1. Alzheimer’s Disease Robert Nagele, PhD Professor of Medicine
UMDNJ–SOM NJISA
Anita Chopra, MD, FACP
Professor, Geriatrician
and Director
UMDNJ –SOM NJISA
Campus image created by the University of Medicine & Dentistry of New Jersey School of Osteopathic Medicine

2. Alzheimer’s Disease
This medical student presentation is offered by the New Jersey Institute for Successful Aging.
This lecture series is supported by an educational grant from the Donald W. Reynolds Foundation Aging and Quality of Life program.

3. Learning Objectives
Discuss prevalence and economic impact of Alzheimer’s disease (AD)
Identify core clinical criteria for diagnosis of Alzheimer’s disease and mild cognitive impairment (MCI)
Discuss pathophysiology and potential biomarkers of Alzheimer's disease
Describe evaluation and management of patients affected by the disease

4. What is AD?
Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills.
Image copyright © 1997 PhotoDisc, Inc. (
The risk of developing AD increases with age
In most cases, symptoms first appear after age 60
Familial AD appears early – 1 to 2% of cases are inherited and nearly all of these are as a result of mutations in the presenilin gene
AD is not a part of normal aging – it is a fatal brain disease.

5. AD Statistics
AD is the most common cause of dementia among people age 65 and older.
Estimate that around 4.5 million people now have AD.
For every 5-year age group beyond 65, the percentage of people with AD doubles.
By 2050, 13.2 to 16 million older Americans are expected to have AD - if the current numbers hold and if no preventive treatments become available.
Worldwide, 100 million are expected to be affected by 2050
Images 1 & 2: Copyright © 1997 PhotoDisc, Inc. (
Image 3 Source: Microsoft Office Images #MP (
Top and middle images copyright © 1997 PhotoDisc, Inc. (
Bottom image source: Microsoft Office Images #MP (

6. Care and its Costs Where are people with AD cared for? Home
Assisted living facilities
Nursing homes (special care units)
Source: PhotoSearch Mature Lifestyles 2 #58307
The national cost of caring for people with AD is about $120 billion every year.
Top Image Source: PhotoSearch Mature Lifestyles 2 #58307
Bottom Image Source: Microsoft Office Images #MP by iStockphoto (
Source: Microsoft Office Images #MP by iStockphoto (

7. This report was released on September 21, 2010 by Alzheimer’s Disease International (ADI), which is a World Health Organization-related international federation. According to this report, the number of people with dementia will grow over 100 million in 2050, of which 50-70% will be the Alzheimer’s type. The total estimated worldwide costs of dementia were US $604 billion in 2010, higher than the annual revenues of Walmart or Exxon Mobil, which are the top 2 in the world.
If dementia care were a country, it would be the world’s 18th largest economy, ranking between Turkey and Indonesia. All that tells us that humans are faced with a big fight against AD. That tells us the fight with dementia and AD are turning intense and very serious.
Images from Alzheimer’s Disease International World Alzheimer Report 2010: The Global Economic Impact of Dementia. London, UK: Alzheimer’s Disease International (ADI), 2010.
Figures from Alzheimer’s Disease International World Alzheimer Report 2010: The Global Economic Impact of Dementia. London, UK: Alzheimer’s Disease International (ADI), Used by permission.

8. Alzheimer's Dementia: Core Clinical Criteria
Meets criteria for dementia and in addition, has the following characteristics
Insidious onset: symptoms have been gradual
Clear-cut history of worsening of cognition
The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories.
Amnestic presentation: most common, deficits include impairment in learning and recall of recently learned information
Nonamnestic presentations: language problems, executive dysfunction, visualspacial presentation
The diagnosis of probable AD dementia should not be applied when there is evidence of (a) substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or (b) core features of dementia with Lewy bodies other than dementia itself; or (c) prominent features of behavioral variant frontotemporal dementia; or (d) prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or (e) evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition.

