L9 NEUROCLIN II Clinical Trials and Drug Discovery

To know the brief history of how clinical trials were developed To recall what a clinical trial is and the key steps involved. To explain important terminology used in clinical trials To describe the roles academics, researchers, patients and institutions take in clinical trials and their responsibilities. To describe the basic principles of the drug discovery process

what is the first written documentation of a (sort of) novice clinical trial?

Book of Daniel, Old Testament, Bible

• King Nebuchadnezzar ordered his ppl to eat only meat and drink only wine to keep them strong

• several young men of royal blood objected as they only ate vegetables

• king allowed them to eat legumes and water for only 10 days

• atp vegetarians appeared more nourished than the meat eaters

→ altho not a clinical trial, first example of human experiment guiding decision abt public health

valley of death

• when u go from research in lab to treatment of patients

• where 95% of all promising drugs fail

• after the drug discovery phase

current treatments on the market for Alzheimer’s disease

• only 2

• only slow Alz by 27% in a very specific population and have very bad side effects

clinical trial

• medical research studies involving ppl

• not just for drugs, interventions- e.g. cld be interventions to modify lifestyle or behaviour

• can be done for many diff reasons

reasons clinical trials are used

1. prevent disease + reduce number of ppl who become ill (e.g. vaccinations)

2. treat illness + increase number of ppl cured

3. improve quality of life for ppl living with illness- reducing symptoms or side effects (e.g. currently untreatable conditions like dementia, can use technologies/robotics, assistive techn in the home)

4. for disease diagnosis + health problems (e.g. can a blood test to develop alz 25y earlier be developed?)

brief history of clinical trials

1. book of daniel, old testmanet

2. 1747 scurvy clinical trial, james lind

3. Jenner, 1790-1800s

4. European clinical trials in hospitals + Jenner

5. 1800s- emergence of plecebo, defined 1811

6. 1863: USA Medic Autstin Flint used placebo in clinical study

7. 1943: first double-blind controlled trial (Patulin, penecillin related) (MRC)

8. 1946: first randomised curative trial- using streptomycin to treat TB (MRC)

one of the first clinical trials in the modern era

Scurvy clinical trial, James Lind, 1747

James Lind, 1747

• scurvy trial

• first clinical trial in modern era

• scurvy terrible disease effecting sailors on ships- lesions → death

• lind thought related to diet

• split sailors into 6 groups with diff food and drinks

• had 12 sailors w scurvy and treated them w separate food supplements

• two sailors who had oranges and lemons recovered v quickly and a third who had cider was the next best

• vitamin c deficiency → scurvy

James Lind, 1753

• using his 1747 findings, published Treatis On Scurvy

• not only first desc of a controlled trial but also a systematic review of the previous literature on scurvy

• took british navy 50 years to adopt the findings in full

James Lind impacted modern clinical trials how?

• first one in modern era

• published lit review w his findings

• still part of modern clinical trials

• must to lit review to assess what been done prior to ur trial

Edward Jenner reasoning

• sidestepped clinical trial process

• 1700s, rural England

• been taking notes and making observations on patient population for years

• noticed all milk maids on farms did not contract the deadly small pox disease

• hwvr all milk maids reported they had all prev caught a similar milder disease called cow pox, which did not have lasting effects

• he reasoned the exposure to the milder disease somehow prevented them from getting the deadly disease

Edward Jenner May of 1796

• performed the first ever experimental vaccination on an 8yo boy called James Phipps

• escaped small pox so far, Jenner infected him with cow pox then exposed him to small pox

• experiment worked- if this was done today scientist wld face jail

• hwvr, argued this experiment led to modern vaccination which has saved the most human lives in history of science

• vaccinations saves millions of lives a year

Jenner’s 1700s battle

• when he presented his findings he was rejected and told to collect a larger sample data set

• he did this , and the set included his own son

• finally published Inquiry into the Causes and Effect of Variolae Vaccinae (1798)

• but finding was still wildly ridiculed in society, especially amongst religious groups

• battle from renaissance (where science was invented to prove gods existence) thruought history, even today

• thght against god to put smth from a cow in a human

Jenner and 1800s development

• not until 1800s several major hospitals across europe began to do studies (clinical trials)

