Activities of daily living,behavioral and psychological symptoms of dementia,and cognitive and physical function according to thyroid function in Alzheimer's disease

Abstract

Background

The relationships between thyroid hormone profiles and activities of daily living (ADLs), behavioral and psychological symptoms (BPSD), cognitive status, and physical function in patients with Alzheimer's disease (AD) remain poorly understood.

Objective

This study investigates the relationships among ADLs, BPSD, and cognitive and physical function relative to thyroid status in patients with AD.

Methods

We recruited 2484 outpatients diagnosed with AD aged 65 and older with serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels measured at their first memory clinic visit. The participants were divided into five groups by their serum FT4 and TSH levels: euthyroidism, hypothyroidism, subclinical hypothyroidism, hyperthyroidism, and subclinical hyperthyroidism. Differences in dependent variables among these groups were compared using analysis of covariance. Correlations of the dependent variables with FT3, FT4, FT3/FT4, and TSH levels and the presence of non-thyroidal illness syndrome (NTIS) were examined using a multiple regression model.

Results

No significant differences in ADLs, BPSD, and cognitive or physical performance were observed among the groups stratified by FT4 and TSH levels. Although there were slight variations according to the analytical method employed, the overall results indicated that lower FT3, higher FT4, and lower FT3/FT4 were correlated with worse ADLs, mood, and cognitive and physical function. AD patients with NTIS exhibited notably worse basic ADLs than other groups.

Conclusions

These results suggest that thyroid hormone levels are associated with ADLs, mood, and cognitive and physical function in AD patients, suggesting the need for careful monitoring of AD patients with lower FT3, higher FT4, lower FT3/FT4, and NTIS.

Keywords

activities of daily living Alzheimer's disease behavioral and psychological symptoms of dementia cognitive function physical function thyroid function

Introduction

According to World Health Organization, the worldwide number of individuals with Alzheimer's disease (AD) is expected to reach 152.8 million by 2050. Patients with AD and their families are affected by not only by a declining cognitive function, but also by a drop in activities of daily living (ADLs), the development of behavioral and psychological symptoms of dementia (BPSD), and reduced physical function.¹

Thyroid hormones are essential for normal brain development, particularly during fetal and early postnatal periods. Their functions include neurogenesis, synaptogenesis, myelination, and the differentiation and migration of neuronal and glial cells.² Beyond development, thyroid hormones remain essential for maintaining normal brain functions, influencing synaptic plasticity, memory processes, and cognitive function.³ Suboptimal thyroid hormone levels have also been implicated in the pathophysiology of AD, including increased production of protein aggregates that form amyloid plaques and neurofibrillary tangles, and impaired clearance of these molecules from the brain parenchyma across the blood-brain barrier or microglial phagocytosis.⁴

While numerous studies have explored the clinical associations between thyroid function parameters and dementia or AD risk, notable inconsistencies have been observed. Some investigations reported that both subclinical and overt hyperthyroidism^5,6 were associated with an increased risk of dementia or AD,^7–9 whereas others implicated hypothyroidism.^10–12 In contrast, several studies have also reported that subclinical hypothyroidism was associated with a reduced risk of dementia.⁶ On the other hand, lower serum free triiodothyronine (FT3) levels^13–15 and higher free thyroxine (FT4) concentrations¹⁶ have both been independently linked to increased dementia incidence. Thus, the relationship between thyroid dysfunction and AD risk remains a subject of ongoing scientific debate.¹⁷ Moreover, the link between thyroid hormone levels and the severity of the cognitive and non-cognitive impairment in affected AD patients is still not fully understood.

Thyroid hormones also play critical roles in regulating metabolic processes, musculoskeletal function, and systemic physiological resilience,¹⁸ all of which are essential determinants of an individual's capacity to perform activities of daily living (ADLs). Consequently, thyroid dysfunction can contribute to ADL decline and frailty progression. Epidemiological evidence indicates that elevated FT4 levels or reduced FT3 concentrations are independently associated with heightened frailty risk among elderly individuals^19–21 and patients with type 2 diabetes mellitus.²² Notably, non-thyroidal illness syndrome (NTIS)—characterized by decreased serum T3 and/or T4 levels, occasionally accompanied by suppressed thyrotropin (TSH)—typically presents in patients with acute or chronic systemic illnesses and correlates with adverse clinical outcomes.²³ Nevertheless, the relationship between thyroid hormone levels and measurable declines in ADL capacity or physical performance remains poorly characterized in patients with AD.

In clinical practice, when older adults with AD who live alone or provide care for another older person visit a medical facility, healthcare professionals may sometimes find it difficult to comprehensively assess their ADLs, BPSD, physical function, and, at times, even cognitive function. If thyroid hormone levels obtained from routine blood tests are associated with these clinical parameters, such measurements could serve as meaningful and objective indicators of patients’ overall functional status. For instance, clinicians occasionally encounter older individuals with NTIS who present without any specific complaints. However, it remains unclear whether these individuals truly have no difficulties in ADLs, BPSD, cognitive performance, or physical function.

Based on previous evidence, we hypothesized that (1) both lower elevated FT4 levels or reduced FT3 concentrations would be associated with poorer ADL, BPSD, cognitive, and physical function profiles, and (2) individuals with NTIS, even those without subjective decline in food intake or body weight, would demonstrate lower functional performance compared to those without NTIS. Given the inconsistent findings of previous studies regarding how ADL, BPSD, cognitive, and physical functions differ between older adults with subclinical hypothyroidism or subclinical hyperthyroidism and those with euthyroid function, no a priori hypothesis was established for these groups; instead, these comparisons were treated as exploratory analyses.