9. The 10 Warning Signs of AD (from the Alzheimer’s Association)
Memory changes that disrupt daily life
Challenges in planning or solving problems
Difficulty performing familiar tasks at home, at work or at leisure
Confusion with time or place
Trouble understanding visual images and spacial relationships
New problems with words in speaking or writing
Misplacing things or loosing the ability to retrace steps
Decreased or poor judgment
Withdrawal from work or social activities
Changes in mood and personality
These 10 warning signs can help individuals and family members to recognize the possibility of AD early in the course of the disease.

10. Preclinical AD and Mild Cognitive Impairment
Signs of AD are first noticed in the entorhinal cortex, then it proceeds to the hippocampus.
Affected brain regions begin to shrink as brain neurons cells die.
Changes can begin years before symptoms appear.
May notice subtle behavioral and memory changes usually attributed to “old age”.
Memory loss is the first sign.
Wide variety of symptoms – hard to diagnose with certainty
Images courtesy of the National Institute on Aging/National Institutes of Health
Images courtesy of the National Institute on Aging/National Institutes of Health
Blue stipple indicates disease spread and extent

11. Mild Cognitive Impairment (MCI) Core Clinical Criteria
Concern regarding a change in cognition
Evidence of lower performance in one or more cognitive domains that is greater than would be expected for the patient’s age and educational background
Generally maintain their independence of function in daily life, with minimal aids or assistance
Impairment in episodic memory (i.e., the ability to learn and retain new information) is most commonly seen in MCI patients who subsequently progress to a diagnosis of AD dementia.
There should be evidence of lower performance in one or more cognitive domains that is greater than would be expected for the patient’s age and educational background. If repeated assessments are available, then a decline in performance should be evident over time. This change can occur in
a variety of cognitive domains, including memory, executive function, attention, language, and visuospatial skills. An impairment in episodic memory (i.e., the ability to learn and retain new information) is seen most commonly in MCI patients who subsequently progress to a diagnosis of AD dementia.
To meet the core clinical criteria for MCI, it is necessary to rule out other systemic or brain diseases that could account for the decline in cognition (e.g., vascular, traumatic, medical). The goal of such an evaluation is to increase the likelihood that the underlying disease is a neurodegenerative disorder with characteristics consistent with AD.

12. Mild to Moderate AD
AD spreads through the brain. The cerebral cortex begins to shrink as more and more neurons stop working, lose their synapses, and die.
Mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety.
Moderate AD signs can include increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements.
Images courtesy of the National Institute on Aging/National Institutes of Health
Note preferred spread to frontotemporal and more posterior regions
Images courtesy of the National Institute on Aging/National Institutes of Health

13. Severe AD
In severe AD, extreme brain shrinkage occurs. Brain retracts from cranial vault – brain ventricles expand. Patients are completely dependent on others for care.
Symptoms can include weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control.
Death usually occurs from aspiration pneumonia or other infections. Caregivers can turn to a hospice for help and palliative care.
Images courtesy of the National Institute on Aging/National Institutes of Health
Note pathology is widespread – symptoms become similar from one person to the next.
Images courtesy of the National Institute on Aging/National Institutes of Health

14. Alzheimer’s Disease Progression
Mild Cognitive Impairment
Death from pneumonia and/or other comorbidities
Mild
Loss of recent memory
Faulty judgment
Personality changes
Moderate
Verbal and physical aggression
Agitation
Wandering
Sleep disturbances
Delusions
Severe
Loss of all reasoning
Bedridden
Incontinence
8 years average. Range: 2-20 years

15. Clinical Expression of AD
COGNITION
BEHAVIOR
Unique
Symptom
Pattern of AD
Alzheimer’s disease is complex. It affects memory, behaviors and, in the later stages, physical functioning in terms of self-care capacity. The combination of these effects makes AD a total body disorder.
FUNCTION

