SELENE MARQUEZ

ARGOSY UNIVERSITY

ALZHEIMER’S DISEASE: WHAT DO WE ACTUALLY KNOW

DEFINING ALZHEIMER’S DISEASE

AUGUSTE DETER, FIRST PERSON DIAGNOSED WITH ALZHEIMER'S DISEASE. PHOTOGRAPH TAKEN BY RUDOLPH, HOSPITAL PHOTOGRAPHER, AT STÄDTISCHE HEILANSTALT FÜR IRRE UND EPILEPTISCHE (1901)

• Most common form of dementia¹ (brain disorder that causes progressive decline in brain function²)

• Neurodegenerative disease: damages and kills neurons ( cells/ building block of nervous system, specialized for receptions, conduction, and transmission of electrochemical signals- brain’s messengers)²

• Early stage: selective decline in memory loss, deficits in attention, and personality changes²

• Intermediate stages: confusion, irritability, anxiety, and deterioration of speech²

• Advanced stages: deterioration to the extent simple responses like swallowing and controlling bladder are difficult²

• Diagnosis on basis of cognitive symptoms²

• Definitive diagnosis can only be made at autopsy²

¹LICHTENBERG, PETER., MURMAN, DANIEL L., MELLOW, ALAN M., (2003). HANDBOOK OF DEMENTIA: PSYCHOLOGICAL, NEUROLOGICAL, ANDPSYCHIATRIC PERSPECTIVES: JOHN WILEY & SONS, INC. RETRIEVED FROM: HTTP://WWW.WEB.EBSOHOT.COM.LIBPROXY.EDMC.EDU²PINEL, JOHN P. J. (2011). BIOPSYCHOLOGY, (8 TH ED.), BOSTON, MA: PEARSON EDUCATION, INC.

DEFINING CHARACTERISTICS OF ALZHEIMER’S DISEASE

• neurofibrillary tangles and amyloid plaques: considered “hallmarks” of Alzheimer’s disease³

• Believed to be involved in neurodegeneration²

• Amyloid plaques: clumps of degenerating neurons and amyloid (a type of protein present in normal brains in small amounts²)

• Believed to cause neurodegeneration in multiple ways, such as, interferene with “cell to cell” communication³

• Neurofibrillary tangles: threadlike tangles of tau ( a type of protein, required for normal structure and functioning of internal support and transport system to carry nutrients and other essential³ material within neuron²)

• Tangles lead to failure of transport system, which is implicated in the decline and death of neurons³

• Decrease in brain size due to substantial neuron loss

²PINEL, JOHN P.J. (2011). BIOPSYCHOLOGY, (8TH ED.), BOSTON, MA: PEARSON EDUCATION, INC.³MAYO CLINIC STAFF. (2011). ALZHEIMER’S DISEASE. RETRIEVED FROM: HTTP://WWW.MAYOCLINIC.COM/HEALTH/ALZHEIMERSDISEASE/DS00161

Healthy Brain Alzheimer’s disease Brain

Drawn by Selene Marquez

• Amyloid plaques, neurofibrillary tangles, and neuron loss tends to occur throughout the brain²

• But they are more prevalent in some areas of the brain than others²

• Entorhinal cortex- involved in aspects of memory²

• Amygdala- involved in aspects of memory²

• Hippocampus- involved in aspects of memory²

• Inferior temporal cortex- mediate complex cognitive functions²

• Posterior parietal cortex- mediate complex cognitive functions²

• Prefrontal cortex- mediate complex cognitive functions²

• Areas of the brain depicted on the following slide

DEFINING CHARACTERISTICS OF ALZHEIMER’S DISEASE

PINEL, JOHN P.J.(2011).BIOPSYCHOLOGY,(8 TH ED.), BOSTON, MA: PEARSON EDUCATION, INC.

I. Entorhinal cortex: portion of the rhinal cortex, crucial for object-recognition²

II. Amygdala: part of the Limbic System (Subcortical System responsible for emotions and motivated behavior: feeling, feeding, fighting, and sexual behaviors), plays important role in memory of the emotional significance of experiences (evidence does not indicate that it is involved in the storage of memory, instead involved in strengthening emotionally significant memories stored in other structures)²

III. Hippocampus: part of the Limbic System, involved in memory of spatial location²

IV. Inferior temporal cortex: lower portion of the temporal lobe (involved in memory, learning, language, audition), identifies complex visual patterns²

V. Posterior parietal cortex: plays role in perceiving the location of both object and own body, directing attention²

VI. Prefrontal cortex: involved in a series of memory processes and cognitive processes: working memory (maintaining relevant memories while completing a task), attention, task management²

Drawn by Selene Marquez

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4

5

6

Typical distribution of amyloid plaques, and neurofibrillary tangles in the brains of patients with Alzheimer’s disease

²Pinel, John J. P.(2011). Biopsychology, (8th ed.), Boston, MA: Pearson Education, Inc.

