Handgrip strength asymmetry and cognitive impairment risk: Insights from a seven-year prospective cohort study

Abstract

Objectives

This study aimed to explore the links of handgrip strength and asymmetry with cognitive impairment.

Design

This was a seven-year prospective cohort study.

Setting and participants

We used data from wave 3 (2015–2017) to wave 5 (2019–2022) from the ongoing Taiwan Initiative of Geriatric Epidemiological Research (TIGER), with wave 3 as the baseline (n = 446). The study included community-dwelling participants aged 65 years or older.

Measurements

Handgrip strength was measured, and abnormalities were determined based on handgrip strength weakness and asymmetry. Handgrip strength asymmetry was categorized into three groups at baseline based on the handgrip strength ratio (left handgrip strength/right handgrip strength). Cognitive tests evaluating global and specific cognitive domains were conducted at baseline and two biennial follow-ups. Generalized linear mixed models were utilized to assess the associations of abnormal handgrip strength with global cognition and multiple cognitive domain progression over time.

Results

This study included 392 dementia-free participants, with an average age of 75.8 years and 179 (45.7%) males. Mild handgrip strength asymmetry was present in 88 participants (22.4%), while 53 (13.5%) exhibited moderate asymmetry. In men, the coexistence of low handgrip strength and handgrip strength asymmetry was linked to cognitive impairment over time. These associations were observed in global cognition ($\widehat{\text{β}}$ = −1.76, 95% CI: −2.79 to −0.74), memory (immediate free recall: $\widehat{\text{β}}$ = −0.67, 95% CI: −1.17 to −0.17), executive function (Trail Making Test-A: $\widehat{\text{β}}$ = −0.54, 95% CI: −0.94 to −0.13), and attention (Digit span-forward: $\widehat{\text{β}}$ = −1.00, 95% CI: −1.46 to −0.54).

Conclusions

This study found that individuals with reduced handgrip strength and handgrip strength asymmetry had an increased risk of cognitive impairment across various domains. Moreover, this association appears to be more pronounced among men than women. Incorporating these simple assessments into regular clinical practice improves the allocation of limited screening resources and timely clinical interventions in older adults.

1. Introduction

As the global incidence and prevalence of dementia rise with aging populations [1], there is a lack of curative therapy despite advances in disease-modifying drugs. Therefore, focusing on prevention is critical for reducing the dementia burden. Several studies have shown that the proactive management of a multidomain approach is effective in delaying the progression or slowing the onset of dementia [[2], [3], [4]]. In particular, the World Health Organization also stated risk reduction guidelines to endorse the importance of modifiable risk factors in cognitive decline and dementia [5]. However, these public health approaches often require considerable workforce and material resources. Therefore, to effectively utilize public health resources, finding an easily measurable preclinical marker to detect dementia early is paramount in clinical practice.

Handgrip strength has been well established as a strong risk predictor for various adverse health outcomes [6,7] as well as cognitive impairment [8]. Handgrip strength is an inexpensive, noninvasive, and widely available assessment in the clinical setting. Therefore, these characteristics make handgrip strength a potential candidate for a preclinical marker to detect cognitive impairment. Recently, handgrip strength asymmetry has been described as an independent predictor of all-cause mortality [9] and several chronic diseases or conditions [10], including cognitive impairment [11]. Another study reported brain structure evidence showing that asymmetrical handgrip strength might be associated with smaller occipital volumes [12]. Therefore, simultaneously assessing handgrip strength and asymmetry might provide additional information and improve the discriminative ability to predict cognitive impairment risk.

However, due to few studies with longitudinal designs, the predictive ability of handgrip strength asymmetry on cognitive impairment and dementia risk remains uncertain and conflicting [11,13,14]. In a cross-sectional study conducted in Singapore, researchers observed that increased handgrip strength asymmetry was not associated with reduced cognitive function and mobility [13]. In contrast, a longitudinal study involving aging Americans revealed that higher handgrip strength asymmetry was positively correlated with lower cognitive function [11]. Similarly, another longitudinal study involving older Chinese adults established a connection between handgrip strength asymmetry and the risk of developing self-reported neurodegenerative disorders [14].

More importantly, cognitive impairment is a clinically heterogeneous presentation that usually involves deficits in different domains. Less is known about differences in the relationship between handgrip strength asymmetry and specific cognitive domains. Additionally, a previous study has identified that handgrip strength and decline rate vary by sex [15]. Furthermore, elevated levels of inflammatory cytokines are linked to reduced skeletal muscle strength and mass [16]. Longitudinal study design and the impact of sex differences and inflammatory cytokines have been much less investigated. To address existing knowledge gaps, we aimed to elucidate the association between handgrip strength, handgrip strength asymmetry, and their combination with future impairments in both global and specific cognitive domains via a well-designed prospective cohort study.