16. The Brain’s Vital Statistics
Inside the Human Brain
To understand Alzheimer’s disease, it’s important to know a bit about the brain…
The Brain’s Vital Statistics
Adult weight: about 3 pounds
Adult size: a medium cauliflower
Number of neurons: 100,000,000,000 (100 billion)
Number of synapses (the gap between neurons): 100,000,000,000,000 (100 trillion)
Image courtesy of the National Institute on Aging/National Institutes of Health
Images courtesy of the National Institute on Aging/National Institutes of Health

17. Pathophysiology of AD
Deposition of insoluble amyloid peptide both in and around neurons – primarily involves pyramidal neurons – amyloid may or may not be directly toxic (e.g., excessive accumulation of anything can be bad)
Formation of millions of amyloid (neuritic) plaques – small spherical accumulations of amyloid – each may be the end result of a single neuron cell death event
Formation of neurofibrillary tangles containing primarily the hyperphosphorylated tau protein – the tau protein associates with microtubules in axons and dendrites of neurons
Inflammatory response
astrocytosis (activation of astrocytes – an early event involved in clearing of synaptic debris)
microgliosis (activation of microglia – a later event involved in clearing of dead cell debris and initiating a more global inflammation)
Cholinergic deficit – loss of acetylcholine receptors in cholinergic neurons – each neuron less able to “perform” – acetylcholinesterase inhibitors like Aricept help resolve this

18. Histological Hallmarks of AD
In 1907, in the first report, Alois Alzheimer described senile plaques (SP) and neurofibrillary tangles (NFT) SP are found in neocortex, hippocampus and in several subcortical areas.
NFT density correlates with disease duration and severity of dementia.
amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells
neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell
NFTs
Amyloid
Plaques
Senile (Amyloid) plaque
Neurofibrillary tangle

19. Vulnerable Neurons in AD
Basal forebrain cholinergic system (nucleus basalis)
Monoaminergic system
Hippocampus (CA1 and CA2 pyramidal cells)
Amygdala
Entorhinal cortex
Neocortex

20. Amyloid (Abeta42) deposition makes neurons sick.
Sick neurons retract their axons and dendrites and lose synaptic
connections with each other  Loss of memory and cognition
Sick
neuron AP
Amyloid
plaque
Lower right shows what neurons look like in a healthy brain. In AD brains, neurons are either sick, dying or dead. When they are sick, synaptic connections break down – the processes retract and have a corkscrew appearance. Loss of synapses means loss of brain function, including memory, and the ability to think and learn. The loss of neurons in the AD brain has been linked to the accumulation of a material called amyloid. You can see it here in this picture as a cloud of material called an amyloid plaque.
Images courtesy of the National Institute on Aging/National Institutes of Health
Retracted
“corkscrew”
dendrites
Amyloid plaques contain Abeta42
Images courtesy of the National Institute on Aging/National Institutes of Health

21. AD and the Brain Beta-amyloid Plaques
Amyloid precursor protein (APP) is the precursor to amyloid plaque.
1. APP sticks through the neuron membrane.
2. Secretase enzymes cut the APP into fragments of protein, including beta- amyloid.
3. Beta-amyloid fragments come together in clumps to form plaques. 1. 2.
Images courtesy of the National Institute on Aging/National Institutes of Health
In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex. 3.
Images courtesy of the National Institute on Aging/National Institutes of Health

22. Neurofibrillary Tangles
AD and the Brain
Neurofibrillary Tangles
Image courtesy of the National Institute on Aging/National Institutes of Health
Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles.
Image courtesy of the National Institute on Aging/National Institutes of Health

23. The Continuum of Alzheimer's Disease
This is Figure 1 from Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011;7(3): It appears on page Permission for usage granted by Elsevier.
Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia 2011;7(3): Used with permission from Elsevier.

24. Hypothetical Model of the Alzheimer’s Disease Pathophysiological Cascade
This is Figure 2 from Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011;7(3): It appears on page Used by permission of Elsevier.
Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia 2011;7(3): with permission from Elsevier.

