Current treatments and future prevention of dementia

John O’Brien

Professor of Old Age Psychiatry

University of Cambridge

PM Challenge on dementia 2020. By 2020

• England to be the best place

in the world to undertake dementia research

• 25% of people with diagnosed

dementia on Join Dementia Research (JDR)

• 10% participating in research

(up from 4.5% today)

• On track for cures or disease modifying therapies by 2025

Frau Auguste Deter. (“Auguste D”)

In 1901 aged 51 started accusing husband of having an affair with a

female neighbour

Rapidly increasing memory impairments

“Home life became disordered” for 8 months before Karl asked for help from the family doctor and Auguste was admitted to the

Municipal Asylum for the insane and epileptic in Frankfurt am Main.

Asked to write her name she was unable and said

“I have, so to speak, lost myself.”

Frequently agitated she spent long periods in

the bath and in an isolation room at night

Died April 1906 mute and bedfast with pneumonia and bedsores

Alzheimer reported on a

“peculiar substance in the cerebral cortex”

Cholinergic Loss in AD

Anti-dementia drugs:

a rational therapeutic approach

Currently licenced drugs for AD

• Donepezil (Aricept)• Mild to moderate AD• 5-10 mg od

• Rivastigmine (Exelon)• Mild to moderate AD• 1.5 - 6 mg bd (now daily patch)

• Galantamine (Reminyl)• Mild to moderate AD• now XL dose, 8-24mg od

• Memantine (Ebixa)• NMDA receptor antagonist• Moderate to severe AD• 5- 10 mg bd (now 10-20 mg od)

Broadly similar in efficacy

and side effects

Introduced 1997-2002

No new drug for 15+ years

Treatments since 1997: Donepezil in Mild to Mod AD

Rogers et al, 1998

134 subjects with ADDonepezil 10mg

Placebo

Donepezil

Holmes et al, 2004

Gauthier et al, 2008;

Mecocci et al, 2009

Memantine in Mod to Severe AD: effects on cognition and behaviour

Pooled analysis

The double hurdle

Licensing:

MHRANHS use:

NICE

Effect of dementia severity on ADAS-cog change (n=5216)

Mild

(21+)

N=2218

Moderate

(15-20)

N=2163

Moderately severe

(10-14)

N=835

Meta-analysis

(all drugs)

1.86

(0.83-2.89)

3.98

(3.22-4.74)

5.44

(3.94-6.94)

MCR biostatistics analysis for NICE, Jan 2006, www.nice.org.uk

Benefit of drugs more apparent in non-responders than responders

NICE 2005 re-analysis of responder data

R

NR

0 10 20 30 40 50 60

COG+G+F

COG+G

COG

Patients’ Meeting Definition of Clinical Worsening (%)

P < .0001

* Analysis of clinical worsening at Week 24.

.

51.2%

36.3%

31.4%

16.0%

21.3%

7.2%

Donepezil

Placebo

Proportion With Clinical Worsening (Mild AD, MMSE 18-26)

P < .001

P < .01

Wilkinson D, et al. Dement Geriatr Cogn Disord2009;28:244251

RCT of Rivastigmine in Dementia with Lewy Bodies

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Rivastigmine

Placebo

Change From Baseline–Week 20 on Neuropsychiatric Inventory

Improvement

Apathy

Anxiety

Hallucinations

Delusions

Irritability

McKeith et al. Lancet. 2000;356:2031-2036.NB No drugs are licensed for the treatment

of dementia with Lewy bodies

Cognition Global ADL Neuropsychiatric

symptoms

Galantamine (Gal-INT-06), Erkinjuntti et al,

(n=121 with NINDS/AIREN probable VaD)

No (p=0.06)

-1.8 points on ADAS-Cog

No No No

Galantamine (Gal-INT-26), Auchus et al,

(n=788 with NINDS/AIREN probable VaD)

Yes (p<0.001)

-1.9 points on ADAS-Cog

No No No

Donepezil (307), Black et al

(n=603 with NINDS/AIREN probable or possible VaD)

Yes (p<0.001)

-2.2 points on ADAS-Cog

No Yes N/A

Donepezil (308) , Wilkinson et al

(n=616 with NINDS/AIREN probable or possible VaD)