In this cross-sectional study, we systematically examined potential links between thyroid function profiles and ADL performance, BPSD, cognitive status, and physical function metrics in patients with AD. Specifically, this study aimed to address the following three research questions. First, irrespective of a history of thyroid disease or medication use, we examined whether patients classified into subclinical hyperthyroidism, subclinical hypothyroidism, hyperthyroidism, or hypothyroidism groups—according to serum TSH, free T4, and free T3 levels—exhibit distinct profiles in ADLs, BPSD, physical function, or cognitive function. Second, we investigated the associations of serum FT4, FT3, and the FT3/FT4 ratio with ADLs, BPSD, physical function, and cognitive performance, and examined whether these thyroid hormone indices could provide cutoff values predictive of poorer function. Third, we explored the clinical characteristics of patients with NTIS, with particular attention to those who did not report decreased food intake or body weight loss, to clarify whether their ADLs, BPSD, physical, and cognitive functions differ from those without NTIS.

Methods

Participants

The present study included 2484 AD patients who had at least one of the following measurements: serum FT3, FT4, or TSH. All participants were Japanese adults aged 65 years or older who attended an initial visit at our memory clinic at the National Center for Geriatrics and Gerontology from July 2010 to June 2021. All patients were diagnosed with AD based on detailed neuropsychological tests and examinations, as described in our previous report.¹ AD was diagnosed based on the U.S. National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines. AD biomarkers were not measured in the current subjects.

Serum FT4, FT3, and TSH levels were obtained at the initial visit, which coincided with the clinical diagnosis of AD. At this visit, comprehensive assessments of cognitive and physical function were also performed. Using the lower and upper cutoffs for serum FT4 (0.70 ng/dL and 1.48 ng/dL) and TSH (0.35 μIU/mL and 4.94 μIU/mL) shown in Supplemental Table 1, the participants were divided into five groups regardless of the use of thyroid medication: 2329 with euthyroidism, 7 with hypothyroidism, 47 with subclinical hypothyroidism, 4 with hyperthyroidism, and 47 with subclinical hyperthyroidism. FT3 was defined as low when it was less than or equal to 1.68 ng/dL, and a condition in which FT3 was low while FT4 and TSH remained within normal ranges was defined as NTIS. Participants diagnosed with NTIS were asked about changes in food intake and body weight over the past three months. Specifically, they were asked to report whether they had experienced a marked decrease, moderate decrease, or no decrease in food intake, and whether they had experienced a weight loss of ≥3 kg, uncertain weight change, a weight loss of 1–3 kg, or no weight loss during the same period.

Comorbidities and their medications related to thyroid function, such as levothyroxine sodium hydrate, were also surveyed from medical records and interviews with the participants and their families. The number of comorbidities was counted, including liver disease, heart disease, cancer, hypertension, lung disease, stroke, dyslipidemia, kidney disease, and diabetes mellitus.

ADLs, BPSD, and cognitive and physical function

Basic ADL performance was assessed using the Barthel Index (BI),²⁴ while instrumental ADL (IADL) performance was assessed using Lawton's IADLs.²⁵ For Lawton's IADLs, “food preparation”, “housekeeping”, and “laundry” were examined among only women in this study. Regarding the IADL, the score was calculated as a percentage based on the number of points obtained out of five items for men and eight items for women.

BPSD was surveyed using the Dementia Behavior Disturbance Scale-28 (DBD-28) by interviewing the patients and their families. Patients with a Geriatric Depression Scale-15 (GDS-15) score ≥ 5 were classified as having a depressed mood. When patients had difficulty answering questions by themselves because of visual, auditory, limb movement, or motivational problems, family members helped them to answer the questions. The cutoff for the DBD-28 was not used because an appropriate cutoff was not found.

Each respondent's cognitive function was measured using the Mini-Mental State Examination (MMSE),²⁶ the Frontal Assessment Battery (FAB),²⁷ the Digit Span Backward test of the Wechsler Adult Intelligence Scale (WAIS)²⁸ (as a clinical assessment of attention), and Logical Memory Tests II of the Wechsler Memory Scale-Revised (WMS-R) as a clinical assessment of memory. Cognitive impairment was indicated by an MMSE score ≤ 23, a FAB score ≤ 11,¹⁸ a Digit Span Forward score ≤ 5, A Digit Span Backward score ≤ 3, and a WMS-R Logical Memory II subtest raw score ≤ 8 for > 16 years of education, ≤ 4 for 8–15 years of education, and ≤2 for 0–7 years of education.¹⁹

Physical function was assessed using the one-leg standing (OLS) test, timed up and go (TUG) test, and grip strength (GS). The OLS test requires an active movement of the body's center of mass in anticipation of a postural transition from one body position to another.²⁹ The OLS test measures how long (in seconds) that a subject can stand unassisted on one leg with eyes open, up to a maximum of 60 s. Each leg was tested, and we used the average of the left and right OLS times as the OLS time. In the TUG examination, we measured the time in seconds that it took for the subject to rise from sitting on a standard chair, walk 3 m, turn, walk back to the chair, and sit down. We also used the average of both sides’ GS as the GS expressed in kilograms.³⁰ An OLS < 15 s³¹ and TUG ≥ 13.5 s³² were considered to indicate poor physical function. Low GS was defined as < 28 kg for men and <18 kg for women.³³ In the sub-analysis, we also applied cutoff values of 10 s³⁴ and 20 s for the OLST and 15 s³⁵ and 20 s³⁶ for the TUG.

Statistical analysis

This is a cross-sectional study. The Kruskal-Wallis test and chi-square test were used to compare patients’ characteristics among groups. An analysis of covariance (ANCOVA) with Bonferroni post-test and multiple regression models were used to examine the correlation among ADLs, BPSD, and cognitive and physical function according to FT3, FT4, FT3/T4, and TSH. The following covariates were used: age, sex, years of education, comorbidities, body mass index (BMI), medication, and MMSE. To evaluate whether impairments in ADLs, mood, and cognitive or physical function could be assessed using serum FT3, FT4, and FT3/FT4, receiver operating characteristic (ROC) analysis was performed for serum FT3, FT4, and FT3/FT4. The area under the curve (AUC) was calculated to assess the predictive performance of serum FT3, FT4, and FT3/FT4. Statistical analysis was performed using SPSS software (ver. 29.0; SPSS, Chicago). A P value of 0.05 and less was considered statistically significant. This study received the approval of the research ethics committee of the National Center for Geriatrics and Gerontology. (No.1645-2)

Results

The participants’ characteristics are shown in Table 1. A comparison of the five groups by their FT4 and TSH levels is shown in Table 2. There were significant differences in sex among the five groups, but no significant differences in ADLs, BPSD and mood, and cognitive and physical function among the five groups, even after adjustment for covariates using ANCOVA.

Table 1.

Participants’ characteristics.

	n	Median (25^th–75^th percentile) or n (%)
Age, years	2484	80.0 (76.0–84.0)
Women, n (%)	2484	1740 (70.0)
Years of education	2437	9.0 (9.0–12.0)
Comorbidity, n	2484	1.0 (0.0–2.0)
Body mass index, kg/m²	2475	21.5 (19.4–23.9)
Blood tests and medication
TSH, μIU/mL	2482	1.4 (0.9–2.1)
Free T3, pg/mL	2465	2.5 (2.3–2.8)
Free T4, ng/mL	2477	1.1 (1.0–1.2)
Levothyroxine sodium hydrate, n (%)	2484	13 (0.5)
Thiamazole, n (%)	2484	0 (0.0)
ADLs
Barthel Index	2476	100.0 (90.0–100.0)
Barthel Index ≤ 80	2476	325 (14.2)
Lawton's IADLs	2471	63 (50–88)
Lawton's IADLs ≤ 80	2471	1846 (74.7)
BPSD and mood
Dementia Behavior Disturbance Scale-28	2467	15.0 (9.0–24.0)
Geriatric Depression Scale	2441	3.0 (2.0–5.0)
Geriatric Depression Scale-15 ≥ 5	2441	831 (34.0)
Neuropsychological tests
Mini-Mental State Examination	2473	19.0 (15.0–22.0)
Mini-Mental State Examination ≤ 23	2473	2173 (87.9)
Frontal Assessment Battery	1894	10.0 (8.0–12.0)
Frontal Assessment Battery ≤ 11	1894	1653 (87.3)
Digit Span Backward	1927	3.0 (3.0–4.0)
Digit Span Backward ≤ 4	1927	1787 (92.7)
Logical Memory II	1941	3.0 (3.0–3.0)
Worse Logical Memory II	1941	1905 (98.1)
Physical function
One-leg standing test, s	1699	5.4 (2.3–13.8)
One-leg standing test < 15 s	1699	1305 (76.8)
Timed up and go test, s	2122	12.2 (9.9–15.2)
Timed up and go test ≥ 13.5 s	2122	821 (38.7)
Grip strength, kg	1515	16.6 (12.1–21.4)
Weak grip strength	1515	1099 (72.5)

ADL: activities of daily living; BPSD: behavioral and psychological symptoms of dementia; IADL: instrumental activities of daily living.

Table 2.

Comparison among groups according to free T4 and TSH.

