J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website http://www.jofem.org

Original Article

Volume 9, Number 4, August 2019, pages 82-89

Association Between Thyroid Dysfunction and Incident Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study

Figure 1. Age, sex, race-center, APOE, income, education and TSH adjusted HR (95% CI) of incident dementia in relation to serum FT4*, ARIC, 1990 - 2017. *Analyzed using restricted cubic splines with knots at the fifth (0.90 ng/dL), 50th (1.11 ng/dL) and 95th (1.35 ng/dL) percentiles of the FT4 distribution. FT4 hormone levels were truncated at the first (0.71 ng/dL) and 99th (1.61 ng/dL) centiles to minimize the influence of extreme values. TSH: thyroid-stimulating hormone; HR: hazard ratio; CI: confidence interval; FT4: free thyroxine; ARIC: Atherosclerosis Risk in Communities.

**Table 1.** Baseline Characteristics Stratified by Clinical Categories of Thyroid Dysfunction, ARIC 1990 - 1992
Risk factors	Hypothyroidism	Euthyroidism (n = 10,956)	Hyperthyroidism
Mean ± standard deviation. ^aBased on self-report of some high school education or less at visit 1 (1987 - 1989). ^bBased on self-report of family income at visit 1 (1987 - 1989). ^cDefined as diastolic blood pressure ≥ 90 mm Hg, systolic blood pressure ≥ 140 mm Hg, or use of hypertensive medication. ^dDefined as non-fasting blood glucose ≥ 200 mg/dL, fasting blood glucose ≥ 126 mg/dL, self-report of diabetes, or reporting taking medication for diabetes or high blood sugar. ^eDefined as prevalent stroke, coronary heart disease, myocardial infarction, or atrial fibrillation at visit 2. ^fParticipants who reported thyroid medication use at baseline. ARIC: Atherosclerosis Risk in Communities; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease; TSH: thyroid-stimulating hormone; FT4: free thyroxine; TPO: thyroid peroxidase.
Age, years	58.4 ± 5.4	58.4 ± 5.7	56.8 ± 5.7	56.5 ± 5.8	57.1 ± 5.8
Men, %	22.8	33.4	45.9	33.6	19.7
African American, %	12.8	11.0	25.1	41.5	23.1
APOE4 carriers, %	29.2	29.6	29.9	27.3	28.2
Basic education^a, %	23.1	16.8	21.5	29.2	16.2
Family income < $16,000^b, %	24.2	21.3	25.2	34.3	22.2
Current alcohol drinker, %	48.8	58.7	57.1	49.2	56.0
Current tobacco smoker, %	13.9	12.9	22.3	29.6	25.2
BMI, kg/m²	28.9 ± 5.7	27.7 ± 5.5	28.0 ± 5.4	27.6 ± 5.4	27.4 ± 5.4
Hypertension^c, %	34.1	30.9	35.8	40.0	32.6
Diabetes^d, %	7.5	10.3	11.3	15.9	12.8
HDL cholesterol, mg/dL	49.4 ± 16.6	49.7 ± 16.3	49.4 ± 16.8	52.8 ± 17.9	52.1 ± 15.7
Total cholesterol, mg/dL	229.2 ± 48.9	214.3 ± 41.2	209.7 ± 39.2	208.1 ± 38.0	199.5 ± 35.2
Prevalent CVD^e, %	8.5	8.1	8.8	11.0	9.8
Thyroid medication use^f, %	40.9	28.6	2.8	27.5	71.4
TSH, mIU/L	26.3 ± 32.7	8.0 ± 4.4	2.0 ± 1.0	0.3 ± 0.2	0.1 ± 0.2
FT4, ng/dL	0.7 ± 0.2	1.0 ± 0.1	1.1 ± 0.1	1.2 ± 0.1	1.8 ± 0.6
Anti-TPO positive (> 34 IU/L), %	79.4	51.1	9.3	13.8	27.4

Table 1. Baseline Characteristics Stratified by Clinical Categories of Thyroid Dysfunction, ARIC 1990 - 1992

Risk factors

Hypothyroidism

Euthyroidism (n = 10,956)

Hyperthyroidism

Overt (n = 281)

Subclinical (n = 581)

Subclinical (n = 429)

Overt (n = 234)

