Alejo Nevado-Holgado, Simon Lovestone’s team, University of Oxford

1. The inflammation component of AD
Imperial College London
April 24th-25th
Alejo Nevado-Holgado,
Simon Lovestone’s team
University of Oxford

2. What is the inflammatory component?
• Inflammation: It is the so-called unspecific part of the immune system,
which responds in the same manner to all health threads such as injure,
infection, toxins…
• Link to AD: A central role for inflammation in AD has long been suggested
(Akiyama2000). Evidence coming from multiple sides:
•  Tissues: Seen in the behaviour of microglia (Prinz et al. 2011), cytokines
(Swardfager et al. 2010), chemokines (Cartier et al. 2005) and complement
molecules/receptors (Harold et al. 2009; Lambert et al. 2009) during AD
•  GWAS: Inflammatory genes are among those showing the highest odds
ratio for AD (Jones et al. 2010, Hardy 2015).
•  Epidemiology: Prior history of inflammatory drugs (Wang et al. 2015) and
diseases (McGeer et al. 1996, Wallin et al. 2012) affect AD risk later in life.

3. Tissue studies
• Microglia are the main brain white cells. They have an important role on Aβ
and tau clearance (Prinz et al, Nat. Neurosci. 14, 1227-1235).
• Chemokines are signalling proteins used by the immune system. Their
receptors are localised in microglia and other white cells, and they can
trigger cell death (Cartier et al, Brain Res, 48, 16-42).
• The complement system are a group of small proteins that potentiate the
immune reaction. GWAS studies very often point to this system (Nat. Genet.
41, 1088-1093).

4. GWAS studies
• GWAS studies find which SNPs (1 letter mutations) appear most frequently
in people with AD. The genes most frequently found are from: (1) vesicle
recycling; (2) lipid metabolism; and (3) inflammatory system. (Jones et al. 2010
PLoS One 5, e13950; Hardy et al, J. Internal Med. 275, 296-303).

5. Epidemiology studies
• People regularly taking NSAIDs earlier
in life, have fewer risk of developing AD
(J Alzheimer's Dis. 44, 385-396).
• The longer and earlier taking NSAIDs,
the better.
• However, using NSAID as a therapy is
not effective (Schneider et al, J Internal Med,
275, 251-283).

6. Epidemiology studies
• Rheumatoid arthritis late in life decreases AD risk.
• But rheumatoid arthritis earlier in life may increase AD risk.
Citation Design ADs / controls OR
Graves et al 1990 Case control of AD 130 / 130 1.18
French et al 1985 Case control of AD 78 / 156 0.62
Heyman 1984 Case control of AD 40 / 80 1.19
Broe et al 7 Case control of AD 170 / 170 0.56*
Li et al 8 Case control of AD 70 / 140 0.16*
Can Health 10 Case control of AD 201 / 468 0.54*
Breitner et al 11 Case control of AD 50 / 50 0.64
Jenkinson et al 14 Case control of AD 96 / 92 0.17*
Lindsay et al 2002 Random population based 194 / 3894 0.6
Tyas et al 2001 Random population based 36 / 658 0.81
McGeer et al 4 Random population based 29 / 7461 0.15
Myllykangas et al 16 Random population based 2 / 1613 0.23*
Beard et al 15 Random population based 23 / 498 -
Wallin et al 2012 Random population based (20 yrs) ? / 1449 2.46*

7. Epidemiology studies
• Gout has also been studied, but
much less than rheumatoid arthritis
or NSAIDs.
• A matched population study with
Taiwan data found no Gout-AD
effect (989 patients, 3956 controls)
(Shin-Wei et al, 2013, Int J Geriatr
Psychiatry, 28, 1205-1206).
• A matched control study with UK
data found Gout-AD effect (2251
patients, <250000 controls, odds
ratio 0.76) (Na Lu et al, 2015, Ann
Rheuym Dis).

8. Our project
• The presented results make very clear that there is an inflammation-AD
link, and that this link has a crucial role, but they say very little about the
nature of this link.
• To learn about the nature of the link, we would need to answer:
•  What other inflammatory diseases, drugs and genes alter AD?
•  Through which mechanism do they produce this alteration in AD?

9. Our project
Investigating the inflammation link
• Three levels approach:
diseases, drugs and genes
• Using two types of data: EHRs
and -omics
• EHRs: ideal for diseases and
drugs, but more difficult to
access
• Omics: The only ones for
genes, and easy to access
(ArrayExpress & GE-omnibus).
• We can also address some
aspects of drugs and diseases
with the omics data.
Fig. NSAID data power in Rotterdam cohort(Veld 2001
New Eng J Med) ANM and UK biobank.

10. Our project
• EHRs: ideal for diseases and
drugs, but more difficult to
access.

11. Our project
• Omics: The only ones for
genes, and easy to access
(ArrayExpress & GE-
omnibus).
• We can also address
some aspects of drugs
and diseases with the
omics data.
Fig (↗). Over-respresentation analysis ran
on the genetic multi-signatures. The multi-
signatures capture which genes may
potentially link AD with each drug.

12. Our project
• We can run our analysis with different prior inflammatory drugs or
diseases, and with different tissues of AD patients:
•  Blood data: 600 samples. Looking for more.
•  Brain data: 300+600 samples. More are accessible.
• Next, we would like to compare these results with epidemiological data.
Fig (←). Inflammation link in
AD brain
Fig (→). Inflammation link in
AD blood

13. Simon’s team:
Jessica Ash
Ben Liu
Alison Braid
Elena Ribe
Corinne Prescot
Laura Thei
Sarah Westwood
And of course, Simon Lovestone
The EMIF team for Inflammation:
Usha Gungabissoon
Donal Skelly
Angelika Wientzek
Mark Gordon
Meritxell Sabido
Sandra Guedes
Many thanks to: