Dementia TREATMENT Research Update 2019

Dr. Jared R. Brosch, M.D., M.Sc.Associate Professor of Neurology

Associate Program Director Neurology ResidencyIndiana Alzheimer’s Disease Center

Do Not Replicate without Permission

• Disclosures– Dr. Brosch receives support from the following companies for

dementia clinical trial work:• Abbvie• Accera• Axovant• Avanir• Biogen • C2N/Abbvie• Eisai• Eli Lilly• Genentech• Roche• Lundbeck• Chase Pharmaceuticals• TauRx

– I use images in this presentation that are freely available and give credit with URLs to the image

• Objectives

– Lifestyle Hot Topics– Alzheimer’s drug development– Other Neurodegenerative diseases

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• Three Major Studies Show Lifestyle Matters!!

https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png

• Three Major Studies Show Lifestyle Matters!!

https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png

• 2.5 hours a week of moderate intensity exercise.

• 20-30 minute blocks of time• Brisk walk• Elliptical• Recumbent bike• Zoomba• Pickleball• Any activity that gets heart rate elevated

for 20-30 minutes• Some reports that FAR LESS than 50% of

all those over 60 years of age achieve this goal.

• Three Major Studies Show Lifestyle Matters!!

https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png

• Mediterranean Style Diet• VEGETABLE based diet• DE-EMPHASIZE: red meat, butter,

cheese, pastries, sweets, simple carbs• Healthier protein choices – vegetable

protein, fish/chicken• Mixed nuts• Legumes• Healthy oils – olive oil

• Three Major Studies Show Lifestyle Matters!!

https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png

• Cognitive Exercise• 20-30 minutes a day• NOT TV WATCHING• Many studies used computer based

games• No clear evidence on what is best• Social activity may count!• Crosswords, Sudoku, Word finds,

workbooks• Art projects

• Three Major Studies Show Lifestyle Matters!!

https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png

• No smoking• Enough said• Probably affects cognition through

vascular disease• Potent known vascular risk factor

• Three Major Studies Show Lifestyle Matters!!

https://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://cdn.prod-carehubs.net/n1/802899ec472ea3d8/uploads/2018/02/an-illustration-of-equivalent-amounts-of-beer-hard-alcohol

• Zero or Moderate Alcohol consumption• Don’t start drinking now• If you do, limit to ONE DRINK per night• If you skip a few nights, try not to “catch

up” for the week• No safe known amount of alcohol for

the body/brain• Seems to have some cardiovascular

benefit in low amounts, perhaps may help with cerebrovascular blood flow

• AREA OF UNCERTAINTY

• Three Major Studies Show Lifestyle Matters!!– FINGER STUDY

• Finnish Geriatric Intervention Study, 1300 people• 25% improvement in test scores, could delay onset and

reduce burden of AD– UK STUDY

• 200,000 adults >60yrs of age• 32% reduction in risk of dementia over 8 years

– RUSH STUDY• 2000 people• 60% reduction in rate of developing AD over 6-9 years in

people who adopted all lifestyle changes REGARDLESS OF GENETIC RISK PROFILE!!!

https://jamanetwork.com/journals/jama/article-abstract/2738355?guestAccessKey=c635f7cd-e7f5-4956-85f1-71950acad390&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=071419https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60461-5/fulltexthttps://www.aarp.org/health/dementia/info-2019/healthy-lifestyle-alzheimers.html

• Drug Development Update– Approved Drugs WORK

• Donepezil (Aricept)• Rivastigmine (Exelon)• Galantamine (Razadyne)• Memantine (Namenda)

– NOT MEMORY ENHANCERS– Slow progression of Alzheimer’s and prevent need

for nursing home placement by YEARS

• NEW Drug Development Update

https://www.orthocuban.com/2016/08/continuing-debate-over-scientific-research/

• Drug Development Update• 2015 Data

https://browzine.com/articles/54105797

• Drug Development Update

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http://www.nature.com/gim/journal/v10/n4/images/gim200836f2.jpg

