The Causes of Alzheimer’s Disease: Deconstructing the Puzzle

7/31/2019 The Causes of Alzheimers Disease: Deconstructing the Puzzle

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Lorenzo M Refolo PhD

National Institute on Aging

National Press Foundation, May 21st 2012

The Causes of Alzheimers Disease:

Deconstructing the Puzzle


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Alzheimers Disease (AD): Overview

Progressive, degenerative CNS disorder

Most common cause of dementia (60%-70%) in people

aged 65 and over

Characterized by memory impairment plus one or more additional

cognitive disturbance

Gradual decline in three key symptom domains Activities of daily living (ADL)

Behavior and personality

Cognition


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2012 Alzheimers Facts and Figures, Alzheimers Association

As many as 5.4 million people in the United States are living with

Alzheimers.

Projected by 2050 -13.2 million in the U.S. alone.

Every 69 seconds,someone develops Alzheimers.

Alzheimer's is the sixth-leading cause of death.

The direct and indirect costs of Alzheimer's and other dementias to

Medicare, Medicaid and businesses amount to more than $200 billion each

year.

Socioeconomic Burden of AD


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Clinical Features of AD

Impaired recent memory-short term

Executive dysfunction- changes in attention and problem solving abilities

Language dysfunction

Personality changes , withdrawal, decreased initiative

Loss of long term memory

Loss of ability to function independently

Loss of ambulation, unable to control bladder and bowel function


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The brain has billions of

neurons, each with an axon

and many dendrites.

To stay healthy, neurons must

communicate with each other,

carry out metabolism, and

repair themselves.

AD disrupts all three of these

essential functions- leading to

neuronal cell death.

AD Disrupts Essential Neuronal Functions


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AD is Characterized by Atrophy in Brain Areas

that Support Cognition


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Pathological features of AD

The major neuropathological features

- beta- amyloid plaques

- neurofibrillary tangles

- neuronal cell loss

Beta-amyloid plaque and NFT Neurofibrillary tangle


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Two Main Types of Alzheimers Disease: familial

(FAD) and sporadic (SAD)

FAD is rare (approx 3% cases),

heritable form with an earlyonset (30y to 60y).

SAD or late onset AD (LOAD)

represents more than 95% casesand usually affects people over

age 65.


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FAD is an Autosomal Dominantly Inherited

Disease

There are 3 FAD genes

APPamyloid precursor protein

PS1- presenilin 1

PS2presenilin 2

Mutations in all 3 FAD genes lead to an increase in the production of beta-amyloid

peptide (Abeta).


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Causes of Late Onset Sporadic AD

Aging

Genetic risk factors

Metabolic

Vascular

Psychosocial

Other Environmental Factors


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The Abeta Peptide is Part of the Amyloid Precursor

Protein (APP)


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APPAbeta

alpha-

secretase BACE

Gamma-secretase

A-beta is Produced by ProteolyticCleavage of APP

PS1 and PS2 are key components of the gamma-secretase enzyme


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The Pathobiology of AD

Amyloid cascade hypothesis

Abeta production

Abeta clearance

Synaptic dysfunction Neural network failure


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Amyloid Cascade

The amyloid cascade hypothesis has been the dominant organizing principle drivingthe Alzheimers research agenda.


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AD Pathogenesis and the Amyloid Cascade

Hypothesis

Mucke, Nature(2009) 461:895-897


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Abeta accumulation in the brain is a result of the balance

between its production and its clearance.

Abeta Production vs. Clearance


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Abeta Clearance

Enzymatic degradation

- Neprilysin

- Insulin degrading enzyme (IDE)

Transport across the blood-brain-barrier

-ApoE

-LRP

-clusterin (ApoJ)


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Clearance (Removal) of Abeta from Brain


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Querfurth and La Ferla NEJM(2010)362: 329-44

Abeta Oligomers Mediate Synaptic Dysfunction


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Amyloid beta Oligomers Induce Dysfunction of Synapses, Neuronal Circuits

and Networks Resulting in Cognitive Impairment and Dementia


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Abeta-Mediated Neuroinflammation Kills Neurons


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AD Pathobiology: Tau

Tau- microtubule stabilizing protein

- phosphorylation

- neurotoxic oligomeric forms

- connection with Abeta

- trans-synaptic spread of tau pathology


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Tau Functions to Hold the Nerve Cells

Cytoskeleton Together

Hyperphosphorylation of Taudestabilizes the cytoskeleton leadingto impaired axonal transport andcausing nerve cells to functionpoorly.


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Oligomeric Forms of Phospho-Tau are Toxic to

Nerve Cells

hyperphosphorylated tau toxic tau oligomers NFTs


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Connecting Abeta and Tau

According to the amyloid hypothesis Abeta drives tau- toxicity


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Tau Spreading Pathways in Alzheimers Disease


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Interneuronal Spread of Tau Pathology

-unknown mechanism(s)-


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Interneuronal Spread of Tau: Therapeutic Implications


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Pathobiology of AD cont

Mitochondria and bioenergetics

Neurovascular mechanisms


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Mitochondria: The Power House of Nerve Cells


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Mitochondria Provide Energy for Synapse

Formation and Maintenance


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Abeta, Mitochondrial Failure and Oxidative Stress


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Pathobiology of AD: Neurovascular Mechanisms

