A presentation about Alzheimer's disease, it's definition, it's etiology, its mechanism of development as well as actual treatment and developing treatments.

1. Fotso Bennis Mounir
Scientific supervisor: PhD, Associate Professor Zhadan S.A.
Department of Pathological Physiology
Belarusian State Medical University, Minsk

3.  Alzheimer's disease (AD) is a chronic neurodegenerative disease with a slow start
and which gets worse with time, the most common form of dementia, a brain
disorder that leads to progressive decline of its function.
 It is marked by amnesia and loss of cognitive abilities, severe enough to disturb the
normal life of the person affected.
 As the patients’ condition declines, they tend to isolate themselves from family and
society. Death is then caused by gradual loss of bodily functions.
 The deterioration of the brain is due to a build up of amyloid plaques within neuron
and neurofibrillary tangles.

5.  Amyloid Plaques
 The body produces normally some protein fragments called amyloid. The β-
Amyloid comes from an amyloid precursor protein (APP) and is normally broken
down and eliminated in healthy brains. However, in Alzheimer’s disease, the
fragments accumulate to form hard plaques.
 Neurofibrillary Tangles
 They are insoluble twisted fibres, consisting of Tau proteins and forming part of
the microtubule. The microtubule is involved in nutrients’ transport from one part
of the nerve cell to another. In AD, the tau protein is abnormal and the
microtubules collapse.

9.  The cause and reasons of AD is still not know to this day. However, many theories
have been formulated regarding the development of the disease.
 It is however important to mention that genetics are involved as well and there’s a
higher risk of contracting Alzheimer if the diseases has occurred previously in the
family.
 First is the cholinergic hypothesis: the oldest, which proposes that AD is caused by
reduced synthesis of the neurotransmitter acetylcholine.
 The second is the amyloid hypothesis: which postulates that extracellular amyloid
beta Aβ deposits are the fundamental cause of the disease.
 Third, we have the Tau hypothesis: it proposes that tau protein abnormalities
initiate the disease cascade.
 Finally, other hypotheses state that the poor functioning of blood-brain barrier
may be involved

10.  Age is the greatest risk factor4
 Affects 10% of population over the age of 65²
 Affects 35% in those over the age of 85²
 Women at greater risk because of longer life expectancy5
 Estimated 24 million have dementia, most have Alzheimer’s disease4
 United States of America among countries with largest number of affected
individuals4
 Major Public concern due to medical costs4
 Two victims: patient and caregiver4
 Increase in elderly population5
 Baby boomers aging5
 Life span increase due to advancement in medical technology5
 Slow progression4
 on average live 7 years after diagnosis ( can span from 2 to 18 years) 4
 Advanced stages require assisted living and nursing home care4
²Pinel, John P. J.(2011). Biopsychology, Boston, MA: Pearson education, Inc.
4Ballard, Clive C., Gauthier, Serge S., Corbett, Anne A., Brayne, Carol C., Aarsland, Dag D., and Jones, Emma.(2011). Alzheimer’s
disease, 377, 1019-1031. Retrieved from: http://search.proquest.com.libproxy.edmc.edu/docview/85824866?accountid=34899
5Lichtenberg, Peter A., Murman, Daniel L., and Mellow, Alan M.(2003). Handbook of Dementia: Psychological, neurological, and
Psychiatric Perspective: John Wiley & Sons. Retrieved from: http://www.web.ebsohot.com.libproxy.edmc.edu

11.  Reviews of twin and family studies have evaluated the genetic heritability of the
diseases from 49% to 79%. Around 0,1% are of autosomal dominance, developing
before the age of 65 and known as early onset familial AD. This form can be
attributed to mutations in one of three genes: those encoding APP and presenilins
1and 2.
 Most cases, termed sporadic AD showed no autosomal-dominant inheritance and
genetics act more as risk factors. The best known genetic risk factor is the
inheritance of the ε4 allele of the apolipoprotein E. Recent genome-wide
association studies have found 19 other areas in genes affecting the risk. These
are CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B,
SORL1, ZCWPW1, SIC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1,
CD2AP.
 A suggested mechanism of action is that when TREM2 is mutated, white blood
cells in the brain are no longer able to control the amount of beta amyloid present.
The mutation of this gene have shown 3 to 5 times higher risks of developing AD