25. Biomarkers of AD Biomarkers of Abeta accumulation:
abnormal tracer retention on amyloid PET imaging
low CSFAbeta42
Biomarkers of neuronal degeneration/injury
elevated CSF tau (both total and phosphorylated tau)
decreased fluorodeoxyglucose uptake on PET involving temporoparietal cortex
atrophy on structural magnetic resonance involving medial, basal, and lateral temporal lobes and medial and lateral parietal cortices

26. Biomarkers of Alzheimer’s Disease
This is Figure 3 from Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011;7(3): It appears on page Used by permission of Elsevier.
Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia 2011;7(3): with permission from Elsevier.

27. Risk Factors for AD Age Gender – female has more risk
Low education and low IQ
Positive family history of AD or dementia
Apolipoprotein alleles (esp. Apo E4 genotype – ApoE4 has been shown to be a carrier of the amyloid peptide across the blood-brain barrier)
Mutations in Amyloid Precursor Protein (APP) – generate more amyloid
Mutations in genes processing APP (presenilin 1 & 2) – generate more amyloid
Down’s syndrome (chr. 21) – contains APP gene % incidence of Alzheimer’s disease
Head injury
Low serum levels of folate and vitamin B12 – evidence weak
Elevated plasma and total homocysteine levels – evidence weak

28. Protective Factors for AD
High education
NSAIDS
Statins
Red wine, beer?
Curcumin - curry
Blueberries – it’s the color - antioxidant
Intellectual leisure activities, socialization
Cardiovascular health

29. Diagnosing AD A detailed patient history
Information from family and friends
Physical and neurological exams and lab tests
Neuropsychological/cognitive tests
Imaging tools such as CT scan or magnetic resonance imaging (MRI). PET scans are used primarily for research purposes.
Source: Photodisc Health & Medicine, Volume 18 #18038
Image Source: Photodisc Health & Medicine, Volume 18 #18038

30. Why Diagnose AD Early? Safety (driving, cooking, etc.)
Family stress and misunderstanding (blame, denial)
Early education of caregivers on how to handle patient
Advance planning while patient is competent (will, proxy, power of attorney, advance directives)
Patient’s and Family’s right to know
Make use of specific treatments now available
May help delay symptoms
May delay nursing home placement

31. AD vs. Other Dementias Alzheimer’s disease (AD) 60-80%
Vascular dementia (VaD) 10-20%
Dementia with Lewy bodies (DLB) 10-20%
Parkinson’s disease dementia (PDD) 1-3%
Frontotemporal dementias (FTD) 1-2%
Potentially reversible dementias

32. Diagnostic consideration
Atypical Features that Suggest a Diagnosis Other than Alzheimer's Disease
Feature
Diagnostic consideration
Abrupt onset
Vascular dementia (multi-infarct)
Stepwise deterioration
Vascular dementia: involves brain quadrants fed by major vessel that becomes blocked or has blood-brain barrier breakdown
Prominent behavior changes
Frontotemporal dementia
Profound apathy
Prominent aphasia
Frontotemporal dementia, vascular dementia
Progressive gait disorder
Vascular dementia, hydrocephalus
Prominent fluctuations in levels of consciousness or cognitive abilities
Delirium due to infection, alcohol, medications, or other causes; dementia with Lewy bodies; seizures
Hallucinations or delusions
Delirium due to infection, medications, or other causes; dementia with Lewy bodies
Extrapyramidal signs or gait
Parkinsonian syndromes, vascular dementia

33. Assessment History Of The Development Of The Dementia
Ask the patient what problem has brought him to see you
Ask the family, companion about the problem
Specifically ask about Memory Problems
Ask about the First Symptoms
Inquire about Time of Onset
Ask about Any Unusual Events around the Time of Onset, e.g., stress, trauma, surgery
Ask about Nature and Rate of Progression
Physical Examination
Neurological Examination
Laboratory Tests
Neuropsychological/Cognitive Assessment

34. Neuropsychological Testing
Memory: short-term, remote
Verbal function, fluency
Visuo-spatial function
Attention
Executive function
Abstract thinking