• only then cld Jenner’s vax method be robustly assessed

• led to development of modern vax we see today

• laid down foundations for rigorous clinical trials we see around the world

Jenner’s legacy

huge → saved most lives in all science

polio, aids, MMR, covid- groundwork for these vax

(he also gave James Phipps a house)

in 1800s, emergence of a very important term…

placebo

placebo was first defined as… (+ when, by who)

an epithet given to any medicine more to please than the benefit of the patient (Hoopers Medicial Dictionary, 1811)

first use of placebo

• 1863

• USA medica Austin Flint used a placebo in a clinical study

• he gave a ‘pleceboic remedy’ for rheumatism to patients

• all reported positive effects, bc they thght was working, even tho placebo did nothing to treat disease

• shows importance of having placebo in clinical trials to control for placebo effects → important compound to test for when assessing therapeutic efficacy

first double blind control trial

1943, testing Patulin, related to penicillin, wanted to try and treat common cold

1943 double blind control trial

• first one

• testing Patulin, related to penicillin, to try and treat common cold

• never cured common cold so didnt work

• carried out by medical research council (MRC)

• recruited 1000+ subjects from british offices and factory workers suffering from common cold- difficult in wartime

• both drs and patients blinded to the treatment

• → failed to show effect

Medical Research Council

• set up to promote human health

• assess which clinical trials to fund

• still funds lots to this day

strength of double bind

protects against bias

when was first randomised curative trial

1946, using streptomycin to treat TB, carried out by MRC

1946 first randomised curative trial

• using streptomycin to treat tb

• carried out by mrc

• patients had systematic and randomised enrolment rather than alternating, as used in prev studies into treatment and control groups

• drs looking at x ray results were blinded to diff patient groups- did not know which was treated and which not

• study set group work for basis of clinical trials (randomised control ones) we see today

• → included establishment of national and international regulatory frameworks globally

why are clinical trials important?

• health professionals need evidence for best way to compare approaches

• want to be able to properly test different treatments

• ensure using most optimised treatment for separate patient populations

what could happen without clinical trials?

patients cld be given meds that do not work

→ wastes resources bc expensive

→ worse, meds cld be given that make patients worse or are not safe

who is in control of clinical trial process?

• generally designed by doctors and other specialists but involve wide variety of people:

• doctors, nurses, patients, statisticians, trial managers, and representatives from pharmaceutical companies to design the best possible trial

• designed to offer least risk to patient but maximum potential new treatment/intervention being tested

what do statisticians do?

calculating the power of study, e.g. how many animals needed in preclinical aspect or patients needed to see if statistical difference

pharmaceutical companies role in clinical trials

• get bad press

• investing money into process

• will make profit in the end

• key player in it bc provide resources ans tend to be able to do things at scale re manufacturing of drugs

what are clinical trials designed to offer?

least risk to a patient plus maximise potential of intervention being test

what should be done before a clinical trial?

• systematic review of previous trials

• look at similar drugs, is there gap in market, is smth that can be taken further or has it been done before etc

• systematic review of previous trials performed in same area of disease using similar drugs to assess firstly whether research already been done (so no need for trial)

gaining ethical approval

• who is trial protocol sent to

• who does this include

• what do they do

• what do they focus on

• trial protocol sent to research ethics committee

• independent group of ppl that includes doctors, nurses, other medical staff, members of public, sometimes lawyers

• decide whether trial is ethical

• focus on:

1. do the potential benefits of treatment/intervention outweigh costs?

2. that information provided to potential Ps is clear and satisfactory

3. will ppl be approached in appropriate way

• emotional involvement, cannot force or promise ppl, be objective and clear, clear they may not even get treatment

4. is compensation in place for Ps if smth goes wrong?

• often checkpoints in place in case

• sometimes if trial going rly well can move placebo group onto drug but only if stats in place and proper controls in place to ensure satisfied all criteria, otherwise u cannot move onto next stage

• trials often stopped early bc found side effect not anticipated even w pre clinical testing

4. travel expenses- are they in place?