	n	Euthyroidism	n	Hypothyroidism	n	Subclinicalhypothyroidism	n	Hyperthyroidism	n	Subclinicalhyperthyroidism	p
Age, years	2329	80.0 (76.0–84.0)	7	82.0 (81.0–86.0)	47	82.0 (79.0–85.0)	4	81.5 (80.3–85.0)	47	80.0 (75.0–84.0)	0.1
Men, n (%)	2329	689 (29.6)	7	5 (71.4)	47	24 (51.1)	4	1 (25.0)	47	12 (25.5)	0.003
Years of education	2284	9.0 (9.0–12.0)	7	9.0 (9.0–12.0)	46	9.0 (9.0–12.0)	4	9.0 (9.0–11.3)	47	9.0 (9.0–12.0)	0.2
BMI, kg/m²	2320	21.6 (19.4–23.9)	7	22.7 (20.7–23.4)	47	21.1 (19.1–24.8)	4	20.7 (18.1–23.9)	47	20.4 (18.8–23.5)	0.7
Blood tests and medication
TSH, μIU/mL	2329	1.4 (0.9–2.0)	7	44.8 (16.0–92.5)	47	6.4 (5.4–8.4)	4	0.03 (0.01–0.2)	47	0.2 (0.1–0.3)	<0.001
Free T3, pg/mL	2321	2.5 (2.3–2.8)	6	2.2 (1.7–2.6)	45	2.4 (2.1–2.7)	4	2.7 (2.3–3.0)	45	2.7 (2.4–2.9)	<0.001
Free T4, ng/mL	2329	1.1 (1.0–1.2)	7	0.6 (0.4–0.6)	47	1.0 (0.9–1.0)	4	2.1 (1.6–2.4)	47	1.2 (1.1–1.3)	<0.001
Thiamazole, n (%)	2329	9 (0.4)	7	0 (0)	47	2 (4.3)	4	1 (25.0)	47	1 (2.1)	<0.001
ADLs^a
Barthel Index	2322	100 (95.0–100.0)	7	100 (95.0–100.0)	46	100 (85.0–100.0)	4	67.5 (28.8–95.0)	47	100.0 (95.0–100.0)	0.2
Lawton's IADLs (%)	2318	0.6 (0.5–0.9)	7	0.8 (0.6–0.9)	46	0.6 (0.4–0.8)	4	0.0 (0.0–0.3)	47	0.8 (0.5–0.9)	0.1
BPSD and mood^a
DBD-28	2313	15.0 (9.0–24.0)	77	16.0 (7.0–32.0)	46	19.0 (11.5–30.3)	4	24.5 (11.5–43.5)	47	13.0 (9.0–22.0)	0.5
GDS-15	2286	3.0 (2.0–5.0)	7	3.0 (1.0–6.0)	47	4.0 (2.0–5.0)	4	4.0 (1.8–5.5)	47	3.0 (2.0–6.0)	0.9
Neuropsychological tests^b
MMSE	2319	19.0 (15.0–22.0)	7	20.0 (17.0–22.0)	46	19.0 (15.0–22.0)	4	14.0 (4.8–18.8)	47	18.0 (15.0–21.0)	0.1
FAB	1783	9.0 (6.0–10.0)	6	7.5 (4.0–10.8)	33	9.0 (6.0–10.0)	3	4.0 (5.0–6.5)	39	8.0 (7.0–10.0)	0.7
Digit Span Backward	1810	3.0 (3.0–4.0)	6	2.5 (0.0–3.5)	36	3.0 (2.3–3.0)	3	2.0 (3.0–3.0)	40	3.0 (3.0–3.5)	0.6
Logical Memory II	1823	0.0 (0.0–0.0)	6	0.0 (1.0–4.25)	37	0.0 (0.0–0.0)	3	0.0 (0.0–0.0)	40	0.0 (0.0–0.0)	0.1
Physical function^a
One-leg standing test, s	1591	5.4 (2.3–13.9)	5	9.2 (1.0–1115.8)	27	5.6 (2.7–9.0)	4	2.1 (0.5–24.4)	34	5.4 (2.3–12.6)	0.6
Timed up and go, s	1987	12.2 (9.9–15.1)	6	14.7 (10.6–17.6)	43	14.8 (12.1–16.2)	4	9.2 (2.2–17.5)	39	12.4 (10.1–16.3)	0.9
Grip strength, kg	1424	16.6 (12.1–21.5)	4	20.7 (3.0–31.8)	26	16.7 (12.6–21.9)	3	9.5 (4.7–14.9)	29	16.6 (13.1–19.7)	0.7

Median (25^th–75^th) or number (percentage) are shown.

p values: Kruskal-Wallis test was used for age, years of education, and TSH, free T3, and free T4 values. χ² test was used for sex and medication. ANCOVA was used for ADLs, BPSD, neurological tests, and physical function.

Adjusted for age, sex, years of education, comorbidities, BMI, medication, and MMSE.

Adjusted for age, sex, years of education, comorbidities, BMI, and medication.

ADL: activities of daily living; ANCOVA: analysis of covariance; BMI: body mass index; BPSD: behavioral and psychological symptoms of dementia; DBD-28: Dementia Behavior Disturbance Scale-28; FAB: Frontal Assessment Battery; GDS-15: Geriatric Depression Scale-15; IADL: instrumental activities or daily living; MMSE: Mini-Mental State Examination; TSH: thyroid-stimulating hormone.

As shown in Table 3, in the logistic regression model, each one-unit increase in FT3 was associated with odds ratios of 0.5 for having a BI score ≤ 80 (p < 0.001), 0.9 for having a MMSE ≤ 23 (p = 0.04), 0.6 for having a FAB ≤ 11 (p = 0.02), 0.6 for having a Digit Span Forward ≤ 4 (p = 0.02), 0.6 for having an OLS < 15 (p = 0.01), and 0.6 for having a TUG ≥ 13.5 (p < 0.001). In addition, each one-unit increase in FT4 was associated with odds ratios of 2.5 for having a BI score ≤ 80 (p = 0.001), 2.1 for having IADLs ≤ 80 (p = 0.02), 1.7 for having a GDS-15 ≥ 5 (p = 0.05), 4.2 for having a Digit Span Forward ≤ 4 (p = 0.03), 39.3 for having a worse Logical Memory (p = 0.003), and 0.4 for having an OLS < 15 (p = 0.009). TSH levels were not significantly associated with any of the measured variables.

Table 3.

Logistic regression model for ADLs, BPSD, and cognitive and physical function according, free T3, free T4, and TSH.

		Free T3			Free T4			TSH
	n	OR (95% CI)	p	n	OR (95% CI)	p	n	OR (95% CI)	p
ADLs^a
Barthel Index ≤ 80	2401	0.5 (0.4, 0.8)	<0.001	2413	2.5 (1.2, 5.4)	0.001	2419	0.97 (0.9, 1.1)	0.4
Lawton's IADLs ≤ 80	2396	0.8 (0.6, 1.1)	0.2	2408	2.1 (1.1, 4.0)	0.02	2415	0.99 (0.97, 1.0)	0.8
BPSD and mood^a
DBD-28	2393	0.3 (−1.0, 1.6)	0.7	2405	−0.6 (−3.3, 2.2)	0.7	2412	−0.002 (−0.1, 0.1)	0.97
GDS-15 ≥ 5	2384	0.9 (0.7, 1.1)	0.3	2394	1.7 (1.0, 2.8)	0.05	2401	1.0 (0.99, 1.0)	0.4
Psychological tests^b
MMSE ≤ 23	2404	0.9 (0.5, 0.99)	0.04	2416	0.7 (0.3, 1.5)	0.4	2423	0.99 (0.96, 1.0)	0.7
FAB ≤ 11	1851	0.6 (0.4, 0.9)	0.02	1861	0.8 (0.3, 2.0)	0.7	1868	0.99 (0.96, 1.0)	0.5
Digit Span Forward ≤ 4	1883	0.6 (0.4, 0.9)	0.02	1894	4.2 (1.2, 14.7)	0.03	1901	0.99 (0.96, 1.0)	0.2
Worse Logical Memory II	1898	0.6 (0.2, 1.6)	0.3	1909	39.3 (3.4, 461.2)	0.003	1916	0.97 (0.94, 1.0)	0.08
Physical function^a
One-leg standing test < 15 s	1657	0.6 (0.4, 0.9)	0.01	1662	0.4 (0.2, 0.8)	0.009	1669	1.0 (0.97, 1.0)	0.7
Timed up and go test ≥ 13.5 s	2076	0.6 (0.4, 0.8)	<0.001	2084	1.2 (0.7, 2.2)	0.5	2091	1.0 (0.99, 1.0)	0.4
Weak grip strength	1476	0.7 (0.5, 1.1)	0.1	1485	2.0 (0.9, 4.4)	0.1	1492	0.99 (0.97, 1.0)	0.8