14. Early onset
Late onset
Region 1q31-q42
presinilin 2 IP5EN2I
Region 19q13.2
apoliprotein E
(ApoE)
Region 21q1.4
amyloid precursor
protein (APP)
Region 14q23.4
presinilin 1 IP5EN1I
Region 10p13
AD7
Region 10q24
AD5
Region 12p11.23 q13,12
AD3
Region 12p13.3
p12,3
Alpha 2
macroglobulin
Region 12q13.1
p13,3
Low density
lipoprotein
receptor-related
protein 1

15.  The oldest, which proposes that AD is caused by reduced synthesis of the neurotransmitter
acetylcholine. Other cholinergic effects have also been proposed, for example, initiation of large-
scale aggregation of amyloid, leading to generalised neuro-inflammation.
 The hypothesis states that a possible cause of AD is the reduced synthesis of acetylcholine, a
neurotransmitter involved in both memory and learning, two important components of AD.
 Thus it was proposed that degeneration of cholinergic neurons in the basal forebrain and the
associated loss of cholinergic neurotransmission in the cerebral cortex and other areas
contributed significantly to the deterioration in cognitive function seen in patients with
Alzheimer’s disease.
 Further studies on the cholinergic system and AD demonstrated acetylcholine plays a role in
learning and memory. When young adults perform memory and attention tasks, brain activation
patterns are balanced between the frontal and occipital lobes, creating a balance between
bottom-up and top-down processing. Normal cognitive aging may affect long term and working
memory, though the cholinergic system and cortical areas maintain performance through
functional compensation. Adults with AD presenting with dysfunction of the cholinergic system
are not able to compensate for long-term and working memory deficits.
 Therefore, a disruption to the cholinergic system has been proposed as a consequence of AD
rather than a direct cause.

18.  According this theory, the pathology of AD (Alzheimer’s disease) is due mainly to
amyloid plaques formed by aggregates of Aβ peptide that result from the
proteolytic cleavages of APP (Amyloid Precursor Protein).
 It is stated that AD develops according two mechanisms: mutations in APP or
Presenilin 1 or 2 gene (which are the inherited forms of the disease) OR failure of
Aβ clearance mechanisms by inheritance of ApoE4. This results in faulty Aβ
degradation and increased Aβ42 production throughout the life, with gradual rise
of Aβ42 levels in the brain.
 Subtle disturbances in synaptic efficacy (neuron communication) occurs because of
gradual deposition of as diffuse plaques. Microglia and astrocytic neurons are
activated and initiate inflammatory response. Altered neuronal ionic homeostasis
results in oxidative injury. Altered kinase/phosphatase activities lead to tangles
formation. Soon, neuronal/synaptic dysfunction spreads and selective neuronal
loss appears.

22.  This hypothesis states that Tau protein, a highly soluble microtubule-associated
protein (MAP), is abnormally or excessively phosphorylated, resulting in the
transformation of normal adult tau into PHF-tau (paired helical filament).
 Tau protein, through its isoforms, interacts with tubulin and stabilizes
microtubule assembly. Mutations altering the function and isoform expression of
tau lead to hyper-phosphorylation. Thus aggregation occurs. These hyper-
phosphorylated tau disassemble microtubules and lock normal tau, MAP1, MAP2
and ubiquitin into tangles. This insoluble structure damages cytoplasmic
functions and interferes with axonal transport, leading to cell death.

25. 25
Alzheimer's disease cause the patients to experience problems with
memory, judgment, thinking, making it hard for them to work or
even doing the simples tasks in life.
As the disease is chronic and slowly develops, many symptoms take
time to occurred or better to say to be noticed. It is common that
family members and friends had to look back to realize the moment
the changes started.