• trial can start only once ethical approval in place

what type of research is becoming funded a lot more in alzheimers + why?

patient led/ patient involved research

• bc what patients to buy into what is going on, so younger ones can understand what is being tested and how it can even benefit then

• can involve friends and family of those suffering bc they important voice to be heard

legal NHS perspective in UK, what do you need for a clinical trial?

a sponsor

sponsor (in context of NHS research)

nhs trust, individual, company, instituition, or group of organisations that takes on responsibility for initiation, management, and financing of research

what must all research falling under the remit of Secretary of State for Health have?

a formal sponsor

→ includes insurance provision

sponsorship of involving medicines

legal requirement for any clinical trial of aan investigational medicinal product (CTIMP) to be sponsored

• this includes provision for insurance in case things go wrong

why sponsors neccessary?

mitigate any bad effects if something does go wrong

what are the distinct phases of clinical trials + their durations?

there are 4 stages

• preclinical (several years)- drug discovery process

• phase 1 (months) - early stage, usually small groups of health subjects but sometimes patients, safety, large side effects

• phase 2 (months to years) - lot more known, larger group of ppl, see if positive effect in patients, side effects

• phase 3 (years to decades)- 100-1000s of ppl, often international, compare new drug to standard treatment, how well works/length of effects/side effects

• phase 4 (ongoing)- licensed and used as treatment, large population, long term risks and benefits, rare side effects

phase 1- clinical trial

• early stage

• months

• generally small groups of health subjects

• sometimes patients

• used to test how safe treatment is- are there any large side effects?

in cancer research:

• small, <30ppl

• designed to find safe dose of new treatment, determine how treatment shld be given, learn how it affects body

• if safe dose found, move to phase 2

phase 2- clinical trial

• months to years

• by this stage, a lot more known about the treatment

• now tested in larger group of ppl to assess safety and side effects in greater detail

• first time- see if treatment has positive effect in patients

in cancer research:

• more patients enrolled, usually </=100

• study how treatment affects body, how treatment works for certain type of cancer

• if found to be safe and have some benefit, go to phase 3

phase 3- clinical trial

• years to decades

• moves up to hundreds if not 1000s of ppl

• often international groups of ppl

• compare new drug to a standard treatment

• how well drug works

• how long effects last for

• finds out abt any serious side effects + how long they last for

• need more longitinal, cld serious side effects be in smaller groups etc, test for rarer

in cancer research:

• many Ps needed, usually 100+ and sometimes thousands

• compare new treatment w current to see which is better

phase 4- clinical trial

• ongoing

• drug now licensed and being used as treatment

• get stats on how well drug is working in large pop

• any long term risks and benefits

• rare side effects

key terms in clinical trials

• placebo

• controlled trials

• blind trials + double blinded trials

• randomisation

• informed consent

what happens during a trial?

assess whether treatment is working

also assess:

• any potential side effects

• any new symptoms

• wider effect of treatment such as quality of life, day to day activities

• mental state- is treatment making u happy/sad, anx/dep

• cost effectiveness of treatment- are u able to work, how often u need to visit doctor

what happens at the end of a trial?

trials can last for years altho as seen w COVID19 process can be dramatically sped up

• all Ps will have access to results if want them

• results published to help other researchers in field and allow advancements to be undertaken by all

• in some instances, treatment used as part of trial may not be available on NHS- at end of trial will be given standard treatment

• in some cases u may be able to buy new treatment

• all ur info kept confidential- key requirement

what needs to happen before start of trial?

• arrangements in place incase smth goes wrong and ppl are harmed

• ethical committee can refuse permission if this not in place

• important for Ps to know insurance in place before trial starts

controlled trials

• designed to compare different treatments

• usually 2 groups

• trials group - given new treatment

• control group - given standard treatment

• where no standard treatment, control may given none or may be given placbo

importance of controlled trial

• understand if new drug better than standard

• esp bc standardised more likely to be off patent, meaning cheap, whereas new one probably controlled by pharmaceutical company which cld cost fortune, so need to ensure doing smth better than standard treatment

what point have a lot of Alz drugs failed + impact?

• at controlled trials

• costing billions of pounds

• found it works in preclinical models, e.g mice

• but not translated

blind trial

Ps not told which group they are in

blind trial challenges and importance

can be very difficult on patients and families, especially if complicated and/or life threatening disease, bc dk if recieving poss treatment or placebo

protect integrity of trial

doubled blind trial

means Ps and teams treating them do not know which group they are in

→ takes away bias of treatment team treating patient in terms of hoping going to work

what is important re blind trial

for all groups not to know or guess which one they are in - treatments must look identical

randomisation

• essential and usually assigned by a computer

• ensures no biases and groups have similar mix of age,sex, health state

• with random allocation- if one groups does better than the other, likely that treatment is working