Adjusted for age, sex, years of education, comorbidities, BMI, medication, and MMSE.

Adjusted for age, sex, years of education, comorbidities, BMI, and medication.

ADL: activities of daily living; BPSD: behavioral and psychological symptoms of dementia; CI: confidence interval; DBD-28: Dementia Behavior Disturbance Scale-28; FAB: Frontal Assessment Battery; GDS-15: Geriatric Depression Scale-15; IADL: instrumental activitiesp of daily living; MMSE: Mini-Mental State Examination; OR: odds ratio; TSH: thyroid-stimulating hormone.

As shown in Supplemental Table 2, multiple linear regression model analysis showed that AD patients with higher FT3 tended to have a higher BI (adjusted β = 0.09, p < 0.001), better MMSE (adjusted β = 0.07, p < 0.001), and better FAB (adjusted β = 0.06, p = 0.01). AD patients with higher T4 tended to have a worse BI (adjusted β = −0.06, p = 0.001), worse IADLs (adjusted β = −0.05, p = 0.005), a higher GDS-15 score (adjusted β = 0.07, p < 0.001), a worse OLS (adjusted β = −0.05, p = 0.004), a better TUG (adjusted β = −0.06, p = 0.01), and a worse GS (adjusted β = −0.05, p = 0.002). TSH levels were not significantly associated with any of the measured variables.

Table 4 shows that a lower FT3/FT4 ratio was correlated with poorer ADLs, mood, and cognitive and physical function, while the results varied among multiple logistic and linear regression models.

Table 4.

Multiple logistic and linear regression models for ADLs, BPSD, and cognitive and physical function according, free T3/T4 ratio.

Logistic regression			Free T3/free T4		Linear regression			Free T3/free T4
	n	B	OR (95% CI)	p		n	β	B (95% CI)	p
ADLs^a					ADLs^a
Barthel Index ≤ 80	2400	−0.6	0.5 (0.4, 0.7)	<0.001	Barthel Index	2400	0.1	2.8 (1.8, 3.9)	<0.001
Lawton's IADLs ≤ 80	2395	−0.4	0.7 (0.5, 0.8)	<0.001	Lawton's IADLs	2395	0.05	0.04 (0.01, 0.07)	0.005
BPSD and mood^a					BPSD and mood^a
DBD-28	-	−	−	−	DBD-28	2393	0.006	0.2 (−0.9 to 1.2)	0.8
GDS-15 ≥ 5	2381	−0.3	0.8 (0.6, 0.9)	0.006	GDS-15	2381	−0.05	−0.3 (−0.6, −0.03)	0.03
Psychological tests^b					Psychological tests^b
MMSE ≤ 23	2404	−0.1	0.9 (0.7, 1.2)	0.3	MMSE	2404	0.05	0.5 (0.08, 0.9)	0.02
FAB ≤ 11	1851	−0.3	0.7 (0.5, 1.0)	0.08	FAB	1851	0.04	0.3 (−0.07, 0.6)	0.1
Digit Span Forward ≤ 4	1883	−0.3	0.8 (0.5, 1.2)	0.2	Digit Span Backward^a	1883	0.04	0.1 (−0.03, 0.2)	0.1
Worse Logical Memory II	1898	−1.1	0.3 (0.2, 0.7)	0.002	Worse Logical Memory II	1898	0.06	0.2 (0.04, 0.3)	0.5
Physical function^a					Physical function^a
One-leg standing test < 15 s	1657	0.02	1.0 (0.8, 1.4)	0.9	One-leg standing test	1657	0.02	15.8 (−19.9, 51.5)	0.4
Timed up and go test ≥ 13.5 s	2076	−0.3	0.7 (0.6−0.9)	0.009	Timed up and go test	2076	0.04	10.1 (−2.4, 22.7)	0.1
Weak grip strength	1477	−0.2	0.8 (0.6−1.1)	0.1	Grip strength	1477	0.03	0.6 (−0.2, 1.4)	0.2

Adjusted for age, sex, years of education, comorbidities, BMI, medication, and MMSE.

Adjusted for age, sex, years of education, comorbidities, BMI, and medication.

ADL: activities of daily living; BMI: body mass index; BPSD: behavioral and psychological symptoms of dementia; CI: confidence interval; DBD-28: Dementia Behavior Disturbance Scale-28; FAB: Frontal Assessment Battery; GDS-15: Geriatric Depression Scale-15; IADL: instrumental activities of daily living; MMSE: Mini-Mental State Examination; OR: odds ratio.