26.  Impaired memory and thinking – At early stages, this symptom manifests with the patient
having difficulties remembering things and even learning new information. In late stages, it is a
long-term well pronounced memory loss with the patient forgetting even the most personal
informations about his life.
 Disorientation and confusion – It manifests with patient getting more and more lost without
being able to realize that they are lost or even how they got to the place where they are. They
even stop recognizing familiar places and situations. Later, they stop recognizing people and
even lose every notion of time.
 Misplacing things – It starts with the patient forgetting where he put things he uses everyday
such as glasses or keys. Later it gets even more pronounced and the patient ends up putting
objects in places where they are not supposed to be placed. For example car keys inside
bathroom.
 Abstract thinking – It begins with the patient having troubles with certain easy tasks, finding
them harder than usual, for example, balancing a checkbook. In advanced stages, he may forget
the use of numbers and even letters.
 Trouble performing familiar tasks – Normal daily tasks such as eating, getting dressed, walking
and so on, become harder and harder to do until the incapacity to do them alone.

27.  Changes in personality and behavior – It can manifests by access of anger, irritability or even
restlessness and quietness. Sometimes, the patient can even develop paranoia, confusion or fear.
 Poor or decreased judgment – The patient tend to make irrational choices such as leaving the
stove on fire, opening windows during winter, going out half-naked.
 Inability to follow directions – It gets harder and harder to follow and even understand simple
instructions. It leads to the patient getting lost easily and wander around.
 Problems with language and communication – It is more and more difficult to recall and use
names of simple objects such as chair, table, pen, book.
 Impaired visual and spatial skills – It becomes harder and ultimately impossible for the patient
to differentiate shape and to rearrange items in a specific order or according to the shape..
 Loss of motivation or initiative – Patients starts to show passiveness, empty stares, closure to
the world
 Loss of normal sleep patterns

28. 28
Signs and symptoms of mild AD can include:
 Memory loss and changes in expressive speech
 Confusion about the location of familiar places
 Taking longer to finish routine, daily tasks
 Difficulty with simple math problems and related issues like handling
money, paying bills, or balancing a checkbook
 Poor judgment which leads to bad decisions
 Mood and personality changes
 Increased anxiety

29. 29
Signs and symptoms of moderate AD can include:
 Increased memory loss
 Shortened attention span
 Difficulty recognizing friends and family
 Problems with language, including speech, reading, comprehension, and writing
 Difficulty organizing thoughts
 Inability to learn new things or cope with unexpected situations
 Restlessness, agitation, anxiety, tearfulness, and wandering, especially in the late afternoon or evening (sometimes
called sundowning)
 Repetitive statements or movements
 Hallucinations, delusions, suspiciousness, or paranoia
 Loss of impulse control (for example, sloppy table manners, undressing at inappropriate times or inappropriate
places, vulgar language)

30. 30
Signs of severe Alzheimer's disease may include:
 Complete loss of language and memory
 Weight loss
 Seizures, skin infections, and difficulty swallowing
 Groaning, moaning, or grunting
 Increased sleeping
 Lack of bladder and bowel control
 Loss of physical coordination

31. 31

32. 32
Cognition
* Recall/learning
* Word finding
* Problem
solving
* Judgement
* Calculation
Function
* Work
* Money/shopping
* Cooking
* Housekeeping
* Reading
* Writing
* Hobbies
Behavior
* Apathy
* Withdrawal
* Depression
* Irritability
IMPAIRMENT
Adapted from Galasko, 1997

33. 33
Cognition
* Recent memory
(remote memory
unaffected)
* Language (names,
paraphasias)
* Insight
* Orientation
* Visuospatial ability
Function
* IADL loss
* Misplacing
objects
* Getting lost
* Difficulty
dressing
(sequence and
selection)
Behavior
* Delusions
* Depression
* Wandering
* Insomnia
* Agitation
* Social skills
unaffected
IMPAIRMENT
Adapted from Galasko, 1997