• if left to doc to assign, may be influenced by putting treatments think will respond into treatment group - biasing outcome

informed consent

• researcher shld always ask ur consent and permission to enter u into a clinical trial

• cannot be entered into one without consent

• few exceptions

exceptional circumstances re informed consent

children and other vulnerable groups who lack capacity:

consent process may be different and ppl may be entered into trial w/o their consent, e.g.:

• treatment of severe head injuries

• dementia

if patient lacks ability to give consent

→ in these examples, relatives or other legal representatives play a key role to safeguard inclusion of those who cannot consent

exceptional circumstances re informed consent- children

• process involving children is different and has to be fully explained by trial recruiter

• in these cases the P or representative must be told:

1. the aim of the study- what it is trying to find out

2. how u will be treated

3. what u will need to do to stay in trial- commitments

4. what possible risks and benefits are

• enough info needed to allow deciison to be made to give ur informed consent

• questions shld be encouraged + time given to make decision + no pressuring/coercion to family or anyone, regarding time to decide or space to decide etc

→ language right when beginning recruitment

issue w post treatment

sometimes drugs are shown to work, but regulatory panel in uk- NICE, say they are too expensive for small amounts of benefits they produce

in these cases, patient shld be given option to buy it outside of NHS

problem is, e.g. w alz drugs in states, u can buy in uk but costs 50k. option is there if have resources to get it but not accessible.

ethical issue re inequalities in healthcare bc only rich can afford the treatments

big problem going forward too

NICE is there to keep level playing field so if something is effective even if it costs mills it will go on NHS

but bc not endless money, NICE difficultly balance and weigh up between drugs worth it for population of uk as a whole

leaves some without support

confidentiality

• all info kept confidental

• reason partially for ethics application

• is data on subjects going to be anonymised, how to store it, any chance of data leaks etc?

• if funded by MRC, have criteria for gov funded research where must keep data secure in its original format for over 10 years and also make that accessible to anybody else that wants it

• open science

case where clinical trial went terribly wrong everywhere (except the usa)

thalidomide 1960s

thalidomide 1960s

• “one of darkest episodes of pharmaceutical research history”

• drug marketed as a mild sleeping pill safe for even pregnant women in late 1950s

• as it seemed to reduce morning sickness, many pregnant ppl took it

• caused thousands of babies worldwide to be born with malformed limbs

• during testing process on animals, no tests were included to look at effects on pregnancy

• damage revealed in 1962- before then, every new drug was seen as beneficial

• hwvr, thalidomide been shown to reduce the symptoms of leprosy and still used to treat it

• in usa: boss of FDA, frances kelsey, despite huge pressure from pharma industry refused a license bc she felt insufficient evidence for its safety- john f kennedy praised her as national heroine

big issue w thalidomide

• preclinical testing

• not tested on pregnant animals

• missing chance to identify if something very wrong with drug

• in usa- thousands of baby saved but only by one strong woman, needed more robust clinical trials

cost of clinical trials

• very expensive

• calculated that avg cost of a 5.5 year non pharmacological clinical trial involving collecting data across 20 centres in uk (stage 2 or 3) wld cost on avg, £1 million to administer

• staff needed were highest costs, including managers, researchers, statisticiains, around 30% costs for non-staffing expenses like ethical approval

• in uk, price of taking a drug from development to market is £1.1 billion

• 1/10 drugs make it thru to stage 4 in clinical trials

• partially explains why drugs developed are so expensive- bc companies have so many failures

calculated that avg cost of a 5.5 year non-pharmacological clinical trial involving collecting data across 20 centres in uk (stage 2 or 3) wld cost on avg…

£1 million to administer

in uk, price of taking a drug from development to market is

£1.1 billion

how many drugs make it thru to stage 4 in CTs?

1/10

highest cost in clinical trials

staff needed, including managers, researchers, statisticiains,

around 30% costs for non-staffing expenses like ethical approval

also reducing dropout rate- big issue

what is changing in uk re pharmaceutical research and why?

• the whole pharmaceutical research structure has changed bc it nearly bankrupted them

• what they r changing to now, a lot of the big companies like Pfizer, AstraZeneca- they are actually closing down

• was a massive site in Alley Park, one of biggest non-uni scientific centres in country all owned by AstraZeneca- now moved to cambridge

• so now moving closer to big unis, bc unis can do a lot of the research, the preclinical stuff, and potentially for cheaper than a pharmaceutical company

• and if that collaboration is better, that will ensure that the drugs won’t cost 1.1billlion

• bc seen that it is too big a gamble for the pharma companies sometimes, bc once the drug comes thru, they have abt 10 years when they have the patents to make as much money as poss from that one drug and then fund the other drugs coming up

taking a step back- crucial process linked to clinical trials

drug discovery

→ important essential bc otherwise wld not have compounds/meds to test

valley of death

process of going from drug discovery to developing a new medicine

drug discovery vs clinical trials re cost

DD almost as expensive, esp getting data, and also has high failure rate

controversy + overview of current debates in field of drug discovery

• problems where it has gone v wrong, how to make better

• current play of field cld mean end of research done with mouse models of disease

• cld not be a bad thing in terms of moving towards more patient cell-based systems- modern way

• organ on a chip , brain organoids

• things done now at SITran

• gearing up for drug discovery process

• part of research taking cell from forearm of MND or PD or Alz , take cell, and repurpose it back into a stem cell, differentiate it in a dish into a neuron/astrocyte - do research on cell based systems or even grow into mini brains if want to

• sidestepping animal research bc human based cellular research

• big advantages to that

• one argument for value of animal research is in Jason research for example bc cannot get nice blood flow or cerebral blood flow in cell based system on a chip

• altho ppl trying to build those too- artificial blood vessels based on human tissue

• dynamic area of research + lots changing

• pressures - lots of cmpanies developed to stem cell based research

• Animal Rights lobby do not believe animal research shld progress

• tensions which cld mean in NIH if doing prelin like him, must link to some human researchers → he thinks good think bc helps drug discovery and clinical trial process get more accurate results that do relate to humans

• in gov, trying to reduce animal research by 30% in next 10 years

• mistakes made via animal reseach, e.g. thalimode

big debate

research process

T0: Basic Science Research

• preclin and animal studies

• defining pathology, mechanisms, targets, lead molecules, initial regulatory interaction

T1: Translation to Human

• phase 1 clinical trials

• safety, proof of mechanism, and proof of concept, pk/pd

• new methods of diagnosis, treatment, and prevention

T2: Translation to Patients

• phase 2/3 clinical trials

• dose selection, proof of efficacy, safety

• controlled studies leading to effective care, benefit/risk profile, health economic data

T3: Translation to Practice

• phase 4 clinical trials and clinical outcomes research

• delivery of recommended and timely care to the right patient, post marketing safety, new indications

T4: Translation to Community

• population level outcomes research

• true benefit to society

T0

Basic Science Research

• preclin and animal studies

• defining pathology, mechanisms, targets, lead molecules, initial regulatory interaction

T1

Translation to Human

• phase 1 clinical trials

• safety, proof of mechanism, and proof of concept, pk/pd

• new methods of diagnosis, treatment, and prevention

T2

Translation to Patients

• phase 2/3 clinical trials

• dose selection, proof of efficacy, safety

• controlled studies leading to effective care, benefit/risk profile, health economic data

T3

Translation to Practice

• phase 4 clinical trials and clinical outcomes research

• delivery of recommended and timely care to the right patient, post marketing safety, new indications

T4

Translation to Community

• population level outcomes research

• true benefit to society

where do the valleys of death fall

• translation from basic science to human studies

• between T0 and T1, T1 and T2, T2 and T3, T3 and T4

• gap between academia and industry in translational science, education, academic drug discovery centres, business incubators/accelerators, academia, industry consortia where research dies-

causes of the valley of death

• reproducibility

• clinical relevance

• structural

• investigator base

• technical expertise

• support

• intellectual

• regulatory

• privacy issues

• funding

• incentives

• risk

• collaboration

• follow through

• time

steps in the drug discovery process

• discovery

• → screening

• development

• → in vitro and in vivo testing

drug discovery - discovery

typically, researchers discover new drugs thru:

• new insights into a disease process that allow researchers to design a product to stop or reverse the effects of disease

• many tests or screening of compounds to find the possible beneficial effects against diseases

• repurposing/orphan drugs: existing treatments that have unexpected effect against new disease → cld be quick route to clinic as often these drugs been safely tested already

• proved true for potential covid19 treatments- vaccine methods that r already proven to be safe

• new technologies- e.g. those providing new ways to target the medicine to specifics sites within the body, i.e. across BBB

• at this stage- thousands of compounds may be potential candidates for development

• after early testing, only a small number of compounds deemed promising + req further study

example method of drug screening

1. target validation: genetic, cellular, and in vivo experimental models to id and validate target

2. compound screening: HTS and selective library screens; structure based design. reiterative directed compound synthesis to improve compound properties

3. secondary assays: in vitro and ex vivo secondary assays (mechanistic). selectivity and liability assays.

what does this show?

where is the point between discovery and development?

