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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.
Clinical Features of AD
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.
Pathological features of AD
The major neuropathological features - beta- amyloid plaques - neurofibrillary tangles - neuronal cell loss
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.
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).
Metabolic
Vascular
Psychosocial
Other Environmental Factors
alphasecretase
BACE
Gammasecretase
The Pathobiology of AD
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.
Abeta accumulation in the brain is a result of the balance between its production and its clearance.
Abeta Clearance
Amyloid beta Oligomers Induce Dysfunction of Synapses, Neuronal Circuits and Networks Resulting in Cognitive Impairment and Dementia
AD Pathobiology: Tau
Tau- microtubule stabilizing protein - phosphorylation - neurotoxic oligomeric forms - connection with Abeta - trans-synaptic spread of tau pathology
hyperphosphorylated tau
NFTs
toxicity
-unknown mechanism(s)-
Pathobiology of AD cont
Neurovascular Unit
Zlokovic, 2011
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
synaptic dysfunction and cell membrane processes PICALM, BIN1, CD33, CD2AP and EPHA1
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 ?
, 2011
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
mechanisms?
EPIGENETICS
Interaction between genes and environment
WORKING DEFINITIONS:
EPIGENETICS:
Epigenetics of AD
Identical Twins Discordant for AD
Factors Associated with Reduced AD risk May Operate through Epigenetic Mechanisms
Regular Environment
Environmental Enrichment
Environmental Enrichment
AD is most likely caused by complex interactions among multiple genetic, epigenetic, and environmental factors.
AD is most likely caused by complex interactions among multiple genetic, epigenetic, and environmental factors
Cause A CLU
Cause B Obesity
AD
Cause D Hypertension
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.