TSH > 5.1 mIU/L; FT4 < 0.85 ng/dL

TSH > 5.1 mIU/L; FT4 = 0.85 - 1.4 ng/dL

TSH = 0.56 - 5.1 mIU/L; FT4 = 0.85 - 1.4 ng/dL

TSH < 0.56 mIU/L; FT4 = 0.85 - 1.4 ng/dL

TSH < 0.56 mIU/L; FT4 > 1.4 ng/dL

Mean ± standard deviation. ^aBased on self-report of some high school education or less at visit 1 (1987 - 1989). ^bBased on self-report of family income at visit 1 (1987 - 1989). ^cDefined as diastolic blood pressure ≥ 90 mm Hg, systolic blood pressure ≥ 140 mm Hg, or use of hypertensive medication. ^dDefined as non-fasting blood glucose ≥ 200 mg/dL, fasting blood glucose ≥ 126 mg/dL, self-report of diabetes, or reporting taking medication for diabetes or high blood sugar. ^eDefined as prevalent stroke, coronary heart disease, myocardial infarction, or atrial fibrillation at visit 2. ^fParticipants who reported thyroid medication use at baseline. ARIC: Atherosclerosis Risk in Communities; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease; TSH: thyroid-stimulating hormone; FT4: free thyroxine; TPO: thyroid peroxidase.

Age, years

58.4 ± 5.4

58.4 ± 5.7

56.8 ± 5.7

56.5 ± 5.8

57.1 ± 5.8

Men, %

22.8

33.4

45.9

33.6

19.7

African American, %

12.8

11.0

25.1

41.5

23.1

APOE4 carriers, %

29.2

29.6

29.9

27.3

28.2

Basic education^a, %

23.1

16.8

21.5

29.2

16.2

Family income < $16,000^b, %

24.2

21.3

25.2

34.3

22.2

Current alcohol drinker, %

48.8

58.7

57.1

49.2

56.0

Current tobacco smoker, %

13.9

12.9

22.3

29.6

25.2

BMI, kg/m²

28.9 ± 5.7

27.7 ± 5.5

28.0 ± 5.4

27.6 ± 5.4

27.4 ± 5.4

Hypertension^c, %

34.1

30.9

35.8

40.0

32.6

Diabetes^d, %

7.5

10.3

11.3

15.9

12.8

HDL cholesterol, mg/dL

49.4 ± 16.6

49.7 ± 16.3

49.4 ± 16.8

52.8 ± 17.9

52.1 ± 15.7

Total cholesterol, mg/dL

229.2 ± 48.9

214.3 ± 41.2

209.7 ± 39.2

208.1 ± 38.0

199.5 ± 35.2

Prevalent CVD^e, %

8.5

8.1

8.8

11.0

9.8

Thyroid medication use^f, %

40.9

28.6

2.8

27.5

71.4

TSH, mIU/L

26.3 ± 32.7

8.0 ± 4.4

2.0 ± 1.0

0.3 ± 0.2

0.1 ± 0.2

FT4, ng/dL

0.7 ± 0.2

1.0 ± 0.1

1.1 ± 0.1

1.2 ± 0.1

1.8 ± 0.6

Anti-TPO positive (> 34 IU/L), %

79.4

51.1

9.3

13.8

27.4

**Table 2.** HRs (95% CI) of Dementia by Anti-TPO Positivity Status, ARIC 1990 - 2017
	Anti-TPO negative ≤ 34 IU/L (number of total = 10,821; number of events = 1,932)	Anti-TPO positive > 34 IU/L (number of total = 1,660; number of events = 303)
Model 1: age, sex, race-center, APOE ε4, income and education. Model 2: model 1 + BMI, smoking status, hypertension, diabetes, drinking status, HDL cholesterol and total cholesterol. Model 3: model 2 + prevalent CVD and baseline thyroid medication use. HR: hazard ratio; CI: confidence interval; TPO: thyroid peroxidase; ARIC: Atherosclerosis Risk in Communities; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease.
Model 1 HR	1 (Ref)	0.92 (0.82 - 1.04)
Model 2 HR	1 (Ref)	0.93 (0.82 - 1.05)
Model 3 HR	1 (Ref)	0.90 (0.80 - 1.03)

Table 2. HRs (95% CI) of Dementia by Anti-TPO Positivity Status, ARIC 1990 - 2017

Anti-TPO negative ≤ 34 IU/L (number of total = 10,821; number of events = 1,932)

Anti-TPO positive > 34 IU/L (number of total = 1,660; number of events = 303)

Model 1: age, sex, race-center, APOE ε4, income and education. Model 2: model 1 + BMI, smoking status, hypertension, diabetes, drinking status, HDL cholesterol and total cholesterol. Model 3: model 2 + prevalent CVD and baseline thyroid medication use. HR: hazard ratio; CI: confidence interval; TPO: thyroid peroxidase; ARIC: Atherosclerosis Risk in Communities; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease.