According to ROC analysis, the AUC of FT3, FT4, and FT3/FT4 for predicting worse ADLs, mood, and cognitive and physical function was less than 0.6, indicating no predictive power (Supplemental Table 3). Thus, thyroid hormone levels were unable to distinguish between patients with and without worse mood or functional decline, and the corresponding ROC curves followed a diagonal line. As a result, no meaningful cutoff values could be identified.

A total of 2288 participants had normal levels of FT3, FT4, and TSH, and 32 individuals were diagnosed with NTIS, which is characterized by normal levels of FT4 and TSH and a low FT3. As shown in Table 5, participants with NTIS, even after adjustment for covariates, had a worse BI and IADLs compared with those with normal FT3, FT4, and TSH levels. Among the 32 participants identified as having NTIS, 28 provided information regarding their recent dietary intake. According to their responses, 4 reported a marked decrease and 10 reported a moderate decrease in food intake over the past three months, while the remaining 14 reported no change.

Table 5.

Comparison of participants with normal free T3, free T4, and TSH levels versus those presenting with NTIS.

	n	Normal free T4, TSH, and free T3	n	NTIS	Univariate	ANCOVA
		Median (25^th–75th)		Median (25^th–75th)	P	p
Age, years	2288	80.0 (76.0–84.0)	32	84.0 (80.0–85.8)	0.003	-
Women, n (%)	2288	676 (29.5)	32	9 (28.1)	0.9	-
Years of education	2245	9.0 (9.0–12.0)	30	9.0 (7.5–11.0)	0.02	-
Comorbidity, n	2288	1.0 (0.0–2.0)	32	1.0 (0.0–2.8)
BMI, kg/m²	2281	21.6 (19.5–23.9)	32	21.4 (19.0–24.2)	0.3	-
ADLs^a
Barthel Index	2277	100.0 (95.0–100.0)	32	85.0 (66.3–100.0)	<0.001	<0.001
Lawton's IADLs	2277	62.5 (50.0–87.5)	32	38.8 (20.0–62.5)	<0.001	0.008
BPSD and mood^a
DBD-28	2272	15.0 (9.0–24.0)	32	16.5 (13.0–26.0)	0.1	0.3
GDS-15	2247	3.0 (2.0–5.0)	30	4.0 (1.0–7.0)	0.6	0.5
Psychological tests^b
MMSE	2279	19.0 (15.0–22.0)	31	18.0 (14.0–20.0)	0.1	0.3
FAB	1757	9.0 (6.0–10.0)	19	7.0 (7.0–9.0)	0.2	0.9
Digit Span Backward	1782	3.0 (3.0–4.0)	21	3.0 (2.0–4.0)	0.02	0.9
Worse Logical Memory II	1795	0.0 (0.0–0.0)	21	0.0 (0.0–0.0)	0.4	0.9
Physical function^a
One-leg standing test	1574	5.5 (2.3–13.9)	13	2.7 (0.2–10.5)	0.08	0.8
Timed up and go test	1958	12.2 (9.9–15.0)	23	14.1 (10.1–20.0)	0.1	0.7
Grip strength	1404	16.6 (12.2–21.5)	14	12.1 (7.9–20.8)	0.1	0.2

Adjusted for age, sex, years of education, comorbidities, BMI, medication, and MMSE.

Adjusted for age, sex, years of education, comorbidities, BMI, and medication.

ADL: activities of daily living; ANCOVA: analysis of covariance; BMI: body mass index; BPSD: behavioral and psychological symptoms of dementia; DBD-28: Dementia Behavior Disturbance Scale-28; FAB: Frontal Assessment Battery; GDS-15: Geriatric Depression Scale-15; IADL: instrumental activities of daily living; MMSE: Mini-Mental State Examination; NTIS: non-thyroidal illness syndrome; TSH: thyroid-stimulating hormone.

Regarding body weight, among the 28 respondents, 4 reported a weight loss of ≥3 kg, 7 were unsure, 7 reported a loss of 1–3 kg, and 10 reported no weight loss.

Even among the 16 participants who reported no decrease in food intake and no weight loss but were diagnosed with NTIS, both BI and IADL scores were significantly lower than those in participants without NTIS (adjusted β = –0.05, p = 0.01 for BI; adjusted β = –0.04, p = 0.02 for IADL). In addition, the logistic regression model showed that participants with NTIS had a worse BI (odds ratio, 3.7; 95% CI, 1.6–8.4; p = 0.002) compared with participants with normal FT3, FT4, and TSH (Supplemental Table 4). Among those with normal FT4 and TSH, for every one-unit decrease in FT3, the BI (p < 0.001) and IADL (p = 0.009) scores decreased by 0.1 (Supplemental Table 4).

All the results were not changed by restricting the analysis to individuals not taking medication (data not shown). Regarding the results shown in Tables 3, 4, and 5, we conducted sub-analyses using alternative cutoff values (10 s and 20 s for the OLST, and 15 s and 20 s for the TUG), and the findings were largely consistent with those of the main analysis (Supplemental Table 5).

Discussion

This comprehensive analysis of thyroid function parameters and their associations with ADLs, BPSD, cognitive performance, and physical function in patients with AD revealed that, despite slight variations among the analytical methods employed, lower FT3, higher FT4, and a lower FT3/FT4 ratio are correlated with poor ADLs, mood, and cognitive and physical function. However, in this study, no suitable cutoff was identified. While no significant differences were observed across conventional thyroid function groups using FT4 and TSH, AD patients with NTIS exhibited notably impaired basic ADLs compared with other groups; moreover, even in the absence of self-reported loss of appetite or weight loss, both basic and instrumental ADLs were significantly reduced.