Intracellular TAUExtracellular AMYLOID

• Drug Development Update– Amyloid Hypothesis graph

https://www.nature.com/articles/d41586-018-05718-5

• Drug Development Update– Amyloid Passive Vaccination

• Caused meningoencephalitis!– Anti-Amyloid monoclonal antibodies

• Bapineuzumab (brain hemorrhages)• Solanezumab (still in 2 active studies)• Gantanerumab (in 1 active study)• Crenuzumab (in 1 active study)• Aducanumab (terminated?)• BAN2401 (in 2 active studies, and potentially 2 more)• Donanemab (in 1 active study)

https://www.nme.com/blogs/nme-blogs/terminator-6-dark-fate-release-date-cast-trailer-2451500

• Drug Development Update– Picture of Amyloid molecules showing soluble,

insoluble, monomers, polymers

https://www.bioarctic.se/en/alzheimers-disease-2541/

SolanezumabCrenezumab

GantenerumabDonanemabBapineuzumab

AducanumabBAN2401

• Drug Development Update

https://www.bioarctic.se/en/alzheimers-disease-2541/

• Drug Development Update– Aducanumab Announcement Oct 22, 2019

• Futility analysis led to cessation of all trials in 2019• As all data was collected the following was found:

– EMERGE – MET PRE-SPECIFIED PRIMARY END-POINT!!!» HIGH dose group only. CDR 23% better (reduction in

clinical decline) in treatment than placebo, MMSE 15%, ADAS-Cog 27%, ADCS-ADL 40%.

» Amyloid plaque burden reduced, Tau levels in spinal fluid also changed

– ENGAGE – early terminated, but patients who received sufficient exposure to high dose had similar findings

https://www.medpagetoday.com/neurology/alzheimersdisease/82865

• ADUCANUMAB

https://www.nature.com/articles/nature19323

• Drug Development Update– Aducanumab Announcement

• Side Effects– ARIA-E

» Amyloid Related Imaging Abnormalities – Edema• Leads to headaches• Swelling of small areas of brain on MRI scan• Few to no symptoms clinically other than headache• Resolves spontaneously in 4-16 weeks• Most without any long-term issues

https://www.quora.com/What-is-ARIA-E-And-how-does-amyloid-beta-and-tau-immunotherapy-all-relate-to-it

• Drug Development Update– Aducanumab Announcement Oct 22, 2019

• So many things to think about!– First – AWESOME– Second – Who pays? Will this BREAK MEDICARE?– How will people be deemed eligible? Will we need expensive

PET scans to be approved to?– Complicates further clinical trials because now this becomes

the standard of care? – Negative Amyloid PET scans?– Lastly - AWESOME

https://www.bioarctic.se/en/alzheimers-disease-2541/

• Drug Development Update– Secretase inhibitors

https://www.mybraintest.org/2013/lilly-kills-a-bace-inhibitor-trial-for-alzheimers/

• Drug Development Update– Secretase inhibitors

• Gamma– Furthest along was semagecestat (Lilly) – Phase 3– No improvements in cognition, increased infections and rate of

skin cancer– TERMINATED

• Beta (BACE)– Proven in SEVERAL studies to MAKE COGNITION WORSE, no other

significant side effects– Theoretical issues with retinal depigmentation and skin

depigmentation but not seen in humans– Outstanding question is that these may be viable drugs with

lower amount of secretase inhibition, but cold feet

• Drug Development Update– Tau Drugs

• Drug Development Update– Tau Drugs

• Drug Development Update– Tau Drugs

• Anti-Tau monoclonal antibodies– Most in Phase 2– Stopped early in one study in Progressive Supranuclear palsy

(a Tau based disease)– Data slowly emerging in the next year

• Tau passive immunization• Anti-sense Oligonucleatides (ASO) against Tau

• Drug Development Update– Other Drugs

• Phosphodiesterase Inhibitors• Coconut Oil Derivatives• Riluzole derivative• Diabetes drugs (RAGE)• Drugs affecting the Gut Microbiome• Drugs affecting Inflammation• Drugs targeting Immune cells in the Brain• Seizure drugs• Deep Brain Stimulation• Transcranial Magnetic Stimulation• ETC!