2. Method

2.1. Study design and population

We used data from wave 3 (2015–2017) to wave 5 (2019–2022) from the ongoing Taiwan Initiative of Geriatric Epidemiological Research (TIGER), with wave 3 as the baseline (n = 446) (Supplemental Fig. 1). The study recruited community-dwelling participants aged 65 years or older. Further information regarding the TIGER can be found elsewhere [17]. We excluded participants who lacked cognitive function data and handgrip strength data at baseline, participants who reported a history of brain tumor ≥3 cm, stroke, or history of head trauma, and participants who had taken medications for Alzheimer’s disease. Further exclusions included participants with suspected dementia at baseline [defined as a score of 21 or below on the Taiwanese version of the Montreal Cognitive Assessment (MoCA-T)]. After exclusion, the present study involved 392 participants. All patients in this study signed written informed consent before participating, and the Research Ethics Committee at National Taiwan University Hospital approved the protocol.

2.2. Handgrip strength assessment

Handgrip strength was measured using a hydraulic hand dynamometer (Lafayette Instruments, Lafayette, Ind., USA) following standardized procedures at baseline [18]. Participants were requested to squeeze as hard as possible with their hands. The mean of two maximal strength attempts on each hand, measured in absolute units (kilograms), as described elsewhere [19], was applied in our study. Weakest handgrip strength was defined as the lowest tertile, moderate handgrip strength as the middle tertile, and strongest handgrip strength as the highest tertile of sex-specific handgrip strength. Based on previous studies [20] and our observational findings (TIGER data), the dominant hand exhibits significantly greater strength in right-handed people. Nevertheless, no significant difference between the two sides could be observed among left-handed individuals. Therefore, the handgrip strength ratio was consistently calculated as left handgrip strength (kilograms)/right handgrip strength (kilograms), regardless of whether the subjects were right- or left-handed. In addition, there is no consensus on defining handgrip strength asymmetry. We modified the definition of a previous study [21] and categorized handgrip-strength asymmetry into three groups based on the handgrip strength ratio: normal (less than 15% difference, 0.85< and <1.15), mild (15-25% difference, 0.75-0.85 or 1.15-1.25) and moderate (more than 25% difference, <0.75 or >1.25). This definition might provide another useful framework for the handgrip strength ratio cutoff point.

In addition, to examine the joint effect of handgrip strength weakness and asymmetry, we further classified abnormal handgrip strength into categories based on the degree of handgrip strength decrease and the handgrip strength asymmetry (Fig. 1). Group 1 was the reference group. Group 2 included individuals with moderate handgrip strength or handgrip strength asymmetry between 15% and 25%. Group 3 included individuals with the weakest handgrip strength or handgrip strength asymmetry greater than 25% or those with both moderate handgrip strength and handgrip strength asymmetry between 15% and 25%. Group 4 consisted of individuals with either the weakest handgrip strength and handgrip strength asymmetry greater than 25%, both moderate handgrip strength and handgrip strength asymmetry greater than 25%, or the weakest handgrip strength and handgrip strength asymmetry between 15% and 25%.

Fig. 1.

Groups of abnormal handgrip strength.

Weakest handgrip strength was defined as the lowest tertile, moderate handgrip strength as the middle tertile, and strongest handgrip strength as the highest tertile of sex-specific handgrip strength. The handgrip strength ratio was calculated as left handgrip strength (kilograms)/right handgrip strength (kilograms).

2.3. Cognitive assessment

The cognitive tests included global and specific cognitive domains and were assessed at baseline (2015–2017) and biennial follow-up phases (2017–2019, 2019–2022) by trained examiners using standardized procedures (Supplemental Table 1). Global cognitive function was assessed using the MoCA-T score, ranging from 0 to 30 points, with higher scores indicating better cognitive functioning. A comprehensive neuropsychological test battery was assessed to measure the specific cognitive domains. The Wechsler Memory Scale-Third Edition (WMS-III) (immediate and delayed theme and free recall) was used to measure logical memory [22]. The Trail Making Tests A and B were used to assess executive function and attention performance. The 1-min fruits, fish, and vegetables fluency test was used to measure verbal fluency. The digit span-forward and backward tests were used to assess attention. To increase the interpretability of our model, we multiplied the Trail Making Test scores by −1, thereby making higher scores indicate better performance. Raw scores of these specific cognitive tests were standardized to z scores based on the baseline sample mean and standard deviations of the corresponding tests. To account for the impact of repeated cognitive tests, we also considered the practice effect of each participant (i.e., numbers were assigned to indicate how many times the tests were taken) as a covariate.