Temporal Lobe

ALZHEIMER’S DISEASE IS TERMINAL

FROM ALZHEIMER'S DISEASE: CONFUSION, MEMORY, LOSS, APATHY, DEEP DEPRESSION, HEALTHY STORIES. RETRIEVED FROM: HTTP://MYHEALTHYSTORIES.BLOGSPOT.COM/2011/01/ALZHEIMER-DISEASE.HTML

THE CAUSE OF ALZHEIMER'S DISEASE IS

UNKNOWN

FROM DNA RESEARCH FINDS NEW ALZHEIMER'S DISEASE RISK, 2009. COPYRIGHT 2011 BY THE ANTI AGING AND HUMAN IMMORTALITY NEWS. RETRIEVED FROM: HTTP://WWW.IMMORTALHUMANS.COM/DNA-RESEARCH-FINDS-NEW-ALZHEIMERS-DISEASE-RISK/

EPIDEMIOLOGY

• Age is the greatest risk factor4

• Affects 10% of population over the age of 65²

• Affects 35% in those over the age of 85²

• Women at greater risk because of longer life expectancy 5

• Estimated 24 million have dementia, most have Alzheimer’s disease 4

• United States of America among countries with largest number of affected individuals 4

• Major Public concern due to medical costs4

• Two victims: patient and caregiver4

• Increase in elderly population5

• Baby boomers aging5

• Life span increase due to advancement in medical technology 5

• Slow progression4

• on average live 7 years after diagnosis ( can span from 2 to 18 years) 4

• Advanced stages require assisted living and nursing home care 4²PINEL, JOHN P. J.(2011). BIOPSYCHOLOGY, BOSTON, MA: PEARSON EDUCATION, INC.4BALLARD, CLIVE C., GAUTHIER, SERGE S., CORBETT, ANNE A., BRAYNE, CAROL C., AARSLAND, DAG D., AND JONES, EMMA.(2011). ALZHEIMER’S DISEASE, 377, 1019-1031. RETRIEVED FROM: HTTP://SEARCH.PROQUEST.COM.LIBPROXY.EDMC.EDU/DOCVIEW/85824866?ACCOUNTID=348995LICHTENBERG, PETER A., MURMAN, DANIEL L., AND MELLOW, ALAN M.(2003). HANDBOOK OF DEMENTIA: PSYCHOLOGICAL, NEUROLOGICAL, AND

PSYCHIATRIC PERSPECTIVE: JOHN WILEY & SONS. RETRIEVED FROM: HTTP://WWW.WEB.EBSOHOT.COM.LIBPROXY.EDMC.EDU

RISK FACTORS

• Age = single most important risk factor11

• Gender = female more at risk, but may be due to longer life expectancy11

• Low education, low occupation attainment11

• High education, occupation work complexity, and a mentally and socially integrated life style postpones onset11

• Environmental influences

• Physical activity and maintaining involvement in cognitively stimulating mental activity build resilience of cognitive functioning through aging process11

• Family history = risk increases fourfold with diagnosis of Alzheimer’s disease in first degree relative ( father, mother, brother, or sister) 11

• Head Injury = repeated blows to the head, or head injury that resulted in unconsciousness11

SLIDE ADDED 11/13/2011 6:55PM

11GRANT, IGOR AND ADAMS, KENNETH M. (ED.).(2009). NEUROPSYCHOLOGICAL ASSESSMENT OF NEUROPSYCHIATRIC AND NEUROMEDICALDISORDERS (3RD ED.), NEW YORK, NY: OXFORD UNIVERSITY PRESS, INC.

HISTORY• November 25, 1901, fifty-one year old Auguste Deter was admitted to Städtische Heilanstalt für Irre und Epileptische

psychiatric, a hospital in Frankfurt, Germany, by her husband 6

• Unexplained bursts of anger and series of memory problems 6

• No personal or family history of mental illness 6

• Alois Alzheimer, attending doctor, began file 6

• Notes: She sits on the bed with a helpless expression

“What is your name?”

Auguste.

“Last name?”

Auguste.

“What is you husband’s name?”

Auguste, I think.