• Drug Development Update– Other Drugs

• Phosphodiesterase Inhibitors• Coconut Oil Derivatives• Riluzole derivative• Diabetes drugs (RAGE)• Drugs affecting the Gut Microbiome• Drugs affecting Inflammation• Drugs targeting Immune cells in the Brain• Seizure drugs• Deep Brain Stimulation• Transcranial Magnetic Stimulation• ETC!

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• BEYOND Alzheimer’s disease– Many other neurodegenerative diseases exist and

need support!

http://tbrnewsmedia.com/medical-compass-parkinsons-disease-reducing-risk-and-slowing-progression/https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwii1eOHhbHlAhUET6wKHUVnCEoQjRx6BAgBEAQ&url=https%how-stroke-overview&psig=AOvVaw3qE4v1qjpevEUucHcXtdpg&ust=1571873984490151

Dementia

Alzheimer’sDementia

Parkinson’s Disease Dementia

LewyBody Dementia

Fronto-Temporal Lobar Dementia

Progressive SupranuclearPalsy/CorticobasilarDegeneration

Vascular Dementia

Multiple Systems Atrophy

Many Others!

Dementia Neuropathology

Tauopathies

• PSP• CBD• FTLD with Parkinsonism

(Chr17 – MAPT)• Pick’s Disease

Alpha-Synucleinopathies

• Parkinson’s Disease• Lewy-body

Dementia• Multiple Systems

Atrophy

Amyloid-beta/Tau

• Alzheimer’s disease

• FTLD several forms including:• FTD-ALS C9ORF72 (12/25%) familial (TDP-)• FTD Progranulin (Also Chr17) (TDP+)• FTD-FUS (Fused in Sarcoma) (TDP-)

Other

• BEYOND Alzheimer’s disease– Vascular dementia is #2!

• Can be caused by multiple strokes, or from an accumulation of small blood vessel damage.

• Similar to what is seen in End Stage Multiple sclerosis• Significant gait impairment, bladder dysfunction, severe

slowing of thought process/motor systems.• “Step-Wise” decline – often have abrupt changes in

functionality that don’t improve.• Treat risk factors, keep active• Local Stroke Support Groups (Community, RHI, Franciscan,

etc)

• BEYOND Alzheimer’s disease– Lewy Body Dementia’s

• Parkinson’s disease dementia + Dementia with Lewy bodies

• Hallucinations (starts with visual), Dream Enactment, BIG fluctuations in attention/alertness

• TRADE-OFF’s – treat the Parkinson’s part (worse thinking), treat the hallucinations (worse Parkinsons).

• Profound response to Cholinesterase Inhibitors• Shorter life-span (dementia + mobility/falls!)

• BEYOND Alzheimer’s disease– Lewy Body Dementia’s

• Clinical Trials– 5HT6 drugs (terminated)– 5HT2A drugs (terminated)– Phosphodiesterase Inhibitors (recruiting)– D1PAM drug (recruiting)

• Rock Steady Boxing, The Climb• Local DLB Support Group (Zionsville)

https://consultqd.clevelandclinic.org/research-collaborative-launched-to-advance-progress-against-lewy-body-dementia/

• BEYOND Alzheimer’s disease– Frontotemporal Dementia

• Language Presentation• Behavioral Presentation

– Young, loss of social etiquette, can be difficult to manage in memory care

– Supportive treatments only, other drugs may worsen

• FTD Support Group (Joy’s House)• NEW clinical Trials – Phase 1 – MUST KNOW GENETIC

STATUS!

• Questions?