The lack of significant differences across conventional thyroid function categories suggests that the traditional clinical classification of thyroid status stratified by FT4 and TSH levels may not fully capture the subtle relationships between thyroid function and AD symptomatology. This finding contrasts with population-based studies that have demonstrated significant associations between thyroid dysfunction and cognitive decline or dementia risk in both hyperthyroidism^7–9 and hypothyroidism.^10,12 In contrast to these studies, which targeted the general population, our study focused on patients with AD. In our study, thyroid dysfunction—defined by FT4 and TSH levels—showed no association with cognitive decline. This may be attributable to the preexisting cognitive impairment in patients with AD or be because the impact of thyroid status manifests differently compared to its role in initial AD risk or in healthy aging. With regard to functional capacity and ADLs, neither subclinical hyperthyroidism nor hypothyroidism has been associated with decline in the general elderly population, which is consistent with the findings of the present study.^37,38

Despite the lack of significant differences across thyroid function categories stratified by FT4 and TSH levels, our analysis revealed significant hormone-specific associations. The association between higher FT4 levels and worse ADL performance, as well as reduced physical function, aligns with emerging evidence from aging research. For example, recent longitudinal^20,21 and cross-sectional¹⁹ studies have shown that elevated FT4 concentrations predict functional decline in elderly people. Furthermore, some studies have shown an association of elevated FT4 and dementia risk^16,39 in community-dwelling elderly people. Here, low FT3 levels were associated with worse performance in ADLs, diminished physical function, and lower scores on psychological assessments. Both longitudinal¹⁵ and cross-sectional¹³ studies have demonstrated a significant association between reduced FT3 levels and an increased risk of AD or dementia. Furthermore, a systematic review has shown that the concentrations of serum FT3 and cerebrospinal fluid total T3 are significantly lower in patients with AD than in healthy controls.¹⁴ T3 has been reported to regulate the gene expression of glutamate transporters—excitatory neurotransmitter carriers—and to enhance glutamate clearance by astrocytes in rats. Furthermore, cortical glutamate concentrations are correlated with serum total and free T3 levels, and glutamate elimination by astrocytes is essential for neuroprotection.⁴⁰ The relationship between low FT3 levels and frailty has also been reported in specific populations, including hospitalized older adults²⁰ and patients with type 2 diabetes mellitus.²² In addition, the FT3/FT4 ratio has been inversely correlated with frailty in older adults, as evidenced by recent studies.^41,42 The FT3/FT4 ratio represents the rate of conversion from thyroxine (T4) to triiodothyronine (T3), a process influenced by the activity of deiodinase enzymes. This ratio has been reported to correlate with muscle function and physical performance.⁴³ Moreover, the FT3/FT4 ratio is used to evaluate the rate of T4-to-T3 conversion and reflects peripheral sensitivity to thyroid hormones. It has been shown to correlate with various metabolic and cardiovascular parameters, supporting its validity as a marker of frailty.⁴⁴ Collectively, these findings suggest that increased FT4, decreased FT3, and a lower FT3/FT4 ratio may serve as valuable biomarkers of frailty and cognitive impairment in the aging population and AD patients.

It is estimated that healthy adults produce about 30 µg of T₃ per day. Of this, roughly 5 µg/day is secreted directly by the thyroid gland, while the remaining 25 µg/day arises from peripheral deiodination of T4 by the D1 and D2 enzymes.⁴⁵ Consequently, a pattern of low FT3 and high FT4 reflects impaired T4 deiodination. This is exemplified in patients with SECISBP2 mutations, who have defective selenoprotein synthesis—including the three iodothyronine deiodinases—and exhibit elevated T4, reduced or low-normal T3, and normal to mildly increased TSH.^46,47 Thus, diminished deiodination may underlie the observed link between lower FT3, higher FT4, and reduced ADL performance or cognitive function in our study.

One potential cause of reduced deiodination is inflammation. In NTIS, serum T3 levels inversely correlate with interleukin-6 (IL-6),⁴⁸ and chronic IL-6 administration in patients with metastatic renal cell carcinoma lowers T3 while transiently raising reverse T3 (rT3) and T4.⁴⁹ In vitro, IL-6 suppresses D1- and D2-mediated T3 generation in human cell lines.⁵⁰

Another factor may be selenium deficiency or impaired selenium utilization, because deiodinase activity requires the selenocysteine residue.⁵¹ Indeed, selenium-deficient individuals have a reduced FT3/FT4 ratio.⁵² In Japan, selenium deficiency affects 51.6% of heart failure patients⁵³ and 24% of those with chronic liver disease.⁵⁴ National Health and Nutrition Examination Survey data further show that higher selenium levels are correlated with better cognitive performance.^55,56 Moreover, low serum selenium is independently associated with reduced muscle mass in elderly individuals⁵⁷ —a contributor to frailty—and with decreased survival.⁵⁸ These findings underscore the need for further research into how selenium status, thyroid hormone metabolism, dementia, and ADL limitations interrelate.

Our findings have several important clinical implications. First, they suggest that assessing thyroid hormone levels, particularly FT3 and FT4, may provide valuable information regarding ADLs, BPSD, and cognitive and physical performance in AD patients. The identification of NTIS as a marker of functional impairment indicates that this syndrome deserves particular attention in AD management, even if they do not report loss of appetite or weight loss. Second, the hormone-specific associations that we observed suggest that the relationship between thyroid function and AD is more nuanced than a simple categorization of patients as euthyroid, hypothyroid, or hyperthyroid. Subtle alterations within the reference range may be clinically meaningful in this population. This emphasizes the value of considering actual hormone levels rather than just thyroid function categories when evaluating AD patients. Third, while our study does not provide direct evidence for thyroid hormone supplementation, the identification of specific hormone patterns associated with functional impairment raises important questions about potential therapeutic interventions. Therefore, future research should explore whether targeted interventions addressing specific thyroid hormone abnormalities, particularly low FT3 levels or NTIS patterns, might improve functional outcomes in selected AD patients.