“How long have you been here?”

(She seems to be trying to remember.)

Three weeks. 6

• November 1904, Auguste bedridden, incontinent, immobile 6

• October 1905, notes indicate Auguste became permenantly curled in the fetal position, muttering to self, but unable to speak, required assistance to feed. 6

6 SHENK, DAVID. (2001). FORGETTING: ALZHEIMER'S: PORTRAIT OF AN EPIDEMIC, WESTMINSTER, MD: DOUBLEDAY PUBLISHING

“‘Her gestures showed a complete helplessness,’ Alzheimer later noted in a published report, ‘ She was disorientated as to time and place. From time to time she would state that she did not understand anything that she felt confused and totally lost. Sometimes she considered the coming of the doctor as an official visit and apologized for not having finished her work, but other times she would start to yell out of the fear that the doctor wanted to operate on her [or] damage her woman’s honor. From time to time she was completely delirious, dragging her blankets and sheets to and fro, calling for her husband and daughter, and seeming to have auditory hallucinations. Often she would scream for hours and in a horrible voice.’” 6

6SHENK, DAVID. (2001). FORGETTING: ALZHEIMER'S: PORTRAIT OF AN EPIDEMIC, WESTMINSTER, MD: DOUBLEDAY PUBLISHING

• Auguste Deter died on April 19067

• Alzheimer had left the hospital prior to her death7

• Upon news of her death Alzheimer requested her medical records7

• She was examined by two of Alzheimer’s previous colleagues7

• A year after Deter’s death Alzheimer’s describes her histopathology in a conference in Tubingen7

• Alzheimer describes the Nissl-stained tissue section and a Bielschowsky-stained section from Auguste’s brain7

• Alzheimer describes what are known today as amyloid plaques and neurofibrillary tangles7

• Oskar Fischer, Francesco Bonfiglio and Graetano Perusini had described this condition prior to Alzheimer. 7

• Psychiatrie (1910), by Emil Kraeplin (Alzheimer’s boss at Royal Psychiatric Clinic in Munich) is the first to refer to this disease as Alzheimer’s disease. 7

7 MO. (2001, NOVEMBER 2). ALOIS ALZHEIMER'S FIRST CASE [BLOGGING ABOUT PEER-REVIEWED RESEARCH]. RETRIEVED FROM:HTTP://SCIENCEBLOGS.COM/NEUROPHILOSOPHY/2007/11/ALOIS_ALZHEIMERS_FIRST_CASE.PHP

LEADING HYPOTHESES

AMYLOID HYPOTHESIS

CARDIOVASCULAR DISEASE RISK

FACTORS

AMYLOID HYPOTHESIS

• “golden standard” for scientific investigation of Alzheimer’s disease8

• 1980’s Amyloid β-peptide (Aβ) discovered as primary component of the sticky plaques described by Alzheimer8

• sequenced from meningeal (meninges: the three protective membranes [layers] that cover the brain and spinal cord)² blood vessels of Alzheimer’s disease patients and Downs syndrome patients8

• discovery marked the beginning of the modern era of research for Alzheimer’s disease, focusing research on the neurodegenerative effects of amyloid plaques. 8

• Lead to the amyloid hypothesis, which proposes a sequence of pathogenic events caused by amyloid plaques leading to Alzheimer’s disease. 8

²PINEL, JOHN P. J. (2011). BIOPSYCHOLOGY, (8 TH ED.), BOSTON, MA: PEARSON EDUCATION, INC. 8 HARDY, JOHN AND SELKOE, DENNIS J. (2002). THE AMYLOID HYPOTHESIS OF ALZHEIMER’S DISEASE: PROGRESS AND PROBLEMS ON THE ROAD

TO THERAPEUTICS. SCIENCE, 297, 353-356. RETRIEVED FROM:HTTP://SEARCH.PROQUEST.COM.LIBPROXY.EDMC.EDU/DOCVIEW/213590171?ACCOUNTID=348

1.) Mutations in APP or Presenilin 1 or 2 gene

(Dominantly inherited forms of Alzheimer’s disease) OR 2.)