35. Clinical Tools for Cognitive Assessment
Folstein Mini-Mental State Exam (MMSE)
Clock Drawing
Animal Naming (1 Minute)
Short Blessed
Mattis Dementia Rating Scale
Alzheimer’s Disease Assessment Scale (ADAS)
Activities Of Daily Living
Global Clinical Scale
Clinical Dementia Rating Scale
Global Deterioration Scale/ FAST

36. Mini-Mental State Exam (MMSE)
Orientation to time
Orientation to place
Registration
Attention & calculation
Recall
Language
5 points
3 points
9 points
30 points
Specificity is good (96%) But the sensitivity is poor (63%)

37. Generalized Atrophy in Alzheimer’s Disease
Red highlights depict the enlarged ventricular system, typically found in AD. This type of change is found with all degenerative diseases and is a non-specific finding reflecting the loss of brain tissue. Some studies have pointed to temporal horn enlargements as most informative in AD as it may reflect the local damage to the medial temporal lobe. Recent studies suggest that knowledge of the magnitude of the brain CSF volume is of interest in correcting for the dilution of spinal fluid concentrations of proteins such as tau or hyperphosphorylated tau. These proteins are experimentally used in diagnostic testing for AD.
References:
de Leon MJ, George AE, Reisberg B. Longitudinal CT studies of ventricular change in Alzheimer's disease. AJNR Am J Neuroradiol. 1989;10: © the American Society of Neuroradiology.
Holodny AI, George AE, Golomb J, de Leon MJ (1996) Neurodegenerative disorders. In: Clinical Magnetic Resonance Imaging. Edited by RR Edelman, JR Hesselink, MB Zlatkin. Philadelphia: W.B. Saunders Company. 911‑927. With Permission from Elsevier.
de Leon MJ, Segal CY, Tarshish CY, De Santi S, Zinkowski R, et al. (2002) Longitudinal CSF tau load increases in mild cognitive impairment. Neuroscience Letters 333,
Brain shrinks due to widespread neuron cell death – cerebral cortex and hippocampus.
Note larger space between cerebral cortex and cranial vault.
Ventricles filled with cerebrospinal fluid (CSF) get larger to compensate for cell loss.

38. Image courtesy of the National Institute on Aging/National Institutes of Health

39. Glucose Utilization PET scans showing much reduced glucose utilization
in the AD brain compared to controls
Positron Emission Tomography (PET) studies of glucose metabolism are sensitive to the damages caused by AD. In clinically recognized AD, metabolic reductions in the temporo-parietal and posterior cingulate gyrus areas are useful indicators of disease. In less advanced cases the damage may be more restricted to the medial temporal lobe. In the figure, widespread damage to the medial and lateral temporal lobe can be seen in the patient with AD on the right relative to control.
References:
Ferris SH, de Leon MJ, Wolf AP, Farkas T, Christman DR, et al. Positron emission tomography in the study of aging and senile dementia. Neurobiology of Aging. 1980;1:127‑131.
De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish CY, et al. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiology of Aging. 2001; 22:
de Leon MJ, Convit A, Wolf OT, Tarshish CY, De Santi S, et al. Prediction of cognitive decline in normal elderly subjects with 2-[18F]fluoro-2-deoxy-D-glucose/positron-emission tomography (FDG/PET), Proc. Natl. Acad. Sci. USA, 98, © (2001) National Academy of Sciences, U.S.A
Reason: Cell death means less cells capable of metabolizing glucose

40. Therapeutic Objectives
Control existing symptoms by restoring cholinergic activity
Note: Alzheimer’s disease is considered a cholinergic or cholinoceptive disease. This means that neurons that use acetylcholine as a neurotransmitter are primarily affected.
Delay progression of disease after diagnosis by modifying pathophysiology
Delay emergence of symptoms in persons at risk (e.g., may want to recommend frequent cardiovascular exercise because of the important vascular contribution to this disease)

41. Current Drug Treatments for AD
Acetylcholinesterase inhibitors for mild to moderate AD
Tacrine (Cognex)
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Reminyl)
Neuroprotective agent for moderate to severe AD
Memantine (Namenda)

42. Treatments for AD
Table reproduced from Cummings JL. Alzheimer’s disease. New Engl J Med. 2004;351(1): Used by permission.
Cummings JL. Alzheimer’s disease. New Engl J Med 2004;351(1): Used by permission.

