aged 30 to 60. Some cases of early-onset disease are inherited and are called familial AD (FAD). It is acknowledged that 75% of people with AD have sporadic AD (SAD) a form of lateonset AD (LOAD). This is most likely a multifactorial condition, which involves a combination of genetic, lifestyle, and environmental factors. 25% is familial AD (FAD). Early-onset AD encompasses 5% of FAD cases. Early-onset FAD is inherited in an autosomal dominant manner and is caused by mutations in one of these three genes: APP, PSEN1, and PSEN2. The principal neuropathological changes in ADAD, a form of early-onset AD, neuronal loss, neurofibrillary tangles, senile plaques, and cerebral amyloid angiopathy (CAA) mirror those seen in SAD (LOAD) providing strong support for ADAD as a model for studying AD.

The other is late-onset Alzheimers disease (LOAD). It is by far the more common form and occurs in those 60 and older.

As for LOAD, the only established genetic factor is apolipoprotein E (APOE). APOE associated Alzheimers disease is due to a specific variation in the APOE gene called e4 allele. It is estimated that 4065% of AD patients have at least one copy of the e4 allele. Individuals with two e4 alleles have up to 20 times the risk of developing AD. Nonetheless, a third of patients with AD are ApoE4 negative, and some ApoE4 homozygotes never develop the disease.

More severe medial-temporal lobe atrophy may be present in symptomatic ADAD (early onset) carriers compared with SAD (late onset).

Memory loss that disrupts daily life: forgetting recently learned information, important dates or events; asking repetitively for things; using memory aides (e.g., reminder notes or electronic devices) or family members for things they used to handle on their own. Whats Typical: Sometimes forgetting names or appointments, but remembering them later.

Challenges in planning or solving problems: Some people may experience changes in their ability to develop and follow a plan or work with numbers. They may have trouble following a familiar recipe or keeping track of monthly bills. They may have difficulty concentrating and take much longer to do things than they did before. Whats Typical: Making occasional errors when balancing a checkbook.

Difficulty completing familiar tasks at home, at work or at leisure: People with Alzheimers often find it hard to complete daily tasks. Sometimes, people may have trouble driving to a familiar location, managing a budget at work or remembering the rules of a favorite game. Whats Typical: Occasionally needing help to use the settings on a microwave or to record a television show.

Confusion with time or place: People with Alzheimer's can lose track of dates, seasons and the passage of time. They may have trouble understanding something if it is not happening immediately. Sometimes they may forget where they are or how they got there. Whats Typical: Getting confused about the day of the week but figuring it out later.

Trouble understanding visual images and spatial relationships: For some people, having vision problems is a sign of Alzheimer's. They may have difficulty reading, judging distance and determining color or contrast. In terms of perception, they may pass a mirror and think someone else is in the room. They may not recognize their own reflection.
Whats Typical: Vision changes related to cataracts.

New problems with words in speaking or writing: People with Alzheimer's may have trouble following or joining a conversation. They may stop in the middle of a conversation and have no idea how to continue or they may repeat themselves. They may struggle with vocabulary, have problems finding the right word or call things by the wrong name (e.g., calling a watch a "hand clock").
Whats Typical: Sometimes having trouble finding the right word.

Misplacing things and losing the ability to retrace steps: A person with Alzheimers disease may put things in unusual places. They may lose things and be unable to go back over their steps to find them again. Sometimes, they may accuse others of stealing. This may occur more frequently over time.
Whats Typical: Misplacing things from time to time, such as a pair of glasses or the remote control.

Decreased or poor judgment: People with Alzheimer's may experience changes in judgment or decision making. For example, they may use poor judgment when dealing with money, giving large amounts to telemarketers. They may pay less attention to grooming or keeping themselves clean.
Whats Typical: Making a bad decision once in a while.

Withdrawal from work or social activities: A person with Alzheimer's may start to remove themselves from hobbies, social activities, work projects or sports. They may have trouble keeping up with a favorite sports team or remembering how to complete a favorite hobby. They may also avoid being social because of the changes they have experienced.
Whats Typical: Sometimes feeling weary of work, family and social obligations.