2.4. Covariates

Detailed demographic data and health-related covariates (age, sex, education level, smoking status, drinking status, physical activities, diabetes, hypertension, hyperlipidemia, depressive symptoms, and medication history) were collected from the self-reported baseline assessment questionnaire. A participant meeting any of the following criteria was diagnosed with diabetes: 1) self-reported diabetes; 2) use of antidiabetic drugs; or 3) having a fasting glucose level >126 mg/dl. A participant meeting any of the following criteria was diagnosed with hypertension: 1) self-reported hypertension; 2) use of antihypertensive drugs; or 3) having a systolic/diastolic blood pressure >140/90 mmHg. A participant meeting any of the following criteria was diagnosed with hyperlipidemia: 1) self-reported hyperlipidemia; 2) drug treatment for hyperlipidemia; or 3) dyslipidemia based on blood tests. A participant meeting any of the following criteria was categorized as having depressive symptoms: 1) the Center for Epidemiologic Studies Depression Scale (CES-D) ≥16; or 2) the use of antidepressants. Smoking status was classified as never, former, or current smoker. Physical activities were assessed using the International Physical Activity Questionnaire (IPAQ) and reported as the metabolic equivalent of task-minutes of activity per week (MET-min/week) [23]. Serum high-sensitivity C-reactive protein (hs-CRP) levels (mg/dL) were determined by Beckman Coulter DXC (Beckman Coulter Inc., CA, USA) using immunoturbidimetric assays, while serum interleukin 6 (IL-6) levels (pg/mL) were determined by a TECAN ELISA Reader (TECAN Ltd., Männedorf, Switzerland). Baseline hs-CRP and IL-6 levels (high and low) were divided into two groups with the median. The apolipoprotein E (APOE) ε4 alleles were genotyped by performing TaqMan assays. Participants with at least one ε4 allele were categorized into the APOE ε4 carrier category.

2.5. Statistical analyses

Baseline categorical variables are presented as proportions, and continuous variables are presented as the means and standard deviations (SDs). Differences in continuous variables across the three handgrip strength asymmetry categories were tested for significance using ANOVA or Kruskal–Wallis tests. Differences in categorical variables were tested for significance using the chi-square (χ²) test.

The independent variable was abnormal handgrip strength at baseline. The dependent variables were score changes over time in the aforementioned cognitive tests. First, we used generalized linear mixed models (GLMMs) to assess the association of handgrip strength asymmetry with changes in global cognition and each of the specific cognitive domains over time. Second, we used GLMMs to assess the association of low handgrip strength with changes in global cognition and each of the specific cognitive domains over time. Third, we used GLMMs to assess the association of abnormal handgrip strength (handgrip strength asymmetry plus low handgrip strength) with changes in global cognition and each of the specific cognitive domains over time. These models included a random intercept to account for interpersonal variations. Each model was adjusted for age, years of education, smoking, drinking, hypertension, diabetes, hyperlipidemia, physical activities, depressive symptoms, APOE ε4 status, IL-6, practice effect, and follow-up time. Adjusted covariates were chosen through a review of the relevant literature. In addition to accounting for biological differences in grip strength within sex, each model was analyzed in a sex-stratified manner. To explore whether the relationship between the handgrip strength asymmetry and cognitive impairment varies across different levels of IL6 and hs-CRP. In addition, stratified analyses allow us to identify a subpopulation for intervention purposes. We conducted stratified analyses based on hs-CRP and IL-6 levels (low vs. high) to examine the impact of hs-CRP and IL-6 levels on the significant associations between handgrip strength asymmetry and cognitive function.

Moreover, to reduce the likelihood of a severity order error within the abnormal handgrip strength group, we changed the order from Group 1–4 to Group 1, 3, 2, and 4 (Fig. 1). We conducted separate P trend tests again. The results were reported as beta coefficients together with 95% CIs. All analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC). All statistical tests were two-sided. Significance was indicated by a P value less than 0.05.

3. Results

3.1. Characteristics of the study population

The mean (SD) age of the 392 participants was 75.77 (4.85) years (range 68–90 years). Of the participants, 179 (45.7%) were male (Table 1). The mean (SD) follow-up time was 3.99 (0.33) years. Participants with handgrip strength asymmetry were mostly female, never smokers, and more likely to have a lower handgrip strength. The mean (SD) handgrip strength was 30.29 (6.39) and 18.01 (4.37) kg for males and females, respectively. Mild handgrip strength asymmetry was present in 88 participants (22.4%), while 53 (13.5%) exhibited moderate asymmetry. Moderate handgrip strength was present in 69/75 male/female participants (36.7%), while 56/79 male/female participants (34.4%) exhibited the weakest strength.

