2. Alzheimer’s disease under the sex and gender lens:
the gateway to precision medicine
Dr. Antonella Santuccione Chadha, Women’s Brain Project
The information and views set out in this presentation are those of the author and do not necessarily reflect the official opinion of Roche Diagnostic, which is the official employer of Dr.
Santuccione Chadha
DayOne Basel Expert Event 26th of February 2019

3. Post-mortem definite diagnosis
N
Neurodegeneration
A
Amyloid plaques
T
Tau neurofibrillary tangles
www.sciencemuseum.org.uk
Neuropathological AD signature (ATN)

4. Alzheimer’s- a devastating neurodegenerative disease
with no cure
‘I lost myself’ (Auguste Deter)
•Age. Your risk for Alzheimer's goes
up as you get older. For most
people, it starts going up after age
65.
•Gender. Women get the disease
more often than men.
•Family history. People who have a
parent or sibling with Alzheimer’s
are more likely to get it themselves.
• Down Syndrom. It’s not clear why,
but people with this disorder often
get Alzheimer's disease in their 30s
and 40s.

5. Epidemiological aspects - frequency
63.46%
US
66.6%
Europe
2/3 of AD patients worldwide are women. Are women at higher risk?
Alzheimer Europe, report 2013, Alzheimer’s Facts and Figures 2017; World Alzheimer Report 2015

6. Epidemiological aspects - frequency
WBP

7. Current treatment options for AD

8. Symptomatic treatments and DMTs for AD
Approved symptomatic treatments1* DMTs (all under investigation)1,2
• Cholinesterase inhibitors (donepezil, rivastigmine and
galantamine)
• N-methyl-d-aspartate receptor antagonist (memantine)
• BACE inhibitors (E2609, CNP520, JNJ-54861911)
• γ-secretase inhibitor (NIC5-15)
• Immunotherapy against Aβ
• Active immunisation using full-length Aβ and an N-
terminal Aβ42 peptide (e.g. CAD106)
• Passive immunisation using monoclonal antibodies (AAB-
003, aducanumab, BAN2401, bapineuzumab,
gantenerumab)
• Antioxidants and anti-inflammatory agents
• H3 receptor agonist (SUVN-G3031)
• Tau stabilising agent (TPI287), aggregation inhibitor
(TRx0237), or P-tau clearance agents (AADvac-1 and ACI-35)
• Microglial activation inhibitors (CHF 5074)
• Natural agents/dietary supplements
• *Symptomatic treatments do not affect the disease process, but affect symptoms of the disease with modest clinical effects
• Aβ, amyloid beta; BACE, Aβ secretase; DMT, disease modifying therapy
• 1. Geldenhuys WJ, Darvesh AS. Expert Rev Neurother 2015;15:3–5; 2. Hung S-Y, Fu W-M. J Biomed Sci 2017;24:47

9. Prevention of AD may be possible1
• Delaying AD onset would benefit patients
despite the lack of curative treatments available
• Management of known risk factors including low
education, midlife hypertension and obesity,
poor social engagement, physical inactivity,
smoking and diabetes may prove crucial
• ApoE, apolipoprotein E; DMT, disease-modifying therapy
• Livingston G, et al. Lancet 2017;390:2673–734. Figure adapted from Livingston G, et al. 2017
Potentially modifiable risk
factors: 35%
Late life
5% smoking
4% depression
3% physical inactivity
2% social isolation
1% diabetes
Midlife
9% hearing loss
2% hypertension
1% obesity
Early life
8% less education
ApoEɛ4
7%
Non-modifiable risk factors
65%

10. Preventive strategies
Vascular Risk - FINGER study focused on neuroprotection & neuroplasticity enhancement
(physical training, cognitive training, nutrition) showed a 25% improvement of cognition
within 2 years
•Caerphilly Cohort Study of 2,235 men ages 45-59 Dementia rates declined by 60 percent in those
who ate a healthy diet, maintained normal weight, limited alcohol intake, did not smoke & engaged
in exercises
•Computerized Cognitive Training (CCT) - ACTIVE study (10 yr evaluation) proved that brain
training cuts risk of developing dementia by almost 50%

11. Diagnostic journey in AD

12. An Early Onset Alzheimer’s Patient Journey in Sweden
y journey to figure out what was wrong with me started the summer of 2014. I was
so tired all the time. At the time we lived in the city Varberg in Sweden. I studied at
a university to become a Health pedagog. I went to a doctor and he took some test on me that
showed that I had iron deficiency. So I got some medicine but after 3 month I was still tired. I
started to feel confused and forgetful, I took contact with a new doctor who sent me to a check
of my memory. It went so well that they did not want to continue to investigate what was wrong
with me. I told them about my grandmother, my father and his brother that al died in the disease
so they continued to do test´s. Now I think, I was so early that it would not matter how many test
they would have done. The test to draw a line from A to 1 then B to 2 and so on is still not my
problem. But it was horrible to not be taken seriously. So we moved down south in Sweden to
where I’m from. I contacted my father’s old doctor and he helped me get in contact with the
right people. And so a year and a half after I started, I got my diagnosis. Now I have the most
wonderful team around me. And a couple of days ago I was on a check up at my doctor Moa
Wibom and I have the same test results as I had a year ago. In my world that is great!
M
Sofia Petersson,
41 years, mother of two
teenagers, diagnosed with Early Onset
Alzheimer’s disease
Patient Advocate

