PDA III - Exam 4: Alzheimers Disease - RW

What is meant by the term dementia?

Description of a collection of symptoms

Loss of memory, language skills, perception, reasoning, and judgment

What 2 conditions is dementia distinguished from?

Normal age related cognitive decline

Mild cognitive impairment (MCI)

What is the most common cause of dementia in people over the age of 65?

Alzheimer's disease (AD)

At what age do most cases of AD occur?

Usually after age 60 (late onset)

What type of disease is AD?

progressive neurodegenerative disease

What is the main behavioral feature of AD?

Gradual decline in cognition over many years

Cognition - learning, memory, attention

What is often the 1st symptoms of AD to manifest?

Difficulty retaining new information (short-term memory)

What AD symptoms usually occur 2nd, after AD progresses?

Tendency to get lost (spatial memory)

And, loss of more remote memory (long-term memory)

What AD symptoms usually occur 3rd, after AD further progresses?

Inability to perform daily tasks of self-care

(dressing, hygiene, meal prep, etc.)

As cognitive decline in AD progresses, what other symptoms to patients exhibit?

Behavioral problems can occur

Aggression

Depression

irritability

Paranoia

Hallucinations

Delusions

How did AD used to be diagnosed?

By process of elimination

Using brain scans, electroencephalograms, lab tests and psych evals.

Confirmed at autopsy

What is currently used to diagnose and stage AD?

Biomarkers

PET scans of amyloid

Fluid (plasma/CSF) biomarkers of amyloid and p-tau

What are biomarkers used to diagnose AD?

PET scans of amyloid

Fluid (plasma/CSF) biomarkers of amyloid and p-tau

What was included in the old AD diagnostic criteria?

Memory impairment at at least 1 of:

-Aphasia

-Apraxia

-Agnosia

-Disturbed executive functioning

Cognitive deficits impair functioning

Deficits are a decline from previous higher fxn.

What is aphasia?

Loss of ability to speak with fluency and relevance

What is apraxia?

Inability to carry out a learned, purposeful movement

Even though there is no motor or sensory impairment

There is a deficit in motor planning

What is agnosia?

Failure to recognize sensory stimuli

Cannot recognize objects or people by sight

What are the stages of AD?

Mild

Moderate

Severe

What symptoms are present in mild AD?

Uncharacteristic forgetfulness

Impaired acquisition and retrieval of new info.

Geographic disorientation

Difficulty in proper word selection

Hesitancy in speech

Socially passive, disintersted

What is the MMSE score in mild AD?

21-24

What symptoms are present in moderate AD?

Inaccuracies in long-term memories

Confusion over relationships and identities of friends/relatives

Small tasks require supervision

Disruptive behaviors and psychiatric symptoms

What disruptive behaviors are seen in moderate AD?

Agitation

Restlessness

Sleep disturbances

Agression

What psychiatric symptoms are seen in moderate AD?

Paranoia

Delusions

Hallucinations

What is the MMSE score in moderate AD?

10-20

What symptoms are present in severe AD?

Nearly complete dependence on caregivers

Severe impairment of verbal output and comprehension

Personality disappears

Urinary/fecal incontinence is common

Weight loss is common

What is the MMSE score in severe AD?

<10

What are the 2 defining pathological features of AD?

Amyloid plaques

Neurofibrillary tangles

What are pathological features of AD?

Amyloid plaques

Neurofibrillary tangles

Degeneration of BFCS

Other neuronal degeneration

Brain is shrunken and cerebral BF is reduced

What are amyloid (senile) plaques?

Extracellular deposits of B-amyloid peptide

What are the 2 types of B-amyloid?

40 or 42 amino acid forms

Both can form plaques

42 more likely to

Which form of B-amyloid is more likely to form fibrils and clumps?

42

Where to plaques preferentially develop in the early stages of AD?

Hippocampus

Temporal and Frontal Lobes

Association cortex

(all areas impt. for cognitive fxn.)

What are diffuse plaques?

Consist mainly of the 40-aa form of B-amyloid

What are neuritic plaques?

Consist of both 40- and 42-aa forms of B-amyloid,

Dystrophic dendrites,

And, Glia

Contain filamentous AB (more toxic)

Are B-amyloid oligomers toxic?

Oligomers may be toxic

Or, at least interfere with signaling involved in learning/memory

What are neurofibrillary tangles?

Consist of hyperphosphorylated tau

What type of protein is tau?

Microtubule associated protein

(provides structure to neuron)

What is the basal forebrain cholinergic system (BFCS)?

Major cholinergic neurons in brain

ACh they release regulates cognitive fxn.

What are the parts of the BFCS?

Ch1-CH4

Septum (Ch1)

Diagonal band (Ch2+3)

Nucleus basalis of Meynert (Ch4)

What happens to the BFCS in AD?

BFCS degenerates in AD

Degree of degeneration correlates with the degree of dementia

What are other neuronal populations that degenerate in AD?

Monoamine systems

Hippocampal neurons (CA1)

Cortical neurons

Amygdala neurons

What are characteristics of the brain in AD?

Brain is generally shrunken (ventricles are larger)

And, cerebral blood flow is reduced

What is the role of genetics in late-onset AD?

Late onset (>60) do not have a single genetic cause

Do have some risk factors

Arise from gene-enviroment interactions

Most cases

What is the major gene that influences the risk of late-onset AD?

ApoE

What is the role of genetics in early-onset AD?

Early onset (≤50s) are genetically caused

By autosomal dominant mutations

1-10% of cases

What type of mutations cause early onset AD?