Changes in mood and personality: The mood and personalities of people with Alzheimer's can change. They can become confused, suspicious, depressed, fearful or anxious. They may be easily upset at home, at work, with friends or in places where they are out of their comfort zone. Whats Typical: Developing very specific ways of doing things and becoming irritable when a routine is disrupted

Psychosis is frequent in late onset Alzheimers disease, with a median prevalence across studies of 41%.

Psychosis significantly aggregated within late onset Alzheimers disease families suggesting that it may identify a genetically determined subgroup.

Evidence indicates that psychosis is a marker for more severe cognitive impairments and a more rapidly progressive phenotype of late onset Alzheimers disease.

A 73 year old woman, was brought to neurological evaluation by her brother because of a 3 year history of memory impairment. She had completed high school and worked in a clerical position until her retirement in 1985. She had lived alone and maintained her own home and financial affairs since the death of her husband in 1980. The brother had begun to notice gradually worsening memory impairment and difficulty finding words, but the patient became angry at the suggestion that she may have a progressive impairment. Others had noted decline in housekeeping and financial affairs, but she had no complaints. Elevated arterial blood pressure was documented on several occasions, but she never took medication. She had no children and had a hysterectomy. She was a well-groomed woman who was alert and friendly. General and elemental neurological exams were normal.

Her speech was highly anomic and paraphasic, with a tendency to use vague referents such as "things" and "stuff". She was able to provide her name, but when asked about her current age, she said: "I don't know . . ., about 8 I think." She incorrectly stated her birth month, but then became aware of this. Given three choices, she was able to give the correct month. She was unable to give the year of her birth, the current year, or the name of the current U.S. President. On formal testing, she scored well below average in all cognitive domains. These tests included the Wechsler Memory scale, the Wechsler Adult Intelligence Scale, digit span and similarities subtests, the Boston Naming Test, the CERAD Word List Memory Test, the CERAD Visuo-spatial Construction, the Cross Circle Tests, the California Proverb Test, and the Graphomotor Alternation Test. She tended to perseverate both verbal and motor responses. The conclusion of the evaluation was that she met research criteria for "probable" Alzheimer's disease, that she required complete supervision around the clock to insure her safety, and that she would probably benefit from social stimulation provided by a group living situation.

North American(FDA) and European Union(EMA) regulatory criteria for marketing approval of putative symptomatic and disease-modifying therapeutic agents for AD based on:

a demonstration of efficacy supported by improvements compared to placebo treatment on cognitive function, activities of daily living (ADL)

and often evidence of overall clinical improvement or less overall decline accompanied by adequate evidence of safety.

standardized protocols: mild to moderate AD is indexed by a Mini- Mental State Examination (MMSE) score of 1026 and

the Alzheimers Disease Assessment Scale Cognitive Portion (ADAS-cog), the Alzheimers Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale, or the Disability Assessment for Dementia (DAD).

A clinicians global assessment (known as a Clinician InterviewBased Impression of Change with caregiver input [CIBIC] or ADCS Clinical Global Impression of Change [CGIC]) or the Clinical Dementia Rating (CDR), an interview-based overall dementia severity assessment, are the conventional outcomes measures.

 Acetylcholinesterase inhibitors (AChE-Is) are the first class of agents specifically approved by the US Food and Drug Administration (FDA)or the treatment of mild to moderate AD. The responses to treatment with different AChE-Is have overlapping confidence intervals (CI), and no individual cholinesterase inhibitor has been shown to be superior to others in terms of efficacy Continuing benefit from use of AChE-Is has been shown in trials lasting up to 2 years, among patients followed over that length of time (AD2000 Collaborative Group 2004). In addition, patients with severe ADnot previously treated with AChE-Isrespond to treatment with AChE-Is, and donepezil is approved for treatment in this advanced phase of the disease.