Failure of Aβ clearance mechanisms by inheritance of ApoE4; faulty Aβ degradation (Non-dominant forms of AD)8

i. Increase Aβ42 production throughout life8

ii. Gradually rises Aβ42 levels in brain8

Cascading effects• Subtle disturbances in synaptic efficacy8

(neuron communication²)• Gradual deposition of Aβ42 as diffuse plaques8

• Microglial ( type of glial cell, cell found in the nervous system, that responds to injury by engulfing cellular debris)²and astrocytic (largest glial cell that plays a role in the passage of chemicals from the blood into the central nervous system(brain and spinal cord)² neurons activation and attendant inflammatory response8

• Altered neuronal ionic homeostasis (stability of organism’s internal environment²), oxidative injury8

• Altered kinase/phosphatase activities lead to tangles8

• Widespread neuronal/synaptic dysfunction and selective neuronal loss with attendant neurotransmitter deficits8

Alzheimer’s disease

²PINEL, JOHN P. J. (2011). BIOPSYCHOLOGY, (8 T H ED.), BOSTON, MA: PEARSON EDUCATION, INC.

4BALLARD, CLIVE C., GAUTHIER, SERGE S., CORBETT, ANNE A., BRAYNE, CAROL C., AARSLAND, DAG D., AND JONES, EMMA.(2011). ALZHEIMER’SDISEASE, 377, 1019-1031. RETRIEVEDFROM: HTTP://SEARCH.PROQUEST.COM.LIBPROXY.EDMC.EDU/DOCVIEW/85824866?ACCOUNTID=34899

8HARDY, JOHN AND SELKOE, DENNIS J. (2002). THE AMYLOID HYPOTHESIS OF ALZHEIMER’S DISEASE: PROGRESS AND PROBLEMS ON THE ROADTO THERAPEUTICS. SCIENCE, 297, 353356. RETRIEVED FROM: HTTP://SEARCH.PROQUEST.COM.LIBPROXY.EDMC.EDU/DOCVIEW/213 590171?ACCOUNTID=3

• Amount of genetic risk estimated at 70% (identification of specific risk gene problematic: combinations of risk alleles need to be identified) 4

• Current established genetic cause: • amyloid precursor protein (APP) and presenilin 1 and 2 (PSEn1, PSEN2) 4

• Cause in only 5% of patients, who usually have onset of symptoms in midlife; Affect concentration of amyloid4

• ApoE4• Seven times increased risk of developing disease; Affects the rate of amyloid clearance4

VASCULAR DISEASE RISK FACTORS• Alternative view: Alzheimer’s disease results from combination of genetic, lifestyle, and environmental factors.³

• Some evidence suggests same risk factors for cardiovascular (heart) disease increases chance of developing Alzheimer’s disease.³

• Lack of exercise³

• Smoking³

• Hypertension (High blood pressure)³

• Hypercholesterolemia (High cholesterol)³

• Poorly controlled diabetes³

• Research evidence:

• hypertension linked with increased risk of Alzheimer’s disease 10

• reduction in incidences of dementia in routinely treated hypertension verses non-treated hypertension patients 10

• hypercholesterolemia increase incidence of Alzheimer’s disease 10

• Statins (class of drugs used to lower cholesterol) have been associated with decreased risk of Alzheimer’s disease10

• diabetes with increased risk of dementias10

• Unclear if cardiovascular disease risk factors correlate with disease progression 10

³MAYO CLINIC STAFF. (2011). ALZHEIMER’S DISEASE. RETRIEVED FROM: HTTP://WWW.MAYOCLINIC.COM/HEALTH/ALZHEIMERSDISEASE/DS001611 0PEDRO GIL, JOSÉ LUIS DOBATO AYUSO, JOSÉMANUEL MAREY, MANUEL ANTÓN, AND CARLOS GUZMÁN QUILO. (2008). VARIABILITY IN THE DIAGNOSIS AND MANAGEMENT OF PATIENTS WITH ALZHEIMER’S DISEASE AND CEBROVASCULAR DISEASE, CLINICAL DRUG INVESTIGATION, 28, 429-437.

RETRIEVED FROM: HTTP://SEARCH.PROQUEST.COM.LIBPROXY.EDMC.EDU/PQCENTRAL/DOCVIEW/224982939/ABSTRACT/132EB2167A068D0BCFE/1?ACCOUNTID=34899

Advanced ageing and vascular disease risk factors9

•Cardiovascular-related risk factors9

•Congestive heart failure (heart cannot pump enough blood to meet needs of the body)9

•Cardiac arrhythmia (heart beats too slow, too fast, or irregularly)9

•Hypertension (high blood pressure)9

•Hypotension (low blood pressure)9

•Thrombotic episodes ((formation of thrombosis blocks blood flow at site of formation)9

•High concentrations of homocysteine (substance used to make proteins in the body, too much increases risk of stroke)9