Yes (p<0.001)

-2.1 points of ADAS-Cog

Yes No N/A

Donepezil (319), Roman et al,

(n=974 with NINDS/AIREN probable or possible VaD)

Yes (p<0.001)

-0.9 points on VADAS-Cog

No No N/A

Rivastigmine (VantageE), Ballard et al

(n=710 with NINDS/AIREN probable VaD)

Yes (p=0.028)

-1.3 points on VADAS-Cog

No No No

RCTs of cholinesterase inhibitors in VaD

O’Brien and Thomas, Lancet 2015

Cognitive side effects

greater in memantine

group

Boxer et al, 2013

Boston naming

test

Digit symbol

substitution

test

Mild Cognitive Impairment

NB No drugs are licensed for the treatment

of Mild Cognitive Impairment

Raschetti et al, 2007

D + M

P

D

M

Lopez et al, 2009

Summary of the 4 current anti-dementia drugs

• Work in AD and DLB; not MCI or VaD; make FTD worse

• CholEI effective in mild, mod and severe AD (only licensed for mild to mod)

• No difference in efficacy between donepezil, rivastigmineand galantamine, but SEs differ

• Memantine effective in mod and severe AD, can be co-prescribed with CholEI with added benefit*

• Efficacy worthwhile but modest; “stabilisation/

improvement” equivalent to 6-9 months natural decline

*EFNS Guidelines on co-prescription 2015

Anti-dementia drugs:beyond modest symptomatic improvement

Control AD at time of diagnosis

AD at loss of independence

Brain changes in Alzheimer’s disease

Adapted from Dodel et

al, Lancet Neurology2003

The amyloid cascade

hypothesis of

AD

Inflammation Transmitter loss

12/12 18/12, no

vaccine

18/12, +

vaccine

Schenk et al, Nature 1999

A vaccine for Alzheimer’s disease?

Holmes et al, Lancet, 2008

Salloway et al, 2009

Vasogenic oedema related to Apo E4

(4% if no E4, 33% if homozygous)

Disease modifying trials in AD

Drug and mechanism of action Phase 3 resultsTramiprosate 2007

Abeta aggregation inhibitor

No benefit (Aisen et al. 2011)

Tarenflurbil 2008

Gamma-secretase modulator

No benefit (Green et al. 2009)

Semagecestat 2010

Gamma secretase inhibitor

Significantly worse than placebo, trials halted

Bapineuzumab 2012

Antibody to acids 1-5 of Abeta peptide

Phase 2 studies positive. No benefit in two phase 3

studies, programme suspended in 2012

Solanezumab 2012

Antibody to 16-24 of Abeta peptide

Failed to meet primary endpoint but signal in mild

patients

Solanezumab 2016 Failed to meet primary endpoint

Ongoing trials in dementia

• 25 Phase 3 studies

• 72 Phase 2 studies

• 27 Phase 1 studies

• Targeting amyloid (38), tau (6), inflammation (13), neurotransmitters (20), other

Alz Forum, November 2017

This mutation reduces the production of

Abeta by 20-40% throughout life

Jonsson et al, Nature, 2012

Biomarkers for AD

CSF measures of

A-beta42 and p-tau

Hippocampal

atrophy on MRI

Increased uptake

on amyloid-PET

Hypometabolism

on FDG PET

Increased uptake

on tau (AV1451) PET

Bateman RJ et al. N Engl J Med 2012;367:795-804.

Relationship between AD biomarkers

Sevigny et al, Nature, 2016

ARIA:

5% - Placebo

6% - 1mg

13% - 3mg

37% - 6mg

47% - 10mg

• 18 month RCT n= 891 mild

to mod AD

• 2 doses 75mg &125mg

• Drug missed its co-primary

end points of ADAS-COG

and ADCS-ADL

• 30% drop out

AAIC Toronto July 2016

LMTX (anti-tau) study in AD

30 subjects with AD, first in man study

29/30 developed anti-tau antibodies

No cases vasogenic oedema

One case worsening microbleeds

Ongoing phase 2 in AD (ADAMANT)

Prevention

Villemagne et al, Lancet Neurol, 2013

Amyloid β deposition in Alzheimer’s disease: a prospective cohort study

PREVENT Dementia study (sporadic dementia)

• 4 site study, Cambridge, Imperial, Oxford, Edinburgh

• Aim to recruit 600-700 cognitively normal 40-59 y.o.