Table 1.

Baseline characteristics of study participants according to handgrip strength asymmetry status (N = 392, 2015–2017).

Baseline characteristics	Total (N = 392)	Handgrip strength ratioc			P value
		Normal (<15%) (n = 251)	Mild asymmetry (15%–25%)	Moderate asymmetry (>25%)
			(n = 88)	(n = 53)
Continuous variablesa
Age (years)	75.77 (4.85)	75.76 (4.84)	75.60 (4.91)	76.08 (4.92)	0.85
Education (years)	13.95 (3.48)	14.01 (3.56)	14.01 (3.36)	13.51 (3.33)	0.62
Physical activity (MET-min/week)	2137 (1820)	2200 (1847)	2200 (1903)	1734 (1506)	0.22
Grip strength (kg)	23.62 (8.15)	24.53 (7.70)	22.97 (7.77)	20.39 (9.92)	0.002
Walking speed (m/s)	0.74 (0.20)	0.75 (0.21)	0.73 (0.19)	0.74 (0.19)	0.77
IL-6 (pg/mL)	1.56 (0.67)	1.60 (0.65)	1.44 (0.44)	1.58 (0.99)	0.15
Categorical variablesb
Sex					0.001
Male	179 (45.67)	134 (53.39)	34 (38.64)	11 (20.75)
Female	213 (54.34)	117 (46.61)	54 (61.36)	42 (79.25)
Depressive symptoms	19 (4.8)	10 (4)	6 (6.8)	3 (5.7)	0.54
Hypertension	171 (43.62)	111 (44.22)	36 (40.91)	24 (45.28)	0.84
Diabetes	63 (16.07)	42 (16.73)	10 (11.36)	11 (20.75)	0.30
Hyperlipidemia	232 (59.18)	142 (56.57)	56 (63.64)	34 (64.15)	0.37
APOE ε4 carriers	61 (15.64)	35 (14.06)	16 (18.18)	10 (18.87)	0.52
Cigarette smoking					0.001
Never	338 (86.22)	205 (81.67)	80 (90.91)	53 (100)
Former	41 (10.46)	38 (15.14)	3 (3.41)	0 (0)
Current	13 (3.32)	8 (3.19)	5 (5.68)	0 (0)
Alcohol consumption					0.27
Never	341 (86.99)	213 (84.86)	77 (87.50)	51 (96.23)
Former	26 (6.63)	20 (7.97)	5 (5.68)	1 (1.89)
Current	25 (6.38)	18 (7.17)	6 (6.82)	1 (1.89)

Significant findings are indicated by numbers in bold (P values < 0.05) across handgrip strength asymmetry groups.

Abbreviations: MET, metabolic equivalent of task; APOE, apolipoprotein E; IL-6, interleukin 6.

^aContinuous variables are expressed as the mean (standard deviation).

^bCategorical variables are expressed as numbers (%).

^cThe handgrip strength ratio was calculated as left handgrip strength (kilograms)/right handgrip strength (kilograms).

3.2. Associations between handgrip strength and cognition over time

Over time, increased handgrip strength asymmetry was associated with worsening global cognition [MoCA-T: $\widehat{\text{β}}$ = −1.80, 95% confidence interval (CI): −3.03 to −0.57] and attention (digit span-forward: $\widehat{\text{β}}$ = −0.74, 95% CI: −1.30 to −0.18) over time in men. In contrast, no significant association was observed between handgrip-strength asymmetry and cognition in women (Table 2).

Table 2.

Association between handgrip strength asymmetry and risks of cognitive impairment (2015–2022).