Several limitations must be acknowledged when interpreting these findings. First, the cross-sectional design prevents determination of causality between thyroid dysfunction and functional outcomes, highlighting the need for longitudinal studies to establish temporal relationships and explain disease progression patterns. Future research priorities should include the longitudinal investigation of thyroid hormone trajectories in AD progression. Second, the study relied solely on a single measurement of serum FT3, FT4, and TSH. We did not assess additional markers such as rT3, thyroid-binding globulins, or thyroid autoantibodies, which could refine the definition of thyroid dysfunction. Moreover, variability in assay methods, timing of measurement, and the lack of repeated measurements could lead to misclassification. Notably, spontaneous TSH normalization occurs in up to 46% of individuals with TSH levels below 7.0 µIU/mL within 2 years, underscoring the distinction between transient biochemical elevation and persistent thyroid disease.⁵⁹ In addition, several medications (for example, amiodaron, lithium, sunitinib, or iodine-containing contrast agents) and recovery from various non-thyroid conditions can cause transient abnormalities in the serum TSH level.^59–62 Accordingly, repeated thyroid function tests after 2 to 3 months should be performed in the future study to distinguish persistent from transient subclinical hypothyroidism before clinical interpretation. Third, this study did not investigate associations with neuroimaging findings or AD biomarkers. Incorporating these measures in future studies would enable a more comprehensive understanding of the mechanisms through which thyroid dysfunction influences cognitive function and ADLs. Lastly, we did not assess muscle mass or quality using imaging (MRI/CT) or body composition methods such as ⁶¹dual-energy X-ray absorptiometry or bioelectrical impedance analysis); therefore, sarcopenia could not be formally diagnosed. Future studies incorporating these measurements will be essential to clarify the relationship between thyroid function, muscle quantity, and frailty more precisely. In addition, it has been reported that up to 25% of obese individuals may have moderately elevated TSH concentrations, usually below the threshold of 10 µIU/mL, without any underlying thyroid disease.⁶³ Therefore, though BMI was adjusted in our ANCOVA, residual confounding by obesity-related metabolic factors (such as chronic low-grade inflammation and insulin resistance) may have influenced the interpretation of TSH values, necessitating cautious interpretation of thyroid dysfunction in obese participants.

Conclusion and implications

Thyroid hormone levels are associated with ADLs, mood, and cognitive and physical function in patients with AD, underscoring the need for careful assessment of those with lower FT3, higher FT4, a lower FT3/FT4 ratio, and NTIS.

Supplemental Material

sj-docx-1-alz-10.1177_13872877261424207 - Supplemental material for Activities of daily living, behavioral and psychological symptoms of dementia, and cognitive and physical function according to thyroid function in Alzheimer's disease

Supplemental material, sj-docx-1-alz-10.1177_13872877261424207 for Activities of daily living, behavioral and psychological symptoms of dementia, and cognitive and physical function according to thyroid function in Alzheimer's disease by Chisato Fujisawa, Haruki Fujisawa, Yosuke Matsui, Taiki Sugimoto, Miki Minakami, Kazuhisa Watanabe, Yosuke Yamada, Hirotaka Nakashima, Hitoshi Komiya, Yoshihisa Sugimura, Hiroyuki Umegaki and Takashi Sakurai in Journal of Alzheimer's Disease

Footnotes

Acknowledgements

The authors have no acknowledgments to report.

ORCID iD

Chisato Fujisawa

Ethical considerations

Not applicable

Consent to participate

Not applicable. This study was a retrospective observational study using anonymized data. Information about the study was disclosed using an opt-out approach.

Consent for publication

Not applicable

Author contribution(s)

Chisato Fujisawa: Conceptualization; Funding acquisition; Methodology; Software; Validation; Writing – original draft; Writing – review & editing.

Haruki Fujisawa: Conceptualization; Funding acquisition; Methodology; Software; Validation; Writing – original draft; Writing – review & editing.

Yosuke Matsui: Conceptualization; Validation; Writing – original draft.

Taiki Sugimoto: Data curation; Investigation; Resources.

Miki Minakami: Conceptualization; Visualization; Writing – original draft; Writing – review & editing.

Kazuhisa Watanabe: Conceptualization; Project administration; Visualization; Writing – original draft; Writing – review & editing.

Yosuke Yamada: Conceptualization; Project administration; Visualization; Writing – original draft; Writing – review & editing.

Hirotaka Nakashima: Conceptualization; Project administration; Visualization; Writing – original draft; Writing – review & editing.

Hitoshi Komiya: Conceptualization; Project administration; Visualization; Writing – original draft; Writing – review & editing.

Yoshihisa Sugimura: Conceptualization; Project administration; Visualization; Writing – original draft; Writing – review & editing.

Hiroyuki Umegaki: Conceptualization; Project administration; Visualization; Writing – original draft; Writing – review & editing.

Takashi Sakurai: Conceptualization; Formal analysis; Funding acquisition; Project administration; Resources; Supervision; Visualization; Writing – original draft.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Hori Sciences and Arts Foundation and the Japan Geriatrics Society Research Grant Award in Geriatrics and Gerontology and Research Funding for Longevity Sciences (30-1) from Japan's National Center for Geriatrics and Gerontology, and The Salt Science Research Foundation No. 24C2.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Raw data were generated at the National Center for Geriatrics and Gerontology. Derived data supporting the findings of this study are available from the corresponding author on request.

Supplemental material

Supplemental material for this article is available online.

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