• shows example of steps in drug discovery process

• first three steps- example method of a drug screening (discovery)

• last two steps- development

what is HTS

high throughput screening

test 100,000s of compounds against ur cell/animal model of choice

see which ones have effect u want without causing any toxicology problems

assess function of ur cell of choice e.g. astroyctes, measure activity, see which drugs have toxic effects

minaturisation of screening

development- drug discovery

once researchers ID’d promosing compound for development, conduct experiments to gather info on:

• how it absorbed, distributed, metabolised, and excreted

• potential benefits and mechanisms of action

• best dosage

• best way to give drug

• how toxic the drug is

• how it interacts w other drugs and treatments

• how it compares to existing drugs

toxicity

potential (of a drug) to cause serious harm

two types of preclin research used to assess toxicity

• in vitro

• in vivo

in vitro

often looking at how cells in a test tube are effected by the treatment

in vivo

often involving small animals (usually mice, but some studies, esp brain diseases, non human primates may be used in later stages)

GLP

• good laboratory practices

• strict guidelines for preclin labs to adhere to

• aims to standardise approaches and method

GLP sets minimum basic requirements for…

Study Conduct

• personnel- training of staff

Facilities

• equipment- safe and rigorously checked

• written protocols for all experiments

• standard operating procedures- minimising experimenter error

• clearly writing study reports

• quality assurance oversite for each program of work - ethical approval

preclin studies- size, info, etc

• usually not large

• must provide detailed info on dosing and toxicity levels

• after preclin testing, review findings and decide whether to proceed to clinical trials

why do clinical studies fail? example from stroke research

• accurate and repeatable strokes can be caused in rodents

• hwvr, systematic review of literature showed that:
  over 800 drugs been tested on animal models → 500 work in reducing stroke effects →100 went to clinical trials → only one become treatment

• randomised and blinded experiments had less favourable results

• of 100 studies examined in a diff study, only 36% were randomised and 11% blinded- these are routine in clinical trials

why do clinical studies fail? example from alzheimer’s disease therapy research

• billions £s investment - no disease-modifying alz drug has been developed, just 2 drugs slowing it down on market

• many clinical trials failed, cld be bc:

• wrong targets- most focus on beta amyloid plaques, cld be smth else, e.g. blood supply

• interventions cld be too late- damage already done

• early biomarkers needed- existing treatments cld be re-examined

• clinical trials often <5 years- for alz, might not be long enough, but longer trial far more expensive

• complex and difficult problems to solve

• large cohort human studies may help esp in early biomarker detection

what era are we entering?

dig data era + its powers

large cohort human studies in AD

• many underway

• one of largest is Alzheimer’s Disease Neuroimaging Initiative - ADNI (USA)

ADNI

• what is it

• budget

• what does it collect

• tests include

• large cohort study in AD

• alzheimers disease neuroimaging initiative

• astronomical budget

• so far, $218m: multi modal data from elderly controls and AD patients

• tests include:

1. detailed history of each patient and assessment of health and education

2. neuropsychological tests

3. genetic testing for risk factors- APOE4

4. lumbar puncture- CSF measurement

5. MRI + fMRI

6. PET for glucose consumption, tau, and beta amyloid

7. post mortem histology

does the ADNI approach work?

• yes

• Clifford Jack Diagram- theoretical figure of what shld be produced by all the ADNI studies: a complete time line of disease progression and potential to donate early biomarkers at critical time points for intervention

• 3393 papers been published from ADNI studies and keeps growing

a: Clifford Jack Diagram- theoretical/hypothetical model of late onset alzheimers disease progression

b: data driven model of late onset alzheimers disease progression

hc - healthy control

emci- early mild cognitive impairment

lmci- late mild cognitive impairment

load- late onset alzheimers disease