Vitamin D and All-Cause Dementia in the Cardiovascular Health Study

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1 Vitamin D and All-Cause Dementia in the Cardiovascular Health Study Dr Maya Soni AAIC Boston, July 2013 No conflicts of interest to declare

6) 3 Cognitive decline in older women (OR = 1.6, 1.

2 Previous research Meta-analyses Lower vitamin D levels in AD 1 Poorer MMSE scores associated with vit D deficiency 1 Higher risk of cognitive impairment with vitamin D deficiency 2 Prospective studies Cognitive decline in older Europeans (RR = 1.6) 3 Cognitive decline in older women (OR = 1.6, 1.3) 4 Incident dementia of non-alzheimer s type but not AD (note: n=40) 5 Vitamin D3, cholecalciferol 1 Balion et al. 2012; 2 Etgen et al. 2012; 3 Llewellyn et al. 2010; 4 Slinin et al. 2012; 5 Annweiler et al. 2011

Potential mechanisms Neurodegenerative Amyloid breakdown/ clearance 1 Age related cognitive decline in rats 2 Cellular

3 Atherosclerotic plaques 4 Protective against stroke 5 1 Masoumi et al, J Alzheimer s Dis 2009, 17(3), 703-17; 2 Briones &

Nephrol 2009; 5 Buell et al, Neurology 2010, 74(1), 18-26; 6 Brewer et al, Cell Calcium 2006, 40(3), 277-86; 7 Cai et al,

3 Potential mechanisms Neurodegenerative Amyloid breakdown/ clearance 1 Age related cognitive decline in rats 2 Cellular environment Calcium homeostasis 6 Nerve conduction 7 Axon growth 8 Inflammation 9 Vascular effects Renin-angiotensin system 3 Atherosclerotic plaques 4 Protective against stroke 5 1 Masoumi et al, J Alzheimer s Dis 2009, 17(3), ; 2 Briones & Darwish, J Neuroinflammation 2012, 9, ; 3 Kestenbaum et al, JACC 2011, 58(14), ; 4 de Boer et al, J Am Soc Nephrol 2009; 5 Buell et al, Neurology 2010, 74(1), 18-26; 6 Brewer et al, Cell Calcium 2006, 40(3), ; 7 Cai et al, Cell Calcium 1994, 15, ; 8 Chabas et al, J Neurotrauma 2008, 25(10), ; 8 Villaggio et al, Clin Exp Rheumatol 2012, 30(6), 934-8

4 Vitamin D and all-cause dementia in the CHS Ambulatory older adults free from dementia, clinical CVD/stroke 25(OH)D measured (LC-MS) in Adjudicated dementia status (DSM-IV) over mean 5.6 years (SD 1.6) Cox proportional hazards models Adjusted for age, season of blood collection, sex, education, BMI, alcohol consumption and depressive symptoms

5 Inclusion in final sample 3,268 Blood draw for vitamin D assay 2,323 2,254 1,658 1, (insufficient serum) 69 (prevalent dementia) 596 (no adjudicated dementia status) 5 (missing education/alcohol data) Final restricted sample

6 Loss to follow up Included participants Lost to follow up Mean age in years (SD) 73.6 (4.5) 74.3 (5.4).005 Education %.02 Did not finish high school Finished high school/some college/vocational Finished college/professional Non-white % <.001 Serum 25(OH)D nmol/l (SD) 65.1 (26.5) 61.1 (39.5).007 p

7 Prevalent all-cause dementia 1,727 participants, 69 with dementia at baseline 10 Relative risk 5 0 <25 25-<05 25(OH)D, nmol/l P for trend = <0.001 Adjusted for age, season of vitamin D collection, education, sex, BMI, alcohol consumption, depressive symptoms

8 Incident all-cause dementia 171 people developed all-cause dementia over a mean of 5.6 years Hazard ratio for all-cause dementia < >=50 Serum 25(OH)D (nmol/l) Vitamin D status (nmol/l) P for trend = % of cohort Sufficient ( 50) Deficient ( 25 to <50) Severely deficient (<25) 4.17 Adjusted for age, season of vitamin D collection, education, sex, BMI, alcohol consumption, depressive symptoms

9 Incident all-cause dementia Sensitivity analyses: Excluding >200nmol/L 3 or 4 groups vitamin D Preliminary analysis, unadjusted model

10 Conclusions

Acknowledgements University of Exeter Medical School Dr David Llewellyn Dr Iain Lang Mr Tom Littlejohns Dr Elzbieta Kuzma Dr Katarina Kos Professor William Henley International collaborators Dr