	Handgrip strength ratioa			P trend
	Normal (<15%)	Mild asymmetry (15%–25%)	Moderate asymmetry (>25%)
	(n = 251)	(n = 88)	(n = 53)
	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)
Men
Global cognition (MoCA-T)	Ref.	−0.45 (−1.20, 0.30)	−1.80 (−3.03, −0.57)	0.004
Immediate theme recall	Ref.	−0.21 (−0.59, 0.17)	−0.21 (−0.84, 0.42)	0.27
Immediate free recall	Ref.	−0.15 (−0.51, 0.22)	−0.34 (−0.94, 0.26)	0.20
Delayed theme recall	Ref.	−0.06 (−0.46, 0.32)	−0.67 (−1.31, −0.03)	0.08
Delayed free recall	Ref.	−0.06 (−0.43, 0.31)	−0.53 (−1.12, 0.07)	0.14
Trail Making Test-A	Ref.	−0.13 (−0.42, 0.17)	−0.43 (−0.92, 0.05)	0.08
Trail Making Test-B	Ref.	−0.18 (−0.51, 0.15)	−0.40 (−0.94, 0.14)	0.10
Verbal fluency	Ref.	−0.28 (−0.64, 0.09)	0.20 (−0.41, 0.80)	0.72
Digit span-forward	Ref.	−0.40 (−0.74, −0.07)	−0.74 (−1.30, −0.18)	0.001
Digit span-backward	Ref.	−0.32 (−0.65, 0.01)	−0.20 (−0.75, 0.34)	0.10
Women
Global cognition (MoCA-T)	Ref.	0.07 (−0.47, 0.61)	0.07 (−0.51, 0.64)	0.78
Immediate theme recall	Ref.	−0.16 (−0.44, 0.11)	−0.20 (−0.49, 0.09)	0.13
Immediate free recall	Ref.	−0.03 (−0.32, 0.27)	−0.10 (−0.41, 0.21)	0.53
Delayed theme recall	Ref.	−0.17 (−0.46, 0.12)	−0.20 (−0.50, 0.11)	0.16
Delayed free recall	Ref.	−0.04 (−0.35, 0.26)	−0.18 (−0.51, 0.15)	0.29
Trail Making Test-A	Ref.	0.11 (−0.17, 0.40)	0.06 (−0.25, 0.37)	0.57
Trail Making Test-B	Ref.	−0.08 (−0.40, 0.23)	−0.10 (−0.43, 0.23)	0.50
Verbal fluency	Ref.	−0.06 (−0.36, 0.23)	0.14 (−0.18, 0.45)	0.51
Digit span-forward	Ref.	−0.17 (−0.42, 0.08)	−0.01 (−0.28, 0.26)	0.70
Digit span-backward	Ref.	−0.14 (−0.41, 0.14)	0.05 (−0.24, 0.34)	0.96

All models were adjusted for age, years of education, smoking, drinking, hypertension, diabetes, hyperlipidemia, physical activity, depressive symptoms, APOE ε4 status, IL-6, practice effect, and follow-up time.

$\widehat{\text{β}}$ indicates that the group with handgrip strength asymmetry compared to the normal group was associated with an increase/decrease in the Z score of a specific cognitive domain after adjusting for covariates.

Significant findings are indicated by numbers in bold (P values < 0.05).

Abbreviations: CI, confidence interval; MoCA-T, Taiwanese version of Montreal Cognitive Assessment.

^aThe handgrip strength ratio was calculated as left handgrip strength (kilograms)/right handgrip strength (kilograms).

Low handgrip strength in men was associated with worsening global cognitive function (MoCA-T: $\widehat{\text{β}}$ = −1.21, 95% CI: −2.00 to −0.41), worsening memory function (immediate free recall: $\widehat{\text{β}}$ = −0.46, 95% CI: −0.84 to −0.07; delayed free recall: $\widehat{\text{β}}$ = −0.45, 95% CI: −0.84 to −0.06), worsening executive function (Trail Making Test-A: $\widehat{\text{β}}$ = −0.48, 95% CI: −0.79 to −0.17; Trail Making Test-B: $\widehat{\text{β}}$ = −0.40, 95% CI: −0.79 to −0.05), and worsening attention function (digit span-forward: $\widehat{\text{β}}$ = −0.66, 95% CI: −1.02 to −0.31) over time. Low handgrip strength in women was associated with worsening global cognitive function (MoCA-T: $\widehat{\text{β}}$ = −0.58, 95% CI: −1.14 to −0.01), worsening memory function (immediate free recall: $\widehat{\text{β}}$ = −0.39, 95% CI: −0.69 to −0.08; delayed free recall: $\widehat{\text{β}}$ = −0.42, 95% CI: −0.74 to −0.10), and worsening verbal fluency (1-min fluency test: $\widehat{\text{β}}$ = −0.34, 95% CI: −0.65 to −0.04) over time (Table 3).

Table 3.

Association between low handgrip strength and risks of cognitive impairment (2015–2022).