43. Cholinesterase Inhibitors Approved for Treatment of Mild to Moderate AD
Tacrine (Cognex)
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Rezadyne)
These are the cholinesterase inhibitors currently on the market in the US. They are approved for the treatment of mild to moderate AD. 33

44. Degree of Benefit
Average benefit of cholinesterase inhibitors in patients with dementia is a small improvement in cognition and activities of daily living
Whether these drugs significantly improve long-term outcomes, such as the need for nursing home admission or maintaining critical activities of daily living (ADLs), remains in doubt, and the evidence is conflicting
Response to cholinesterase inhibitors may be quite variable, with as many as 30 to 50 percent of patients showing no benefit , while a smaller proportion (up to 20 percent) may show a greater than average response. These findings reinforce the importance of making individualized decisions for each patient based on clinical response and side-effects

45. Cholinesterase Inhibitors in Treatment of Dementia
Treatment trial with a cholinesterase inhibitor for patients with mild to moderate dementia
In patients with severe dementia, cholinesterase inhibitors can be discontinued, but they should be restarted if the patient worsens without the medication.
There is some evidence of benefit for patients with vascular dementia (VaD), mixed dementia, dementia with Lewy bodies (DLB), and dementia in Parkinson's disease (PD).

46. Namenda (Memantine) NMDA receptor antagonist
Approved for patients with moderate to severe AD
A 2008 systemic review concluded that memantine has been shown to improve cognition and global assessment of dementia, but with effesmall cts that are not of clear clinical significance; improvement in quality of life and other domains are suggested but not proven
As a result, treatment decisions should be individualized and include considerations of drug tolerability and cost.
Well tolerated with fewer side effects
FAST functional assessment
Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: Evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):
Raina P, Santaguida P, Ismaila A, et al. Ann Intern Med 2008;148(5):  

47. Glutamate Hypothesis Abnormal glutamatergic activity leads to
sustained low-level activation of NMDA receptors
Abnormal
Intracellular
Changes
One result of the chronic presence of glutamate is tonic mild activation of N-methyl D-aspartate (NMDA) receptors.
Possible consequences of tonic activation:
a) Excitotoxicity and neuronal death;
b) Disruption of NMDA-mediated learning and memory caused by a decrease in the “signal-to-noise” ratio.
Glutamate is an excitatory neurotransmitter and acts on a variety of receptors. NMDA is one such receptor. NMDA receptor on activation causes potentiation of neuronal activity, but in Alzheimer’s disease, excessive glutamatergic excitotoxicity causes apoptotic cell death and defects in cognition and memory Danysz et al., 2003
Neuronal death
following chronic insult 
Excitotoxicity
Cognitive deficit due
to disruption of learning and
memory

48. AD Research: The Search for New Treatments
Researchers also are looking at other treatments, including:
cholesterol-lowering drugs called statins;
anti-oxidants (vitamins) and folic acid;
anti-inflammatory drugs;
substances that prevent formation of beta-amyloid plaques;
drugs that preserved or repair the integrity of the blood-brain barrier
Image Source: Photodisc Health & Medicine, Volume 18 #18065
Source: Photodisc Health & Medicine, Volume 18 #18065

49. Conclusion
Alzheimer disease is one of the most debilitating diseases affecting the old age.
A clear understanding of the natural history of Alzheimer disease will enable us to develop appropriate trial designs and outcomes for the various stages of this condition.
Treatment can slow disease progression, slow loss of cognitive and functional abilities, and ameliorate behavioral symptoms
Benefit for the treatment of symptoms in mild to severe AD using AChEIs and Memantine is seen.
Also, there is cautious optimism for successful disease modification using a number of agents currently under study.