The Causes of Alzheimers Disease: Deconstructing the Puzzle

Lorenzo M Refolo PhD National Press Foundation, May 21st 2012

National Institute on Aging

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

Socioeconomic Burden of AD

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.

2012 Alzheimers Facts and Figures, Alzheimers Association

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

AD Disrupts Essential Neuronal Functions

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 is Characterized by Atrophy in Brain Areas that Support Cognition

Pathological features of AD

The major neuropathological features - beta- amyloid plaques - neurofibrillary tangles - neuronal cell loss

Beta-amyloid plaque and NFT

Neurofibrillary tangle

Two Main Types of Alzheimers Disease: familial (FAD) and sporadic (SAD)

FAD is rare (approx 3% cases), heritable form with an early onset (30y to 60y).

SAD or late onset AD (LOAD) represents more than 95% cases and usually affects people over age 65.

FAD is an Autosomal Dominantly Inherited Disease

There are 3 FAD genes APP amyloid precursor protein PS1- presenilin 1 PS2 presenilin 2

Mutations in all 3 FAD genes lead to an increase in the production of beta-amyloid peptide (Abeta).

Causes of Late Onset Sporadic AD

Aging
Genetic risk factors

Metabolic
Vascular

Psychosocial
Other Environmental Factors

The Abeta Peptide is Part of the Amyloid Precursor Protein (APP)

A-beta is Produced by Proteolytic Cleavage of APP

APP
Abeta

alphasecretase

BACE

Gammasecretase

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

The Pathobiology of AD

Amyloid cascade hypothesis

Abeta production
Abeta clearance Synaptic dysfunction Neural network failure

Amyloid Cascade
The amyloid cascade hypothesis has been the dominant organizing principle driving the Alzheimers research agenda.

AD Pathogenesis and the Amyloid Cascade Hypothesis

Mucke, Nature (2009) 461:895-897

Abeta Production vs. Clearance

Abeta accumulation in the brain is a result of the balance between its production and its clearance.

Abeta Clearance

Enzymatic degradation - Neprilysin - Insulin degrading enzyme (IDE)

Transport across the blood-brain-barrier -ApoE -LRP -clusterin (ApoJ)

Clearance (Removal) of Abeta from Brain

Abeta Oligomers Mediate Synaptic Dysfunction

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

Amyloid beta Oligomers Induce Dysfunction of Synapses, Neuronal Circuits and Networks Resulting in Cognitive Impairment and Dementia

Abeta-Mediated Neuroinflammation Kills Neurons

AD Pathobiology: Tau

Tau- microtubule stabilizing protein - phosphorylation - neurotoxic oligomeric forms - connection with Abeta - trans-synaptic spread of tau pathology

Tau Functions to Hold the Nerve Cells Cytoskeleton Together

Hyperphosphorylation of Tau destabilizes the cytoskeleton leading to impaired axonal transport and causing nerve cells to function poorly.

Oligomeric Forms of Phospho-Tau are Toxic to Nerve Cells

hyperphosphorylated tau

toxic tau oligomers

NFTs

Connecting Abeta and Tau

According to the amyloid hypothesis Abeta drives tau-

toxicity

Tau Spreading Pathways in Alzheimers Disease

Interneuronal Spread of Tau Pathology

-unknown mechanism(s)-

Interneuronal Spread of Tau: Therapeutic Implications

Pathobiology of AD cont

Mitochondria and bioenergetics Neurovascular mechanisms

Mitochondria: The Power House of Nerve Cells

Mitochondria Provide Energy for Synapse Formation and Maintenance

Abeta, Mitochondrial Failure and Oxidative Stress

Pathobiology of AD: Neurovascular Mechanisms

400 miles of blood vessels,arteries and capillaries each nerve cell is associated with a microvessel

Vascular cast of the brain

Neurovascular Unit

Pathobiology of AD: Neurovascular Mechanisms

Zlokovic, 2011

Pathobiology of LOAD: Genetic Risk

ApoE4 strongest known risk factor for LOAD

Pathological functions of ApoE4

10 LOAD risk factor genes 40-60% of AD Possible pathological functions of LOAD risk factor genes

ApoE4 Major 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 form up to 12 fold increase in risk of LOAD E2 form associated with decreased risk of LOAD