	Handgrip strength			P trend
	Strongest (n = 113)	Moderate (n = 144)	Weakest (n = 135)
	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)
Men
Global cognition (MoCA-T)	Ref.	0.01 (−0.68, 0.69)	−1.21 (−2.00, −0.41)	0.005
Immediate theme recall	Ref.	−0.19 (−0.54, 0.16)	−0.30 (−0.70, 0.11)	0.14
Immediate free recall	Ref.	−0.35 (−0.68, −0.01)	−0.46 (−0.84, −0.07)	0.02
Delayed theme recall	Ref.	−0.12 (−0.49, 0.24)	−0.22 (−0.64, 0.21)	0.31
Delayed free recall	Ref.	−0.35 (−0.68, −0.01)	−0.45 (−0.84, −0.06)	0.02
Trail Making Test-A	Ref.	−0.05 (−0.32, 0.22)	−0.48 (−0.79, −0.17)	0.004
Trail Making Test-B	Ref.	−0.03 (−0.33, 0.28)	−0.40 (−0.76, −0.05)	0.03
Verbal fluency	Ref.	0.04 (−0.30, 0.38)	−0.30 (−0.69, 0.10)	0.16
Digit span-forward	Ref.	−0.11 (−0.41, 0.20)	−0.66 (−1.02, −0.31)	0.0005
Digit span-backward	Ref.	0.01 (−0.30, 0.31)	−0.32 (−0.67, 0.03)	0.09
Women
Global cognition (MoCA-T)	Ref.	−0.34 (−0.90, 0.21)	−0.58 (−1.14, −0.01)	0.046
Immediate theme recall	Ref.	0.10 (−0.18, 0.39)	−0.12 (−0.41, 0.17)	0.38
Immediate free recall	Ref.	−0.21 (−0.51, 0.09)	−0.39 (−0.69, −0.08)	0.01
Delayed theme recall	Ref.	0.04 (−0.26, 0.34)	−0.17 (−0.48, 0.13)	0.24
Delayed free recall	Ref.	−0.26 (−0.57, 0.06)	−0.42 (−0.74, −0.10)	0.01
Trail Making Test-A	Ref.	−0.05 (−0.34, 0.24)	−0.23 (−0.54, 0.06)	0.11
Trail Making Test-B	Ref.	−0.21 (−0.53, 0.11)	−0.11 (−0.43, 0.22)	0.57
Verbal fluency	Ref.	−0.36 (−0.66, −0.06)	−0.34 (−0.65, −0.04)	0.04
Digit span-forward	Ref.	−0.15 (−0.41, 0.11)	−0.13 (−0.40, 0.13)	0.35
Digit span-backward	Ref.	−0.12 (−0.40, 0.15)	−0.15 (−0.43, 0.14)	0.33

Significant findings are indicated by numbers in bold (P values < 0.05).

Abbreviations: CI, confidence interval; MoCA-T, Taiwanese version of Montreal Cognitive Assessment.

All models were adjusted for age, years of education, smoking, drinking, hypertension, diabetes, hyperlipidemia, physical activity, depressive symptoms, APOE ε4 status, IL-6, practice effect, and follow-up time.

$\widehat{\text{β}}$ indicates that the group with handgrip strength asymmetry compared to the normal group was associated with an increase/decrease in the Z score of a specific cognitive domain after adjusting for covariates.

Weakest handgrip strength was defined as the lowest tertile (men: 13.0–27.5 kg; women: 4.0–16.0 kg), moderate handgrip strength as the middle tertile (men: 28.0–32.0 kg; women: 16.5–20.0 kg), and strongest handgrip strength as the highest tertile (men: 32.5–72 kg; women: 20.5–29.0 kg) of sex-specific handgrip strength.

After conducting the sensitivity analysis (Supplemental Table 2), the abnormal handgrip strength group order aligned more reasonably with the order depicted in Fig. 1. The co-existence of low handgrip strength and handgrip strength asymmetry in men was associated with worsening global cognitive function (MoCA-T: $\widehat{\text{β}}$ = −1.76, 95% CI: −2.79 to −0.74), worsening memory function (immediate free recall: $\widehat{\text{β}}$ = −0.67, 95% CI: −1.17 to −0.17; delayed free recall: $\widehat{\text{β}}$ = −0.70, 95% CI: −1.20 to −0.20), worsening executive function (Trail Making Test-A: $\widehat{\text{β}}$ = −0.54, 95% CI: −0.94 to −0.13), and worsening attention (digit span-forward: $\widehat{\text{β}}$ = −1.00, 95% CI: −1.46 to −0.54) over time. The co-existence of low handgrip strength and handgrip-strength asymmetry in women was associated with worsening memory function (immediate free recall: $\widehat{\text{β}}$ = −0.45, 95% CI: −0.84 to −0.06; and delayed free recall: $\widehat{\text{β}}$ = −0.51, 95% CI: −0.91 to −0.10) over time (Table 4).

Table 4.

The effect of co-existence of low handgrip strength and handgrip strength asymmetry on cognitive impairment (2015–2022).