• 50% group at increased risk of dementia (one or both

parents have dementia)

• 50% group at average risk (neither parent has dementia)

• Comprehensive assessment over 3-4 visits

− Baseline physical, cognition, blood, urine and salivary

− Multi-modal 3T MR scan

− Lumbar puncture for CSF

− Additional amyloid imaging and 7T MR planned

• Follow-up at 2 and 5 (and 10) years

Ritchie et al, Alz and Dementia, 2017

No FH n=107 FH n=103 Sig

Age 52.7 53.3 ns

Female 69% 72% ns

Postgrad education 26.4% 39.8% P=0.003

Hypertension 16.8% 17.5% ns

Diabetes 2.8% 6.8% ns

Depressive symptoms 17.8% 15.5% ns

ApoE4 28% 45% P=0.01

Mean age dementia diagnosis in parent = 72 years

Results from first 200 subjects

Hippocampal subfields segmentation

1. Subiculum, 2. Entorhinal cortex (ERC), 3. Cornu Ammonis 1 (CA1) subfield, 4. Cornu

Ammonis 3/dentate gyrus (CA3/DG) subfield 5. Cornu Ammonis 2 (CA2) subfield

Su et al, in preparation

★★★★

• Significant atrophy of the subiculum (p=0.0061) in

subjects with FHSu et al, in preparation

…

…

Learning Phase (37 indoor, 38 outdoor)

Testing Phase (75 old, 25 new)

time

time

3s

2s

3s

2s

Counter-balance L and R hands

Randomized stimuli order

ERS Results

hippocampus

parahippocampus

Su et al, in preparation

Risk and protective factors for Alzheimer’s disease (and other dementias)

• Increasing age

• Female sex

• Down’s syndrome

• Autosomal dominant AD genes

• ApoE4 genotype

• Other risk genes

• Previous head injury

• Past history depression

• Hypertension

• Diabetes

• Smoking

• Obesity

• Stroke

• Raised cholesterol

• Raised homocysteine

• Low educational level

Protective factors (?)

• Exercise

• Diet

• Education

• Statins

• Prior NSAID use

• Hormone replacement therapy

• Social/ mental activities

Study of 7,500 people

Odds ratio 0.7

Lancet 2013

Prevalence of dementia decreased from 30% to 22% over 22 year periodRegression analysis showed effect driven by higher education and reduction in dementia after stroke

Skoog et al, Scientific Reports, 2017

Effects of anti-hypertensives on cognition

Levi Marpillat et al J Hypertension, 2013

Angiotensin Receptor blockers (ARBs) most effective

Effects on preventing dementia

Levi Marpillat et al J Hypertension, 2013

Livingston et al, 2017

Estimated that

one third of all dementia due to

potentially

modifiable risk factors

Pre-DIVA sudy

Also 7y outcomeVan Charante et al, Lancet 2016

Cluster RCT of usual care v 4 monthly Visits to optimise vascular risk reduction

Sig differences between groups in BP and Cholesterol but very small (1.5mmHg)

FINGER study

• FINnish Geriatric intervention study to prEvent cognitive impaiRment and disability (FINGER). CI Mia Kivipelto.

• 1260 people aged 60-77, not demented but high “risk score” (> 6)

Also 7y outcomeNgandu et al, Lancet 2015

FINGER study

Also 7y outcomeNgandu et al, Lancet 2015

OR NTB 1.35 (p=0.04)

Conclusions

• Current symptomatic treatments with modest benefit exist for

Alzheimer’s disease and Lewy body dementia only

• Search for disease modifiers has proved elusive – things that

cure Alzheimer’s in mice have not translated to man

• Pipeline remains strong, with studies moving earlier in disease and aimed at other targets (tau, inflammation)

• Argument that new targets are needed (Dementia Research

Institute)

• Preventative strategies likely need to start in or before mid-life

• Best evidence for controlling vascular risk and exercise; curry, red wine, Mediterranean diet and crosswords may help!