•Atrial Fibrillation (irregular heart rate of the upper chambers of the heart)9

•Presence of APOEєч allele9

•Peripheral risk factors9

•Smoking9

•Alcoholism9

•High cholesterol9•High intake saturated fat9

•Diabetes mellitus9

•Hemorheoloigcal abnormalities (flow of blood and its elements)9

•Brain-related risk factors9

•Ageing9

•transient ischemic attack (type of stoke, “ministroke”, temporarily disrupts blood flow)9

•Ischemic stroke (type of stroke caused by a blockage in an artery)9

•Silent stoke9

•Head injury9

•menopause9

Leads to…• Cerebral hypoperfusion9

• “hypo” : deficiency “perfusion”: the passage of fluid through specific area of the body• In this instance a

deficiency in the passage of blood to the brain

• Energy crisis of neurons and glial cells (nonneural cells of the nervous system)9

• Mild cognitive impairment9

• Neurodegeneration9

Alzheimer's disease

9DE LA TORRE, JACK.(2004). IS ALZHEIMER'S DISEASE A NEURODEGENERATIVE OR A VASCULAR DISORDER? DATA, DOGMA, AND DIALECTICS. THE LANCET NEUROLOGY, 3, 184-190. RETRIEVED FROM: HTTP://SEARCH.PROQUEST.COM.LIBPROXY.EDMC.EDU/PQCENTRAL/DOCVIEW/201472398/ABSTRACT /

RESEARCH LIMITATIONS

• Amyloid hypothesis based investigations cannot be conducted on live human subjects

• Results from amyloid hypothesis based studies using animals, like mice, limited, since cannot be generalized to humans

• Number of amyloid deposits in the brain do not correlate with the degree of cognitive impairment

• Formation of neurofibrillary lesions may be due to separate process

• Unclear of amyloid deposits neurotoxic effects

• Research has expanded knowledge of specific mechanisms involved in amyloid depositions and identified gene involvement, but the cause is still unknown

Gaps of understanding in Alzheimer’s disease, but not compelling evidence to abandon amyloid hypothesis

• Cardiovascular disease risk factor studies have advantage of being able to observe factors in living human subjects with Alzheimer's disease

• Results from studies based on cardiovascular disease risk factors limited since Alzheimer’s disease can only be confirmed at autopsy, subjects may not be true representation of Alzheimer’s disease patient population

WE KNOW MORE THAN WE THINK

ALZHEIMER’S DISEASE IS DEVASTATING

• Cause is still unknown, so research needs to continue investigating cause, equally examining amyloid hypothesis and cardiovascular disease risk factors

• Identification of cause does not guarantee cure

• Devastating effects of Alzheimer’s Disease are clear

• Researchers need to focus on providing therapies to slow progression of disease and assist patients and caregivers live meaningfully

WHAT HAS BEEN ACHIEVED FOR TREATMENT THUS FAR

PRESCRIPTIONS

• Cholinesterase inhibitors: boosts amounts of acetylcholine, chemical messenger important for alertness, memory, and thinking- Alzheimer’s disease decreases levels of acetylcholine³• Common side-effects: nausea, vomiting, and diarrhea³• donepezil (Aricept)

• approved to treat all stages of disease. Taken once daily orally has a pill³• galantamine (Razadyne)

• Approved to treat mild to moderate stages of disease. Taken orally as a pill or syrup³

• rivastigmine (Exelon)• Approved to treat mild to moderate stages of disease. Taken orally, as a pill or

syrup, or transdermally, as a patch)³• Memantine (Namenda): works by regulating glutamate, chemical messenger involved in

learning and memory³• Common side-effects: dizziness, headaches, confusion, and agitation³• Approved to treat moderate to severe stages of disease. Taken orally as a pill or syrup³

³MAYO CLINIC STAFF. (2011). ALZHEIMER’S DISEASE. RETRIEVED FROM: HTTP://WWW.MAYOCLINIC.COM/HEALTH/ALZHEIMERSDISEASE/DS00161

EXERCISE: IMPORTANT FOR WELLNESS

Improves moodMaintain health of joints, muscles, heart

Promotes restful sleep Prevents constipation

*patient should carry identification if walking unaccompaniedStationary bike or chair exercises good alternative if patients present with difficulty walking

³MAYO CLINIC STAFF. (2011). ALZHEIMER’S DISEASE. RETRIEVED FROM: HTTP://WWW.MAYOCLINIC.COM/HEALTH/ALZHEIMERSDISEASE/DS00161

ENVIRONMENT: LIVING SITUATION IMPORTANT PART OF TREATMENT PLAN

• Remove clutter from rooms (remove excess furniture and throw rugs)³

• Install handrails³

• Ensure shoes are comfortable and provide traction³

• Reduce number of mirrors (can cause confusion or fear)³

³MAYO CLINIC STAFF. (2011). ALZHEIMER’S DISEASE. RETRIEVED FROM: HTTP://WWW.MAYOCLINIC.COM/HEALTH/ALZHEIMERSDISEASE/DS00161

• Educate self³

• Build relationships with physicians, social workers, and others involved-ask questions³

• Ask for help³

• Take a break everyday³

• Spend time with friends and loved ones³

• Care for self: maintain health screening appointment, eat healthy, exercise, and adequate sleep³

• Join support groups³

TREATMENT FOR CAREGIVER

³MAYO CLINIC STAFF. (2011). ALZHEIMER’S DISEASE. RETRIEVED FROM: HTTP://WWW.MAYOCLINIC.COM/HEALTH/ALZHEIMERSDISEASE/DS00161

WHERE DO WE GO NEXT PSYCHOTHERAPY

• Psychotherapy often suggested for caregivers, but may also be beneficial to patient

• Misconception that Alzheimer’s disease and other dementia patients cannot benefit from therapy

• Psychotherapy provide safe environment for dementia patients to express self

• patients will not have to fear of letting some one down if they cannot remember

• Patient will not have fear of being corrected

• Patients free to express agitation, frustration, and anger without fear of being abandoned

• Psychotherapy allows for professional to investigate unmet needs and communicate with caregiver

• Behavioral disorders not necessarily linked to disease progression, possibly linked to unmet needs (hunger, exercise, sleep, support) but unable to communicate needs

• Supportive presence

REFERENCES

¹Lichtenberg, Peter., Murman, Daniel L., Mellow, Alan M., (2003). Handbook of Dementia: Psychological, Neurological, and Psychiatric Perspectives: JohnWiley & Sons, Inc. Retrieved from: http://www.web.ebsohot.com.libproxy.edmc.edu

²Pinel, John P. J. (2011). Biopsychology, (8 th ed.), Boston, MA: Pearson Education, Inc.

³Mayo Clinic Staff. (2011). Alzheimer’s disease. Retrieved from: http://www.mayoclinic.com/health/alzheimersdisease/DS001614Ballard, Clive C., Gauthier, Serge S., Corbett, Anne A., Brayne, Carol C., Aarsland, Dag D., and Jones, Emma.(2011). Alzheimer’s disease, 377, 1019-1031.

Retrieved from: http://search.proquest.com.libproxy.edmc.edu/docview/85824866?accountid=348995Lichtenberg, Peter A., Murman, Daniel L., and Mellow, Alan M.(2003). Handbook of Dementia: Psychological, neurological, and Psychiatric Perspective: John

Wiley & Sons. Retrieved from: http://www.web.ebsohot.com.libproxy.edmc.edu6 Shenk, David. (2001). Forgetting: Alzheimer's: Portrait of an Epidemic, Westminster, MD: Doubleday Publishing7 Mo. (2001, November 2). Alois Alzheimer's first case [Blogging about peer-reviewed research]. Retrieved from: http://scienceblogs.com/neurophilosophy/2007/11/alois_alzheimers_first_case.php8 Hardy, John and Selkoe, Dennis J. (2002). The Amyloid Hypothesis of Alzheimer’s disease: Progress and Problems on the Road to Therapeutics. Science,

297, 353-356. Retrieved from: http://search.proquest.com.libproxy.edmc.edu/docview/213590171?accountid=3489de la Torre, Jack.(2004). Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. The Lancet Neurology, 3, 184- 190. Retrieved from: http://search.proquest.com.libproxy.edmc.edu/pqcentral/docview/201472398/abstract / 10Pedro Gil, José Luis Dobato Ayuso, JoséManuel Marey, Manuel Antón, and Carlos Guzmán Quilo. (2008). Variability in the Diagnosis and Management of Patients with Alzheimer’s Disease and Cebrovascular Disease, Clinical Drug Investigation, 28, 429-437.Retrieved from: http://search.proquest.com.libproxy.edmc.edu/pqcentral/docview/224982939/abstract/132EB2167A068D0BCFE/1?accountid=34899

11Grant, Igor and Adams, Kenneth M. (ed.).(2009). Neuropsychological Assessment of Neuropsychiatric and Neuromedical Disorders (3 rd ed.), New York, NY: Oxford University Press, Inc.