ApoE4 May Contribute to AD through Abeta-dependent and Abeta-independent Mechanisms

ApoE4 Can Influence AD Pathogenesis via Multiple Abeta-dependent pathways

ApoE 4 Can Influence AD Pathogenesis Via Multiple Abeta-Independent Pathways

LOAD Risk Factor Genes

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 processes PICALM, BIN1, CD33, CD2AP and EPHA1

Newly Identified LOAD Genes and Putative Links to AD Pathogenesis

Newly Identified LOAD Genes and Putative Links to AD Pathogenesis

Lifestyle and Environmental Factors Associated with AD Risk

ELEVATED RISK Smoking Head trauma Depression/anxiety Cardiovascular disease Type II Diabetes Obesity

REDUCED RISK Education Physical exercise Cognitive activity Social engagement Mediterranean Diet Light-moderate alcohol use

Metabolic and Vascular Diseases in Mid-Life Associate with Increased Risk for Alzheimers Disease in Late Life

High cholesterol Hypertension Insulin resistance/Type 2 diabetes Systemic Inflammation Obesity/Central adiposity
mid-life

mechanisms ?

Increased Risk of LOAD

~30 years later

Type 2 Diabetes and AD Pathogenesis

Vascular Hypothesis for AD

, 2011

Protective Factors Against AD

Education Physical exercise Cognitive activity Social engagement Mediterranian Diet Light-moderate alcohol use
mechanisms ?

Reduced Risk of LOAD

Protective Mechanisms: Lessons from Studies in Animal Models

AD Research Summit 2012

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

Lifestyle and Environmental Factors Associated with AD Risk

ELEVATED AD RISK Smoking Head trauma Depression/anxiety Cardiovascular disease Type II Diabetes Obesity Other? REDUCED AD RISK Education Physical exercise Cognitive activity Social engagement Mediteranian Diet Light-moderate alcohol use Other?

mechanisms?

EPIGENETICS
Interaction between genes and environment

WORKING DEFINITIONS:
EPIGENETICS:

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

sequence

Heritable changes in gene activity and expression that are

independent of DNA sequence
Computer analogy: The genome is the hardware and the epigenome is the software that runs the hardware EPIGENETICS VS. EPIGENOMICS: Epigenetics relates to single genes or sets of genes, while epigenomics refers to genome-wide analysis of epigenetic changes.

Epigenetic Marks: the System Software Microcode

DNA Methylation silences gene by methylating the cytosine of a CpG motif. Noncoding RNAs interfere with transcription and post-transcriptional
regulation of gene expression.

Histone Modification methylation, acetylation, or phosphorylation- regulates gene

transcription.

Major Epigenetic Marks

Epigenetics of AD
Identical Twins Discordant for AD

Complex disease: gene-environment interaction

Environmental Exposures Can be Transmitted via Epigenetic Mechanisms

Factors Associated with Reduced AD risk May Operate through Epigenetic Mechanisms
Regular Environment

Environmental Enrichment

Environmental Enrichment

change in histone acetylation

TAKE HOME LESSON: AD IS A MULTI-FACTORIAL DISORDER

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

The Pathogenesis of AD Is Complex

AD is most likely caused by complex interactions among multiple genetic, epigenetic, and environmental factors

Cause A CLU

Cause B Obesity

AD

Cause C FAD mutation

Cause D Hypertension

Hypothetical Pathogenic Cascades Causing AD

Cause A Cause B

Cause C

Cause D

Mediator 1

Mediator 2

Mediator 3

Mediator 4

Mediator 5

AD-1

AD-2

Acknowledging the multifactorial nature of AD has profound influence on understanding, treating and preventing the disease.

Alzheimers Disease The Etiology of Late-Onset AD is Multifactorial

Roberta Diaz Brinton, Ph.D.