11 Acknowledgements University of Exeter Medical School Dr David Llewellyn Dr Iain Lang Mr Tom Littlejohns Dr Elzbieta Kuzma Dr Katarina Kos Professor William Henley International collaborators Dr Cedric Annweiler Professor Olivier Beauchet Dr Paulo Chaves Professor Linda Fried Professor Bryan Kestenbaum Professor Lewis Kuller Professor Kenneth Langa Professor Oscar Lopez The Cardiovascular Health Study The Alzheimer s Association (NIRG , travel fellowship)

12 Thank you

14 Sensitivity analysis: vitamin D<200 nmol/l Dementia status All-cause dementia Serum 25(OH)D, nmol/l to <50 <25 HR (95% CI) HR (95% CI) p-value for linear trend Model A ( ) 2.24 ( ) Model B ( ) 2.28 ( ) Model A: adjusted for age and season of vitamin D collection Model B: adjusted for Model A and education, sex, BMI, alcohol consumption and depressive symptoms Abbreviations: HR = Hazard ratio, CI = Confidence interval

15 Sensitivity analysis: vitamin in 4 categories Dementia status Serum 25(OH)D, nmol/l to <75 25 to <50 <25 HR (95% CI) HR (95% CI) HR (95% CI) p for linear trend Model A ( ) 1.41 ( ) 2.07 ( ) Model B ( ) 1.32 ( ) 1.98 ( ) Model A: adjusted for age and season of vitamin D collection Model B: adjusted for Model A and education, sex, BMI, alcohol consumption and depressive symptoms Abbreviations: HR = Hazard ratio, CI = Confidence interval

16 Results: Vitamin D and prevalent Alzheimer s disease AD status Serum 25(OH)D, nmol/l to <50 <25 OR (95% CI) OR (95% CI) p-value for linear trend Model A ( ) 4.02 ( ).01 Model B ( ) 3.54 ( ).03 Model A: adjusted for age and season of blood collection Model B: adjusted for Model A and education, sex, BMI, alcohol consumption and depressive symptoms Abbreviations: OR = Odds Ratio, CI = Confidence Interval

17 Results: Vitamin D and incident Alzheimer s disease AD status Serum 25(OH)D, nmol/l to <50 <25 HR (95% CI) HR (95% CI) p-value for linear trend Model A ( ) 2.29 ( ).005 Model B ( ) 2.23 ( ).009 Model A: adjusted for age and season of blood collection Model B: adjusted for Model A and education, sex, BMI, alcohol consumption and depressive symptoms Abbreviations: HR = Hazard Ratio, CI = Confidence Interval

18 Incident dementia in the CHS: baseline characteristics I Baseline characteristics Sufficient Insufficient Deficient Severely 50 to <75 25 to <50 deficient 75 nmol/l nmol/l nmol/l <25 nmol/l p Age (y), M(SD) (4.15) (4.58) (4.53) (5.17) White race (%) < Women (%) < Education Did not finish high school Finished high school/some college/vocational College/professional Current smoker % (n=1,615) BMI (kg/m 2 ), M(SD) (3.99) (4.26) (5.10) (5.20) < 0.001

19 Incident dementia in the CHS: baseline characteristics II Baseline characteristics Sufficient Insufficient 50 to <75 Deficient 25 to <50 Severely deficient 75 nmol/l nmol/l nmol/l <25 nmol/l p Season tested (%) < Dec-Feb Mar-May Jun-Aug Sep-Nov Alcohol use (%) a Non-drinkers Moderate drinkers Heavy drinkers

20 Incident dementia in the CHS: baseline characteristics III Baseline characteristics Sufficient Insufficient 50 to <75 Deficient 25 to <50 Severely deficient 75 nmol/l nmol/l nmol/l <25 nmol/l p MRI evidence of stroke (%) Diabetes (%) b < Hypertension c Normal Treated Untreated Impaired kidney function d Depression e < APOE allele (n=1,518) Years of follow up M(SD) 5.67 (1.03) 5.63 (1.12) 5.44 (1.37) 5.56 (1.23) 0.025

21 Baseline vitamin D in the CHS Density vd5_nmol Vitamin D status (nmol/l) % of cohort Sufficient ( 50) Deficient ( 25 to <50) Severely deficient (<25) 4.17 University of Exeter Medical School, UK

Vitamin D and the risk of dementia and Alzheimer disease

Published Ahead of Print on August 6, 2014 as 10.1212/WNL.0000000000000755 Vitamin D and the risk of dementia and Alzheimer disease Thomas J. Littlejohns, MSc William E. Henley, PhD Iain A. Lang, PhD Cedric