	Group 1 (n = 72)	Group 2 (n = 131)	Group 3 (n = 115)	Group 4 (n = 74)	P trend
	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)
Men
Global cognition (MoCA-T)	Ref.	−0.04 (−0.78, 0.69)	−0.77 (−1.65, 0.12)	−1.76 (−2.79, −0.74)	0.0004
Immediate theme recall	Ref.	−0.33 (−0.71, 0.04)	−0.27 (−0.73, 0.18)	−0.52 (−1.05, 0.01)	0.08
Immediate free recall	Ref.	−0.39 (−0.75, −0.03)	−0.42 (−0.85, 0.01)	−0.67 (−1.17, −0.17)	0.01
Delayed theme recall	Ref.	−0.18 (−0.58, 0.21)	−0.03 (−0.50, 0.44)	−0.53 (−1.08, 0.02)	0.14
Delayed free recall	Ref.	−0.35 (−0.71, 0.02)	−0.33 (−0.76, 0.10)	−0.70 (−1.20, −0.20)	0.01
Trail Making Test-A	Ref.	−0.02 (−0.31, 0.27)	−0.28 (−0.63, 0.06)	−0.54 (−0.94, −0.13)	0.004
Trail Making Test-B	Ref.	0.04 (−0.30, 0.37)	−0.50 (−0.90, −0.11)	−0.38 (−0.84, 0.07)	0.01
Verbal fluency	Ref.	−0.01 (−0.39, 0.36)	−0.23 (−0.67, 0.22)	−0.29 (−0.81, 0.22)	0.17
Digit span-forward	Ref.	−0.27 (−0.60, 0.05)	−0.58 (−0.97, −0.19)	−1.00 (−1.46, −0.54)	<0.0001
Digit span-backward	Ref.	−0.18 (−0.51, 0.15)	−0.37 (−0.77, 0.03)	−0.45 (−0.91, 0.01)	0.03
Women
Global cognition (MoCA-T)	Ref.	−0.38 (−1.07,0.32)	−0.27 (−0.96, 0.40)	−0.56 (−1.29, 0.17)	0.20
Immediate theme recall	Ref.	0.05 (−0.29, 0.40)	0.05 (−0.29, 0.40)	−0.28 (−0.65, 0.08)	0.11
Immediate free recall	Ref.	−0.14 (−0.52, 0.23)	−0.09 (−0.46, 0.27)	−0.45 (−0.84, −0.06)	0.04
Delayed theme recall	Ref.	0.04 (−0.33, 0.41)	−0.01 (−0.38, 0.35)	−0.31 (−0.70, 0.08)	0.08
Delayed free recall	Ref.	−0.13 (−0.52, 0.26)	−0.16 (−0.66, 0.22)	−0.51 (−0.91, −0.10)	0.01
Trail Making Test-A	Ref.	−0.21 (−0.58, 0.16)	−0.22 (−0.58, 0.15)	−0.22 (−0.61, 0.17)	0.33
Trail Making Test-B	Ref.	−0.10 (−0.50, 0.30)	0.07 (−0.32, 0.46)	−0.29 (−0.71, 0.13)	0.23
Verbal fluency	Ref.	−0.28 (−0.66, 0.10)	−0.14 (−0.52, 0.23)	−0.31 (−0.70, 0.09)	0.30
Digit span-forward	Ref.	−0.14 (−0.47, 0.19)	−0.03 (−0.35, 0.29)	−0.21 (−0.56, 0.13)	0.39
Digit span-backward	Ref.	−0.35 (−0.70, −0.01)	−0.13 (−0.47, 0.21)	−0.24 (−0.60, 0.13)	0.60

Significant findings are indicated by numbers in bold (P values < 0.05).

Abbreviations: CI, confidence interval; MoCA-T, Taiwanese version of Montreal Cognitive Assessment.

Group 1: reference; Group 2: moderate handgrip strength or handgrip strength asymmetry (ratio = 15%–25%); Group 3: weakest handgrip strength or handgrip strength asymmetry (ratio > 25%) or moderate handgrip strength & handgrip strength asymmetry (ratio = 15%–25%); Group 4: weakest handgrip strength & handgrip strength asymmetry (ratio > 25%) or moderate handgrip strength & handgrip strength asymmetry (ratio > 25%) or weakest handgrip strength & handgrip strength asymmetry (ratio = 15%–25%).

The handgrip strength ratio was calculated as left handgrip strength (kilograms)/right handgrip strength (kilograms).

$\widehat{\text{β}}$ indicates the other group compared to the group 1 was associated with an increase/decrease in the Z score of a specific cognitive domain after adjusting for covariates.

