Alzheimer’s Disease

Robert Nagele, PhDProfessor of MedicineUMDNJ–SOM NJISA

Anita Chopra, MD, FACPProfessor, Geriatrician and DirectorUMDNJ –SOM NJISA

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.

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

• 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.

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills.

What is AD?

Image copyright © 1997 PhotoDisc, Inc. (http://www.hallogram.com/photodisc/lisence1.html)

• 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

AD Statistics

Top and middle images copyright © 1997 PhotoDisc, Inc. (http://www.hallogram.com/photodisc/lisence1.html)Bottom image source: Microsoft Office Images #MP900185235 (http://office.microsoft.com/en-us/images/)

Where are people with AD cared for?

• Home• Assisted living facilities • Nursing homes (special care

units)

• The national cost of caring for people with AD is about $120 billion every year.

Care and its Costs

Source: Microsoft Office Images #MP900443920 by iStockphoto (http://office.microsoft.com/en-us/images/)

Source: PhotoSearch Mature Lifestyles 2 #58307

Figures from Alzheimer’s Disease International World Alzheimer Report 2010: The Global Economic Impact of Dementia. London, UK: Alzheimer’s Disease International (ADI), 2010. Used by permission.

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 10 Warning Signs of AD

(from the Alzheimer’s Association) 1. Memory changes that disrupt daily life

2. Challenges in planning or solving problems

3. Difficulty performing familiar tasks at home, at work or at leisure

4. Confusion with time or place

5. Trouble understanding visual images and spacial relationships

6. New problems with words in speaking or writing

7. Misplacing things or loosing the ability to retrace steps

8. Decreased or poor judgment

9. Withdrawal from work or social activities

10.Changes in mood and personality

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 10-20 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

Blue stipple indicates disease spread and extent

Images courtesy of the National Institute on Aging/National Institutes of Health

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.

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.Note preferred spread to

frontotemporal and more posterior regions Images courtesy of the National Institute on

Aging/National Institutes of Health

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.

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

Alzheimer’s Disease Progression

Alzheimer’s Disease Progression

Mild Cognitive Impairment

Death from pneumonia and/or other comorbidities

MildLoss of recent memoryFaulty judgmentPersonality changes

ModerateVerbal and physical aggressionAgitationWanderingSleep disturbancesDelusions

SevereLoss of all

reasoningBedridden Incontinence

8 years average. Range: 2-20 years

Clinical Expression of AD

FUNCTIONFUNCTION

BEHAVIORBEHAVIORCOGNITIONCOGNITION

Unique SymptomPattern of AD

Unique SymptomPattern of AD

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)

Inside the Human Brain

Images courtesy of the National Institute on Aging/National Institutes of Health

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

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.

Senile (Amyloid) plaque Neurofibrillary tangle

• 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

Histological Hallmarks of AD

NFTs

AmyloidPlaques

Vulnerable Neurons in AD

• Basal forebrain cholinergic system (nucleus basalis)

• Monoaminergic system• Hippocampus (CA1 and CA2

pyramidal cells)• Amygdala• Entorhinal cortex• Neocortex

Amyloidplaque

Sickneuron

AP

Amyloid plaques contain Abeta42

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

Retracted“corkscrew”

dendrites

Images courtesy of the National Institute on Aging/National Institutes of Health

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.

3.

AD and the Brain

In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex.Images courtesy of the National Institute on

Aging/National Institutes of Health

Neurofibrillary Tangles

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.

AD and the Brain

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

The Continuum of Alzheimer's Disease

Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia 2011;7(3):280-292. Used with permission from Elsevier.

Hypothetical Model of the Alzheimer’s Disease

Pathophysiological Cascade

Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia 2011;7(3):280-292 with permission from Elsevier.

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

Biomarkers of Alzheimer’s Disease

Reprinted from Sperling RA, Aisen PS, Beckett LA, et al. Alzheimer’s & Dementia 2011;7(3):280-292 with permission from Elsevier.

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 - 100% 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

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

• 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.

Diagnosing AD

Source: Photodisc Health & Medicine, Volume 18 #18038

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

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

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 Frontotemporal dementia

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

Atypical Features that Suggest a Diagnosis Other than Alzheimer's

Disease

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

Neuropsychological Testing

• Memory: short-term, remote• Verbal function, fluency• Visuo-spatial function• Attention• Executive function• Abstract thinking

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

Mini-Mental State Exam (MMSE)

• Orientation to time• Orientation to

place• Registration• Attention &

calculation• Recall• Language

=5 points=5 points=3 points=5 points=3 points=9 points

30 points

Specificity is good (96%) But the sensitivity is poor (63%)

Generalized Atrophy in Alzheimer’s Disease

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.

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

Glucose Utilization

Reason: Cell death means less cells capable of metabolizing glucose

PET scans showing much reduced glucose utilization in the AD brain compared to controls

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)

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)

Cholinesterase InhibitorsApproved for Treatment of Mild to Moderate

AD

• Tacrine (Cognex)

• Donepezil (Aricept)

• Rivastigmine (Exelon)

• Galantamine (Rezadyne)

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

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).

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

Raina P, Santaguida P, Ismaila A, et al. Ann Intern Med 2008;148(5):379-397.  

Glutamate Hypothesis

Cognitive deficit due to disruption of learning and memory

Neuronal deathfollowing chronic insult Excitotoxicity

Abnormal glutamatergic activity leads to sustained low-level activation of NMDA receptors

Abnormal Intracellular Changes

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.