34. 34
Cognition
* Attention
* Difficulty
performing
familiar activities
(apraxis)
* Language
(phrases, mutism)
Function
* Basic ADLs
Dressing
Grooming
Bathing
Eating
Continence
Walking
Motor slowing
Behavior
* Agitation
Verbal
Physical
* Insomnia
Adapted from Galasko, 1997
IMPAIRMENT

35. 35

36. 36Aggression
HallucinationsUse the toilet
DelusionsFeed themselves
Fear or panicDress themselvesPraxis
Inappropriate behaviourKeep themselves cleanImpaired perception
RestlessnessAnswer the telephoneExecutive dysfunction
ApathyGo out aloneLanguage difficulties
AnxietyKeep appointmentsDisorientation in time and place
ConfusionDriveAttention deficits
DepressionMemory loss
Behavioural and
psychotic symptoms
Activities of daily
living;
unable to:
Cognitive impairments
Maintain their own finances

37. 37
Impact of Alzheimer’s Disease on the Caregiver

46. Treatment of mild-moderate AD
 Choline esterase inhibitors (Improves cognition & daily activities. Effective for 6
months, early initiation of therapy, decreases troublesome behaviors)
- Donepezil 5 mg/day 4-6 weeks, then 10 mg/day until max tolerated dose
- Rivastigmine 1,5 mg twice a day then step up monthly to maximum 6 mg
twice a day
- Galantamine 8 mg/day monthly increase to 16mg/day maximum 24 mg/day
Treatment of severe AD
 NMDA antagonists (Slows intracellular Ca accumulation and delay nerve damage)
- Memantine (Used in combination with Donepazil) 5mg daily in a week then 5
mg twice a day up to 15 mg/day

47.  Behavioral intervention
 Neuroleptic agents such as haloperidol, chlorpromazine. They are recommended
in low doses in frail and elderly.
 Antidepressants & mood stabilizers like citalopram (20 mg/day max 40mg),
sertraline & fluvoxetine (no benefits according Wintraub & Petrecca study),
mirtazapine (no benefits according Banerjee study)
 Anticonvulsants like gabapentin and sodium valproate
 Anti inflammatory agents NSAID are thought to delay onset of AD even though a
double blind placebo trial (Grundman et al 2003) showed that rofecoxib and
naproxen have no effect on AD progression

48.  Anti amyloid therapy – Vaccination with amyloid species, monoclonal antibodies, IVIG
containing amyloid binding antibodies, selective amyloid lowering agents, beta
secretase inhibitors (Tarenflurbil and Semagacestat). Unfortunately, no phase 3 trials
for this therapy have shown acceptable efficacy.
 Antibiotics for AD - Antibiotics of the class cholinesterase inhibitors may improve the
condition of patients with AD. Daily doxycycline 200mg plus rifampin 300mg or
placebo for 3 months.
 Reversal of excess Tau phosphorylation – Free radical scavengers (High dose of
Vitamin E – 2000U/day – slowed the progression of AD for 2 years according the large
double blind placebo trial by Sano et al 1997). However, because of the risks of
cardiovascular complications, these are not recommended nowadays.
 Estrogen replacement therapy – – It was thought estrogen could improve cognitive
abilities. Control Trials (RCT) with 351 points for 2 weeks showed no beneficial effects
 Cholesterol lowering agents – Some epidemiological studies linked cholesterol
homeostasis and AD. RCT double blinded with 748 pts for 6 months showed no
efficacy.

49.  Selegelline – Acts as a mood stabilizer and improves cognitive functions. RCT trial
conducted in 2010 without positive results.
 Tramiprosate (Alzhemed) – Homotaurine that binds to soluble and insoluble Amyloid
Beta, protecting against amyloid neurotoxicity and reducing tau protein abnormal
phosphorylation. RCT double blinded placebo controlled trial ongoing 2009.
 Cerebrolysin – Peptidergic drug coming from purified pig brain, thought to be
neurotrophic and neuroprotective. RCT double blinded placebo controlled trial ongoing
2010
 Latreperidine(Dimebom) – Anti-histamine, inhibiting burylcholine esterase, AchE,
NMDA signaling pathway. RCT phase 3 trial ongoing Jan 2011
 Nimodipine – Prevents Ca accumulation in neurons, causes vasodilation. RCT with
500pts conducted in March 2010 showed improved cognition and global impression
with doses 90 mg/day & 180 mg/day for 12, 24, 52 weeks.