Mutations that change amyloid processing

What molecule is amyloid derived from?

APP

What is APP processing?

APP undergoing post-translational processing

Mutations can be either non-amyloidogenic or amyloidogenic

What are the 2 pathways of APP processing?

Non-amyloidogenic (non-pathogenic)

Amyloidogenic (pathogenic)

What is involved in non-amyloidogenic APP processing?

a-secretase produces C83

y-secretase produces p3

What is the first step in non-amyloidogenic APP processing?

a-secretase cleaves APP

Creating C83 and sAPPa

What is the second step in non-amyloidogenic APP processing?

y-secretase cleaves C83

Produces p3 (no effects)

What is involved in amyloidogenic APP processing?

B-secreates (BACE-1) creates C99

y-secretase creates B-amyloid

What is the first step in amyloidogenic APP processing?

B-secretase cleaves APP

Creating C99 and sAPPB

What is the second step in amyloidogenic APP processing?

y-secretase cleaves C99

Produces B-Amyloid

What happens to B-amyloid after it is created by amyloidogenic APP processing?

B-amyloid released extracellularly after cleaved

Can form oligomers/fibrils/clumps

And, eventually become a plaque

What type of protease is y-secretase?

A complex of proteins

Made up of:

-Presenilin 1 or 2

-Nicastrin

-PEN2

-APH-1

What proteins make up y-secretase?

Presenilin 1 or 2

Nicastrin

PEN2

APH-1

Which protein is the catalytic core of y-secretase?

Presenilin 1 or 2

(performs the actual cleavage)

Which proteins are the regulatory proteins of y-secretase?

Nicastrin

PEN2

APH-1

(surround the catalytic core)

What are the steps to form a plaque after B-amyloid is released?

AB released as monomers ->

Early aggregates->

Protofibrils->

Fibrils->

Plaque

How are mutations named?

1st letter: original aa

#: where in protein sequence aa is

2nd letter: what the aa becomes in the mutated gene

What letter indicates the aa glutamate?

E

What letter indicates the aa aspartate?

D

What letter indicates the aa lysine?

K

What letter indicates the aa asparagine?

N

What letter indicates the aa methionine?

M

What letter indicates the aa leucine?

L

What letter indicates the aa alanine?

A

What letter indicates the aa threonine?

T

What letter indicates the aa histidine?

H

What letter indicates the aa arginine?

R

What letter indicates the aa glycine?

G

What letter indicates the aa glutamine?

Q

What letter indicates the aa valine?

V

What letter indicates the aa isoleucine?

I

What 3 genes can be mutated to cause early-onset AD?

APP

PSEN1

PSEN2

What is the effect of a mutation that favors B-secretase activity (cutting)?

Favors the pathogenic pathway

Inc. AB production

What is the effect of a mutation that inhibits B-secretase activity (cutting)?

Favors non-pathogenic pathway

What is the effect of a mutation that favors y-secretase activity (cutting)?

Favors the pathogenic pathway

Inc. AB production

What is the effect of a mutation that favors a-secretase activity (cutting)?

Favors non-pathogenic pathway

What is the effect of a mutation that inhibits a-secretase activity (cutting)?

Favors the pathogenic pathway

Dec. non-amyloidogenic processing by a-secretase

Shunts processing to amyloidogenic pathway

Inc. AB production

What can be mutated in y-secretase to increase activity (inc. AB formation)?

Catalytic core - PSEN1 or 2

What is a commonality of all mutations that cause early-onset AD?

All effect APP processing

All mutations result in inc. production of the long form (42) of AB

(more amyloidogenic form)

How are neurofibrillary tangles formed?

Formed by highly phosphorylated tau protein

This causes it to disassociated from microtubule. This makes the microtubule unstable as well as promotes association of multiple phosphorylated tau proteins

Aggregated tau proteins results in fibrils which can lead to tangles which causes the neuron to die

What enzymes phosphorylate Tau?

Kinases

What happens to Tau once it is hyperphosphorylated?

Loses affinity for microtubule

Released to form tangles

What happens to the microtubule once tau dissasociates?

Microtubule is destabilized

Neuron dies

What are the steps to form a neurofibrillary tangle after p-Tau is released?

Monomer ->

P-Tau ->

Soluble Tau aggregates ->

Paired helical filaments ->

Neurofibrillary tangle

What is ApoE?

Apolipoprotein E

Involved in cholesterol transport

May be involved in binding and removing AB from the brain

What is the relationship between ApoE and late-onset AD?

ApoE(4) is a major risk factor for AD

What are the 3 types of ApoE?

E2

E3

E4

Which type of ApoE increases the risk for AD?

E4 may promote formation of plaques

Why is it believed that ApoE4 increases AD risk?

E4 allele may not be good at removing AB from the brain

Allowing more AB to stay in the brain and form plaques

Which type of ApoE decreases the risk for AD?

E2 is protective

(E3 may also be)

What is the correlation between number of ApoE4 alleles and AD risk?

More E4 alleles means an increased risk of developing AD

What is the amyloid cascade hypothesis?

States that AB is the cause of AD

Supported by genetic evidence

What evidence contradicts the amyloid cascade hypothesis?

Can find AB plaques at high levels in people without dementia

Can see cognitive deficits before plaque formation

Can see cognitive deficits when no plaques are present

Can have plaques but no cognitive deficits

What are the 3 categories of treatments?

Symptomatic

Disease modifying

Curative

What are disease modifying therapies?

Slow or stop pathological process responsible for a disease