 Memantine was used in Germany for the treatment of Parkinsons disease prior to its approval in the USA and globally for treatment of AD. Memantine is an NMDA receptor antagonist that replaces potassium in the NMDA receptor channel to reduce entry of calcium into neurons and avoid calcium-stimulated apoptotic cell death cascades. Clinical trials of memantine have been very similar in design to those conducted with AChE-Is, but have involved patients with moderate to severe AD, rather than mild to moderate AD. Memantine is not approved by the FDA for patients with mild AD. European regulatory authorities extended the range of approval for use of memantine to patients with MMSE scores of 19 and below.

Cholinesterase inhibitors and memantine are potential therapies for the management of many cognitive symptoms of AD, but these neurotransmitter-based approaches do not address the underlying pathology of the illness, and ultimately fail to prevent its progression. Gastrointestinal side effects : Anorexia, nausea, vomiting, diarrhea, and weight loss may occur and should be monitored in patients treated with these agents. In addition, cholinergic influences may slow heart rate and bradycardia is a contraindication to use of AChE-Is. In cases where these drugs appear to be effective, patients and caregivers reported a slowing in symptoms such as memory loss, reduced anxiety, improved mood and restored confidence levels. Some patients will respond and others not to AChE-Is.

Once a patient stops taking a drug, their condition will deteriorate over a period of 4 to 6 weeks until they are at the same point as an individual who has not taken the drug.

Passive immunotherapy refers to the direct administration of anti-beta-amyloid antibodies, obviating the need for patients to mount an antibody response. Passive immunotherapy in the form of specifically designed monoclonal antibodies allows for the precise targeting of beta-amyloid epitopes. In contrast, active immunotherapy involves the administration of either full-length betaamyloid peptides or peptide fragments to activate the patients immune system in order to produce anti-betaamyloid antibodies. AN1792, a synthetic beta-amyloid peptide, was the first active amyloid immunotherapy tested in clinical trials. As compared with placebo treated patients, antibody responders had a 25% lower decline in activities of daily living as assessed by the DAD. The trial was stopped due to cases of meningoencephalitis. Bapineuzumab is a humanized monoclonal antibody (passive) that targets the Nterminal region of beta amyloid. Bapineuzumab/placebo differences in 11C-PiB retention were statistically significant in all prespecified cortical regions (anterior and posterior cingulate, frontal, temporal, parietal, and occipital cortex).

Positron emission tomography (PET) carbon-11-labelled Pittsburgh compound B (11CPiB) images from patients treated with bapineuzumab and those given placebo. This finding correlates to an approximately 25% reduction in cortical beta amyloid in bapineuzumab-treated patients.

There is an urgent need for effective, safe, psychotropic agents for treatment of behavioral disturbances in AD and other dementing disorders.

Behavioral disturbances are common in AD, including depression, agitation, irritability, aberrant motor behaviors, and psychosis. There are no agents approved by the FDA specifically for treatment of behavioral disturbances in AD. Antipsychotics both conventional and atypicalare associated with increased mortality and some antipsychotics are associated with increased risk for cerebrovascular accidents or stroke when administered to elderly patients with AD. The risk of death is increased from 2.6% to 4.5% during an average of 10 weeks of therapy. Several 112 week long clinical trials suggest that risperidone and possibly other atypical antipsychotic agents in low doses are efficacious in reducing psychosis and agitation in mainly nursing home patients with AD.

Strategies for use of antipsychotics in patients with AD involve avoiding their use in patients with cardiovascular or pulmonary disease (the two most common causes of death in mortality studies), using these agents only in patients for whom nonpharmacologic interventions have failed and the behaviors are extreme. Clinical trials have been largely negative in showing benefit for treatment of depression in AD with antidepressant medications. Individual practitioners may use practice-based evidence to guide their therapeutic decisions. Anxiolytics and hypnotics are generally to be avoided in patients with AD as they may increase confusion. Short term use of benzodiazepines such as lorazepam or clonazepam may be useful in patients with episodes of agitation. Greater cognitive impairment is by far the most consistent correlate of psychosis in late onset Alzheimers disease. Also, Evidence of familial aggregation of psychosis in Alzheimers disease suggests that this phenotype is under genetic control.

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