Vascular cast of the brain

Neurovascular Unit

400 miles of blood

vessels,arteries and capillaries

each nerve cell is associated with

a microvessel


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Zlokovic, 2011

Pathobiology of AD: Neurovascular Mechanisms


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Pathobiology of LOAD: Genetic Risk

ApoE4 strongest known risk factor for LOAD

Pathological functions of ApoE4

10 LOADrisk factor genes 40-60% of AD

Possible pathological functions of LOAD risk factor genes


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ApoE4Major Genetic Risk Factor for LOAD

Apolipoprotein E is the protein component of particles that

carry lipids throughout the body

3 forms of human ApoE (E2, E3, E4)

E4 formup to 12 fold increase in risk of LOAD

E2 formassociated with decreased risk of LOAD


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ApoE4 May Contribute to AD through Abeta-dependent

and Abeta-independent Mechanisms


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ApoE4 Can Influence AD Pathogenesis via Multiple

Abeta-dependent pathways


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ApoE 4 Can Influence AD Pathogenesis Via Multiple

Abeta-Independent Pathways


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LOAD Risk Factor Genes


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Physiological Functions of LOAD genes

immune system function (both innate and adaptive)CLU, CR1, ABCA7,MS4A cluster, CD33 and EPHA1

cholesterol metabolism

APOE, CLU and ABCA7

synaptic dysfunction and cell membrane processesPICALM, BIN1,

CD33, CD2AP and EPHA1


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Newly Identified LOAD Genes and Putative Links

to AD Pathogenesis


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Newly Identified LOAD Genes and Putative Links

to AD Pathogenesis


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ELEVATED RISK

Smoking

Head trauma

Depression/anxiety

Cardiovascular disease

Type II Diabetes

Obesity

REDUCED RISK

Education

Physical exerciseCognitive activity

Social engagement

Mediterranean Diet

Light-moderate alcohol use

Lifestyle and Environmental Factors

Associated with AD Risk


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High cholesterol

Hypertension

Insulin resistance/Type 2 diabetes

Systemic Inflammation

Obesity/Central adiposity

Increased Risk

of LOADmechanisms ?

Metabolic and Vascular Diseases in Mid-Life Associate

with Increased Risk for Alzheimers Disease in Late Life

~30 years later

mid-life


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Type 2 Diabetes and AD Pathogenesis


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, 2011

Vascular Hypothesis for AD


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Education

Physical exercise

Cognitive activity

Social engagement

Mediterranian Diet


Reduced Risk of LOADmechanisms ?

Protective Factors Against AD


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Protective Mechanisms: Lessons from Studies in Animal

Models

AD Research Summit 2012


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Exercise and Enriched Environment Stimulate Protective

Neurobiological Mechanisms

Increased brain growth factors

Increased vascular function and growth

Increased neurogenesis

Reduced brain inflammation

Decreased oxidative damage in brain

Beneficial changes in gene expression

Reduced beta-amyloid protein


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ELEVATED AD RISKSmoking

Head trauma

Depression/anxiety

Cardiovascular disease

Type II DiabetesObesity

Other?

REDUCED AD RISK

Education

Physical exercise

Cognitive activity

Social engagement

Mediteranian Diet


Other?

Lifestyle and Environmental Factors

Associated with AD Risk

mechanisms?


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EPIGENETICS

Interaction between genes and environment


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Epigenetics relates to single genes or sets of genes, while epigenomics refers togenome-wide analysis of epigenetic changes.

Computer analogy: The genome is the hardware and the epigenome isthe software that runs the hardware

WORKING DEFINITIONS:

EPIGENETICS VS. EPIGENOMICS:

EPIGENETICS:

Study of the regulation of gene activity that is not dependent on genesequence

Heritable changes in gene activity and expression that areindependent of DNA sequence

E M k h S S f


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DNA Methylationsilences gene by methylating the cytosine of a CpG motif.

Noncoding RNAsinterfere with transcription and post-transcriptional

regulation of gene expression.

Histone Modificationmethylation, acetylation, or phosphorylation- regulates gene

transcription.

Epigenetic Marks: the System Software

Microcode


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Major Epigenetic Marks


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Epigenetics of AD

Complex disease: gene-environment interaction

Identical Twins Discordant for AD

l C b d


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Environmental Exposures Can be Transmitted

via Epigenetic Mechanisms

F t A i t d with R d d AD i k M


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EnvironmentalEnrichment

RegularEnvironment

Factors Associated with Reduced AD risk May

Operate through Epigenetic Mechanisms

change in histone acetylationEnvironmental

Enrichment


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TAKE HOME LESSON: AD IS A MULTI-FACTORIAL DISORDER

AD is most likely caused by complex interactions among multiplegenetic, epigenetic, and environmental factors.


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The Pathogenesis of AD Is Complex


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AD

Cause A

CLU

Cause B

Obesity

Cause C

FAD mutation

Cause D

Hypertension

AD is most likely caused by complex interactions among multiple

genetic, epigenetic, and environmental factors


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Cause A Cause B Cause C Cause D

Mediator 1 Mediator 2 Mediator 3

Mediator 4 Mediator 5

AD-1 AD-2

Hypothetical Pathogenic Cascades Causing AD


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Acknowledging the multifactorial nature of AD has

profound influence on understanding, treating andpreventing the disease.


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Alzheimers

DiseaseThe Etiology of Late-Onset AD is Multifactorial

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The Causes of Alzheimer’s Disease: Deconstructing the Puzzle