AD - AAIC plenary session notes from D. Sherman of Lifesci capital.
Plenary Session: Multidomain interventions to prevent cognitive impairment and dementia
Dr. Miia Kivipelto
Treatment for AD is now largely preventative
Increasing evidence from experimental and epidemiological studies that AD is complex and multifactorial. There are multiple disease mechanisms and there are likely mixed pathologies.
There are several modifiable risk factors over the whole course.
Altogether, estimated that at least 30% of AD cases are related to 7 risk factors – diabetes, hypertension, obesity, depression, smoking, low education, physical inactivity
Both pharmacological and non-pharmacological interventions are starting earlier.
It may be that we need to target risk factors and mechanisms simultaneously to get optimal preventative effect
But also, one size does not fit all, need to tailor intervention to individual’s specific risk profile
WHO – highlighting prevention as one of the key elements for preventing global epidemic of AD
Very little evidence from low and middle-income countries. Quite little evidence from RCTs. May not be feasible to get evidence for several of these risk factors in trials. May want to add cognitive outcomes in other trials
How can we consider the evidence from multidomain interventions, which are coming from new studies?
Have some positive signals from trials looking at physical activity, cognitive training and certain dietary patterns
And then have multidomain trials where tried multiple things – FINGER, MAPT, pre-DIVA
FINGER – first large multidimension trial looking at diet, exercise, cognitive training and vascular risk monitoring compared to control people
Looked at at-risk people
2-year intervention and now in long-term follow up
Multidomain – used group and individual training
Summary of primary findings- Ngandu et al 2015
Intervention group had lower risk for cognitive and functional (IADL) decline, better health-related QoL
ApoE E4 carriers saw clear benefits of these interventions. ApoE E4 carriers may be more sensitive to harmful lifestyle factors.
New findings show that FINGER intervention seems to counteract shortening of telomeres among ApoE E4 carriers
Intervention group also had lower risk for multi-morbidities and lower rate of hospital days (20% lower)
MAPT Trial in France
Primary outcome was cognition. Not met.
However, in subgroups, saw some benefit for intervention group
preDIVA trial – all elderly persons were included, no risk-based selection
multi domain intervention – lifestyle and drug treatment over 6 years
primary endpoint was dementia incidence. This was not met.
people who had untreated hypertension exhibited lower dementia incidence
take together all 3 big trials, have over 6000 participants.
So far have learned 3 important things: timing is critical, focus on at-risk individuals, interventions must be “doing the right things and doing enough of them”
Initiated World-Wide FINGERS – trying to use similar methods but still adapting them to fit the needs of individual countries.
US POINTER – try to replicate FINGERs trial as much as possible. 60 – 79 yo, 2000 patients, normal cognition but increased risk, have self-guided lifestyle intervention (education and support, guideline-based health coaching) and structure lifestyle intervention (exercise, nutrition, cog stimulation)
MIND-CHINA – 60 – 79 yo, 3500 patients. Have 2 diff multidomain arms. One is multimodal intervention (focusing on lifestyle aspects in China, such as high salt diet and smoking) and one arm focusing on vascular risk factors.
SINGER in Singapore – first during a feasibility study to see what is most fitting for that culture and setting.
Great hope for blood-based biomarkers. If can start using it, would be helpful for FINGERS study.
GWAS may be helpful for clinical trials too. Want to start using big data in clinical trials.
Tools for combined prevention trials – lifestyle + Disease-modifying drugs together
Developing tools to get there now
MIND-AD pilot trial – combining multidomain lifestyle intervention with medical food. Have hypotheses to believe that there may be synergistic effects.
Do we have some good candidates for disease modifying drugs?
Target population has become more specific
Altogether, more than 200 drug failures in past 30 years, may in Phase 3. A lot of new Ph2 trials too.
In new trials, starting earlier, using adaptive design, more phenotyping
One example is EPAD in Europe – recorded more than 800 people in longitudinal cohort study.
From FINGER simulations – see that there may be cost savings and large societal effects with this type of intervention
Using E-health and M-health tools to support intervention
Take home “action points”:
Multi domain interventions seem effective and feasible
Need more tailored interventions for specific at-risk profiles. Hopefully can combine pharm and non-pharm interventions
Global collaboration is necessary – sharing data, joint projects.
