1. ApoE Gene and Lifestyle Interactions for Risk of Dementia Mortality   Bjørn Heine Strand1, 2, 3, Tor A Rosness1, Knut Engedal3, Per Magnus1, 2, Astrid Liv Mina Bergem4, Henrik Schirmer5, 6, Espen Bjertness1, Gun Peggy Knudsen1 for the GENIDEM-group*. 1. Institute of health and society, University of Oslo, Norway. 2. Norwegian Institute of Public Health, Norway. 3. Norwegian National Advisory Unit on Ageing and Health, Norway. 4. Department of Geriatric Psychiatry, Akershus University Hospital, Norway. 5. Institute of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway. 6. Department of Cardiology, Division of Cardiothoracic and Respiratory Diseases, University Hospital North Norway, Tromsø
NordicEpi 2015, Wed Sept 23rd, 11:15-11:30
Parallell session IV, B18, Bristol Hall 2, Topic: Mental Health.

2. *The GENIDEM-Group
Espen Bjertness (Principal Investigator (PI), University of Oslo)
Tor A Rosness (University of Oslo)
Bjorn Heine Strand (University of Oslo, Norwegian Institute of Public Health and Norwegian National Advisory Unit on Ageing and Health)
Per Nafstad (University of Oslo and Norwegian Institute of Public Health)
Per Magnus (University of Oslo and Norwegian Institute of Public Health)
Kristian Tambs (Norwegian Institute of Public Health)
Gun Peggy Knudsen (Norwegian Institute of Public Health)
Marte Handal (Norwegian Institute of Public Health)
Randi Selmer (Norwegian Institute of Public Health)
Oyvind Nass (Norwegian Institute of Public Health and University of Oslo)
Astrid Liv Mina Bergem (Akershus University Hospital)
Nikias Siafarikas (Akershus University Hospital)
Knut Engedal (Norwegian National Advisory Unit on Ageing and Health)
Grethe S Tell (University of Bergen)
Helga Refsum (University of Oslo)
Jostein Holmen (NTNU)
Henrik Schirmer (The Arctic University of Norway)
Srdjan Djurovic (Oslo University Hospital)
Miia Kivipelto (Karolinska Institute)
Lars Lannfelt (Uppsala University).

3. Acknowledgements
Supported by the Norwegian Research Council (grant No )

4. Background The ApoE gene comes in three types ε2, ε3 or ε4
Carriers of the ε4 allele have increased risk of dementia, while ε2 carriers seem to be protected
Lifestyle related risk factors have been reported to increase dementia risk more among the ε4 carriers than among non-carriers. But studies have small size and power.

5. Aims
1) to investigate the association and interaction between ApoE, risk factors and dementia related mortality, and
2) the possible validation of using dementia related mortality as a proxy for a clinical dementia diagnosis in epidemiological studies.

6. Methods
Stratified nested case control study with 561 cases and 584 controls
ApoE genotyping was performed at the Centre for Integrative Genetics (CIGENE)
Both cases and controls had given informed consent to the study in writing and were ethnic Norwegians
Conditional logistic regression was used for analyses

7. Cases
Cases: Sample among all dementia deaths in CONOR (alive through 2008), either underlyng cause or contributory (N=2095), from 9 birth year strata ( , ,…, )
ICD-codes: ICD-9: 331.0, 294.1, , 797; ICD-10:F00-F03, G30.0-G30.9
A stratified design was used, not one-to-one matching, and hence the amount of cases and controls differs slightly

8. Controls
Alive at and born within same birth year strata as cases.

9. Cases and controls, birth year
Dementia mortality
Birth year
Controls
Cases 80 68 48 43 67 62 47 46 58 57 70 73
133
134 23 21
584
561
1145

11. Covariates Education BMI Cholesterol (total + HDL) Blood glucose
Blood pressure
History of heart disease and or diabetes
Smoking
Physical activity
Mental distress (CONOR MHI-7, above 2.15)

12. ApoE allele freq

16. Discussion
This is one of the largest population-based cases-control studies that has investigated how ApoE interacts with lifestyle-related factors regarding risk of dementia, and it is the first of its kind to use dementia-related mortality as a proxy for a clinical dementia diagnosis.
ApoE ε4 carriers were at more than 2-fold increased odds of dementia related death compared to non-carriers
ApoE ε4 homozygotes were at particularly high risk; 7-8 fold
The ε2-type was associated with a lower risk, about half.
These risk estimates are in line with similar studies with a clinical dementia diagnosis as end point-
Regarding dementia related mortality risk, there was generally no interaction between ApoE and the lifestyle factors, but those with the highest risk were ε4 carriers with several risk factors (ε4 carriers who were ever smokers, hypertensive, physical inactive, and diabetic versus ε4 non-carriers without these risk factors
Nevertheless, ε4 non-carriers having these risk factors had higher dementia related mortality compared to ε4 carriers without these risk factors (OR=3.07, 95% CI 1.11, 8.52).

17. Weaknesses
Using dementia related mortality to study dementia etiology, is hampered by low sensitivity, around 40%, and probably only the most severe cases are included.
On the other hand, specificity and positive predictive values are high ~100%.
Competing risk is an issue.

18. Conclusion
The strongly increased dementia mortality risk for ApoE e4 carriers and the protective effect of e2 carriers resemble reports using a clinical dementia diagnosis as end point.
Secondly, lifestyle-related factors did not interact with the ApoE gene, but when combined they contributed to an increased dementia mortality risk.
Ensuring a healthy lifestyle is important regarding to be able to prevent dementia in population at large, but especially for e4 carriers.

19. Strand BH et al. Dement Geriatr Cogn Disord. 2015;40(3-4):137-47.
Epub 2015 Jun.
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