Model 1 HR

1 (Ref)

0.92 (0.82 - 1.04)

Model 2 HR

1 (Ref)

0.93 (0.82 - 1.05)

Model 3 HR

1 (Ref)

0.90 (0.80 - 1.03)

**Table 3.** HRs (95% CI) of Dementia by Clinical Categories of Thyroid Dysfunction, ARIC 1990 - 2017
	Hypothyroidism	Euthyroidism	Hyperthyroidism
*P-value < 0.05. Model 1: age, sex, race-center, APOE ε4, income and education. Model 2: model 1 + BMI, smoking status, hypertension, diabetes, drinking status, HDL cholesterol and total cholesterol. Model 3: model 2 + prevalent CVD and baseline thyroid medication use. HR: hazard ratio; CI: confidence interval; ARIC: Atherosclerosis Risk in Communities; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease.
Model 1 HR	1.03 (0.80 - 1.33)	0.78* (0.64 - 0.96)	1 (Ref)	1.07 (0.85 -1.35)	1.51* (1.14 - 1.99)
Model 2 HR	1.01 (0.78 - 1.31)	0.76* (0.61 - 0.93)	1 (Ref)	1.03 (0.81 - 1.31)	1.49* (1.12 - 1.98)
Model 3 HR	0.96 (0.73 - 1.26)	0.74* (0.60 - 0.92)	1 (Ref)	1.01 (0.79 - 1.29)	1.40* (1.02 - 1.92)

Table 3. HRs (95% CI) of Dementia by Clinical Categories of Thyroid Dysfunction, ARIC 1990 - 2017

Hypothyroidism

Euthyroidism

Hyperthyroidism

Overt

Subclinical

Overt

TSH > 5.1 mIU/L; FT4 < 0.85 ng/dL (number of total = 281; number of events = 60)

TSH > 5.1 mIU/L; FT4 = 0.85 - 1.4 ng/dL (number of total = 581; number of events = 98)

TSH = 0.56 - 5.1 mIU/L; FT4 = 0.85 - 1.4 ng/dL (number of total = 10,956; number of events = 1,952)

TSH < 0.56 mIU/L; FT4 = 0.85 - 1.4 ng/dL (number of total = 429; number of events = 74)

TSH < 0.56 mIU/L; FT4 > 1.4 ng/dL (number of total = 234; number of events = 51)

*P-value < 0.05. Model 1: age, sex, race-center, APOE ε4, income and education. Model 2: model 1 + BMI, smoking status, hypertension, diabetes, drinking status, HDL cholesterol and total cholesterol. Model 3: model 2 + prevalent CVD and baseline thyroid medication use. HR: hazard ratio; CI: confidence interval; ARIC: Atherosclerosis Risk in Communities; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease.

Model 1 HR

1.03 (0.80 - 1.33)

0.78* (0.64 - 0.96)

1 (Ref)

1.07 (0.85 -1.35)

1.51* (1.14 - 1.99)

Model 2 HR

1.01 (0.78 - 1.31)

0.76* (0.61 - 0.93)

1 (Ref)

1.03 (0.81 - 1.31)

1.49* (1.12 - 1.98)

Model 3 HR

0.96 (0.73 - 1.26)

0.74* (0.60 - 0.92)

1 (Ref)

1.01 (0.79 - 1.29)

1.40* (1.02 - 1.92)