13. Evolving Biomarkers Landscape: An example from oncology
NB!
Attend this session at the
2018 ASCO
ANNUAL
MEETING!
TAILORx: Phase III trial of chemoendocrine therapy versus endocrine
therapy alone in hormone receptor-positive, HER2-negative, node-
negative breast cancer and an intermediate prognosis 21-gene
recurrence score.
CHEMOTERAPY NOT NEEDED
®
CANCER RECURRENCE SCORE
11-25

14. Biomarkers in AD

15. Biomarkers in clinical trials
2018, guidance for clinical trials in AD
The use of biomarkers in AD trials is supported by health authorities A significant proportion of patients enrolled in AD
trials have historically been misdiagnosed1
Up to 30% of patients diagnosed with AD did actually
NOT suffer from the disease
Patients
misdiagnosed
in AD trial
30%
Biomarkers
• diagnostic – for determining diagnosis
• Patient enrichment
• Prognostic
• predictive of clinical response to therapy and for safety
assessment
• pharmacodynamic
Until a biomarker will be qualified
as a reliable surrogate measure of
treatment effect in absence of
a clinically observable change,
patients should be followed up for
a sufficient time to capture relevant
cognitive changes.
“In Stage 1 patients, an effect on the characteristic pathophysiologic changes of AD, as demonstrated
by an effect on various biomarkers, may be measured. Such an effect, analyzed as a primary efficacy
measure, may, in principle, serve as the basis for an accelerated approval (i.e., the biomarker effects
would be found to be reasonably likely to predict clinical benefit, with a post-approval requirement for
a study to confirm the predicted clinical benefit).”
1. Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies
•Nelson et al.

16. The sex and gender factor in AD

17. Sex differences in Alzheimer disease – the gateway to
precision medicine WBP pioneering in the discussion
MRI data were collected from the Alzheimer’s Disease Neuroimaging
Initiative cohort and analysed with tensor-based morphometry.
Results are stratified by age ranges and sex.
Faster atrophy (darker blue) was observed in women than in men.
Biomarker-based evidence of prodromal Alzheimer disease was not
available in this study. L, left; R, right. Modified with permission from
Elsevier.
Maria Teresa Feretti , Maria Florencia Lulita, Enrica Cavedo, Patrizia Andrea Chiesa,
Annemarie Schumacher Dimech, Antonella Santuccione Chadha, Francesca Baracchi,
Hélène Girouard, Sabina Misoch, Ezio Giacobini, Herman Depyrere, Harald Hampel & for
the Women’s Brain Project and the Alzheimer Precision Medicine Initiative
Nature Reviews Neurology 14, 457-469 (2018)
Faster atrophy (darker blue) was observed in women than in
men.

18. Symptoms Sex differences in cognitive decline rate
Lin et al., 2015, A&D

19. Biomarkers Sex-differences in the susceptibility to
neuropathology
Accelerated decline in amyloid
positive women.
Buckley et al., A&D 2018

20. Sex differences in Alzheimer disease – the gateway
to precision medicine

21. Symptoms Sex differences in psychiatric symptoms
β=-0.01; p<0.03 β=-0.151; p<0.005
Hollingworth et al., JAGS 2006
Behavioural dysfunction and mood component scores were worse in women than in men

22. 0
10
20
30
40
50
60
70
80
90
100
Per1000personsaged65+
Antipsychotic prescribing rates, by sex
2015 or nearest year
Male
Female
Slide courtesy: Elina Suzuki, OECD Source: OECD Health Statistics 2017
Women receive a higher prescription of antipsychotic

23. The sex and gender factor in AD:
the gateway to precision medicine

24. Conclusions and discussion
• Publication Bias
• Statistical (Methodological
Consideration)
• Lack of control for
confounding factors
• Lack of clinical data from
trials
• Lack of stratification for
menopausal state
Precision medicine‘one size fits all’
medicine

25. Conclusions and discussion
• Include a sex and gender perspective in all dementia and AD awareness campaigns
• Develop and implement dementia policies and plans taking into consideration the specificities of
women
• Promote early diagnosis of dementia to mitigate disease progression and increase quality of life
• Ensure dementia research include a sex and gender approach, including more women in clinical trials
• Raise awareness and promote sex and gender-sensitive precision medicine in the field of neurology
related to dementia
• Disaggregate dementia and brain research data by sex to ensure precision medicine application for
both women and men

26. The II International Forum on Women’s Brain and Mental Health
Sex & Gender Differences in Mental and Neurological Disease:
The Gateway to Precision Medicine.
HOW TO REGISTER: via our website and if you register by Friday 29 March, you’ll benefit from the Early Bird fee.

27. Meet the WBP Team!