50.  Metal protein attenuating compound(MPAC) (clinoquinol) – Solubilizes and clears
Amyloid Beta. RCT double blinded with 36 pts revealed no efficacy after 36 weeks
of trial.
 Mertrifonate – Irreversible AchE inhibitor. RCT double blinded phase 3 study for
26 weeks showed improvement at a dose of 60-80 mg/day.
 Lecithin – Major source of choline. RCT double blinded placebo failed to show
efficacy.
 Huperzine A – Reversible AchE inhibitor. RCT double blinded Chinese study with
482 pts revealed improvement,
 Transcutaneous electrical nerve stimulation (TENS) – Changes
neurotransmitters, helps in neuron regeneration. 3 RCT in Netherlands and
Japan. Limited data, small improvement.

51. CURRENT
Characteristic DONEPAZIL RIVASTIGMINE GALANTAMINE MEMANTINE
Chemical class Piperidine Carbamate Phenanthrenealkaloi
d
Similar to
Amantadine
Primary mechanism AchE inh AchE inh AchE inh NMDA antagonist
Other mechanism None None Nicotine modulator HT3 receptor
antagonist
Half life 70 h 90 min 7 h 70 h
Metabolism Hepatic Renal Hepatic Hepatic

56. Combined clinical trial data for the three licensed acetylcholinesterase inhibitors:
rivastigmine (♦), donepezil (▴) and galantamine (•) versus placebo (▪).
BULLOCK R BJP 2002;180:135-139
©2002 by The Royal College of Psychiatrists

58.  http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp
 https://en.wikipedia.org/wiki/Alzheimer%27s_disease
 https://halfhillfarm.com/2015/10/25/brains-of-alzheimers-disease-patients-show-signs-of-fungal-infection/
 https://www.alzinfo.org/articles/what-happens-to-the-brain-in-alzheimers-disease/
 https://www.thinglink.com/scene/629317049302122496
 http://memorylanecottage.com/about-alzheimers-and-dementia/how-the-brain-changes-during-alzheimers-disease/
 Alzheimer’s Association: http://alz.org/alzheimers_disease_4719.asp Brain Tour
 About.com Healths Disease and Condition, Carrie Hill, PhD
 MSN Health, Healthwise, http://health.msn.com/health- topics/aging/articlepage.aspx?cp-documentid=100097440
 http://www.mayoclinic.com/health/alzheimersdisease/DS00161
 Pinel, John P. J.(2011). Biopsychology, Boston, MA: Pearson education, Inc.
 Ballard, Clive C., Gauthier, Serge S., Corbett, Anne A., Brayne, Carol C., Aarsland, Dag D., and Jones, Emma.(2011).
Alzheimer’s disease, 377, 1019-1031. Retrieved from:
http://search.proquest.com.libproxy.edmc.edu/docview/85824866?accountid=34899
 Lichtenberg, Peter A., Murman, Daniel L., and Mellow, Alan M.(2003). Handbook of Dementia: Psychological, neurological,
and Psychiatric Perspective: John Wiley & Sons. Retrieved from: http://www.web.ebsohot.com.libproxy.edmc.edu
 Alzheimer's disease beyond APOE by Michael A van Es1 & Leonard H van den Berg1 - Michael A. van Es and Leonard H. van
den Berg are at the Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht,
Utrecht, The Netherlands.
 http://dementiatoday.com/the-genetics-of-alzheimers-disease-whats-new/

59.  Harrisons internal medicine – 18 th edition
 www.clinicaltrials.gov
 www.thecochranelibrary.com
 www.alzheimers.org
 www.alz.org
 www.nia.nih.gov