**Table 4.** HRs (95% CI) of Dementia by Categorical Distribution of Thyroid Hormone Levels, ARIC 1990 - 2017
TSH	Lowest 5%, ≤ 0.54 mIU/L (number of total = 626; number of events = 116)	Middle 90%, 0.55 - 5.97 mIU/L (number of total = 11,226; number of events = 1,998)	Highest 5%, ≥ 5.98 mIU/L (number of total = 629; number of events = 121)	TSH per 6.35 mIU/L (number of total = 12,481; number of events = 2,235)
*P-value < 0.05. Model 1: age, sex, race-center, APOE ε4, income, education and TSH or FT4. Model 2: model 1 + BMI, smoking status, hypertension, diabetes, drinking status, HDL cholesterol and total cholesterol. Model 3: model 2 + prevalent CVD and baseline thyroid medication use. HR: hazard ratio; CI: confidence interval; ARIC: Atherosclerosis Risk in Communities; TSH: thyroid-stimulating hormone; FT4: free thyroxine; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease.
Model 1 HR	1.24* (1.03 - 1.50)	1 (Ref)	0.93 (0.77 - 1.12)	1.03 (0.98 - 1.07)
Model 2 HR	1.13 (0.92 - 1.39)	1 (Ref)	0.94 (0.77 - 1.14)	1.03 (0.98 - 1.07)
Model 3 HR	1.09 (0.87 - 1.36)	1 (Ref)	0.90 (0.73 - 1.11)	1.02 (0.97 - 1.07)
FT4	Lowest 5%, ≤ 0.89 ng/dL (number of total = 628; number of events = 123)	Middle 90%, 0.90 - 1.35 ng/dL (number of total = 11,170; number of events = 1,981)	Highest 5%, ≥ 1.36 ng/dL (number of total = 683; number of events = 131)	FT4 per SD (0.19 ng/dL) (number of total = 12,481; number of events = 2,235)
Model 1 HR	0.96 (0.79 - 1.18)	1 (Ref)	1.30* (1.08 - 1.55)	1.06* (1.02 - 1.09)
Model 2 HR	0.96 (0.78 - 1.17)	1 (Ref)	1.26* (1.05 - 1.51)	1.05* (1.01 - 1.09)
Model 3 HR	0.95 (0.77 - 1.16)	1 (Ref)	1.23* (1.02 - 1.48)	1.05* (1.01 - 1.09)

Table 4. HRs (95% CI) of Dementia by Categorical Distribution of Thyroid Hormone Levels, ARIC 1990 - 2017

TSH

Lowest 5%, ≤ 0.54 mIU/L (number of total = 626; number of events = 116)

Middle 90%, 0.55 - 5.97 mIU/L (number of total = 11,226; number of events = 1,998)

Highest 5%, ≥ 5.98 mIU/L (number of total = 629; number of events = 121)

TSH per 6.35 mIU/L (number of total = 12,481; number of events = 2,235)

*P-value < 0.05. Model 1: age, sex, race-center, APOE ε4, income, education and TSH or FT4. Model 2: model 1 + BMI, smoking status, hypertension, diabetes, drinking status, HDL cholesterol and total cholesterol. Model 3: model 2 + prevalent CVD and baseline thyroid medication use. HR: hazard ratio; CI: confidence interval; ARIC: Atherosclerosis Risk in Communities; TSH: thyroid-stimulating hormone; FT4: free thyroxine; BMI: body mass index; HDL: high-density lipoprotein; CVD: cardiovascular disease.

Model 1 HR

1.24* (1.03 - 1.50)

1 (Ref)

0.93 (0.77 - 1.12)

1.03 (0.98 - 1.07)

Model 2 HR

1.13 (0.92 - 1.39)

1 (Ref)

0.94 (0.77 - 1.14)

1.03 (0.98 - 1.07)

Model 3 HR

1.09 (0.87 - 1.36)

1 (Ref)

0.90 (0.73 - 1.11)

1.02 (0.97 - 1.07)

FT4

Lowest 5%, ≤ 0.89 ng/dL (number of total = 628; number of events = 123)

Middle 90%, 0.90 - 1.35 ng/dL (number of total = 11,170; number of events = 1,981)

Highest 5%, ≥ 1.36 ng/dL (number of total = 683; number of events = 131)

FT4 per SD (0.19 ng/dL) (number of total = 12,481; number of events = 2,235)

Model 1 HR

0.96 (0.79 - 1.18)

1 (Ref)

1.30* (1.08 - 1.55)

1.06* (1.02 - 1.09)

Model 2 HR

0.96 (0.78 - 1.17)

1 (Ref)

1.26* (1.05 - 1.51)

1.05* (1.01 - 1.09)

Model 3 HR

0.95 (0.77 - 1.16)

1 (Ref)

1.23* (1.02 - 1.48)

1.05* (1.01 - 1.09)