All models were adjusted for age, years of education, smoking, drinking, hypertension, diabetes, hyperlipidemia, physical activity, depressive symptoms, APOE ε4 status, IL-6, practice effect, and follow-up time.

3.3. Stratified analyses based on hs-CRP and IL-6 levels

We further conducted stratified analyses for the significant findings presented in Table 2. Although the interaction between IL-6 levels and handgrip strength asymmetry was not statistically significant, among men with higher IL-6 levels, baseline handgrip strength asymmetry (25%) predicted worsening global cognitive function ($\widehat{\text{β}}$ = −1.84; 95% CI: −3.55 to −0.12) (Table 5) and worsening memory function (delayed theme recall: $\widehat{\text{β}}$ = −1.19; 95% CI: −2.06 to −0.33). Similarly, although the interaction between hs-CRP levels and handgrip strength asymmetry was not statistically significant, among men with higher hs-CRP levels, handgrip strength asymmetry (25%) predicted worsening global cognitive function ($\widehat{\text{β}}$ = −2.21; 95% CI: −4.13 to −0.28), worsening memory function (delayed theme recall: $\widehat{\text{β}}$ = −1.05; 95% CI: −1.99 to −0.10) and worsening attention (digit span- forward: $\widehat{\text{β}}$ = −0.87; 95% CI: −1.70 to −0.04).

Table 5.

The effect of handgrip strength asymmetry on cognitive impairment stratified by levels of IL-6 and hs-CRP (2015–2022).

	Handgrip strength ratioa			Pinteractions
	Normal (<15%)	Mild asymmetry (15%–25%)	Moderate asymmetry (>25%)
	(n = 251)	(n = 88)	(n = 53)
	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)	$\widehat{\text{β}}$ (95% CI)
Stratified by IL-6 levels
Global cognition (MoCA-T)				0.98
Low IL-6	Ref.	−0.40 (−1.43, 0.63)	−1.80 (−3.70, 0.11)
High IL-6	Ref.	−0.29 (−1.50, 0.91)	−1.84 (−3.55, −0.12)
Delayed theme recall				0.13
Low IL-6	Ref.	−0.02 (−0.57, 0.51)	−0.25 (−1.26, 0.76)
High IL-6	Ref.	−0.09 (−0.69, 0.51)	−1.19 (−2.06, −0.33)
Digit span-forward				0.98
Low IL-6	Ref.	−0.28 (−0.71, 0.14)	−0.79 (−1.61, 0.02)
High IL-6	Ref.	−0.53 (−1.08, 0.03)	−0.70 (−1.51, 0.11)
Stratified by hs-CRP levels
Global cognition (MoCA-T)
Low hs-CRP	Ref.	−0.47 (−1.27, 0.33)	−0.89 (−2.44, 0.66)	0.52
High hs-CRP	Ref.	0.28 (−1.13, 1.70)	−2.21 (−4.13, −0.28)
Delayed theme recall				0.23
Low hs-CRP	Ref.	0.03 (−0.44, 0.49)	−0.34 (−1.24, 0.56)
High hs-CRP	Ref.	−0.39 (−1.06, 0.28)	−1.05 (−1.99, −0.10)
Digit span- forward
Low hs-CRP	Ref.	−0.35 (−0.79, 0.09)	−0.49 (−1.33, 0.36)	0.64
High hs-CRP	Ref.	−0.35 (−0.95, 0.23)	−0.87 (−1.70, −0.04)

Significant findings are indicated by numbers in bold (P values < 0.05).

All models were adjusted for age, years of education, smoking, drinking, hypertension, diabetes, hyperlipidemia, physical activity, depressive symptoms, APOE ε4 status, IL-6, practice effect, and follow-up time.

Baseline IL-6 and hs-CRP levels were divided into two groups (high and low) with equal numbers of participants across the categories. The median values of IL-6 and hs-CRP were 1.46 (pg/mL) and 0.09 (mg/dL), respectively.

$\widehat{\text{β}}$ indicates that the group with handgrip strength asymmetry compared to the normal group was associated with an increase/decrease in the Z score of a specific cognitive domain after adjusting for covariates.

Abbreviations: hs-CRP, high-sensitivity C-reactive protein; CI, confidence interval; MoCA-T, Taiwanese version of Montreal Cognitive Assessment.

^aThe handgrip strength ratio was calculated as left handgrip strength (kilograms)/right handgrip strength (kilograms).

4. Discussion

This study is the first to show that low handgrip strength, handgrip strength asymmetry, and their combinations were associated with specific domains of cognitive impairment in community-dwelling older adults, especially in men. In addition, these associations were particularly noticeable in participants with elevated hs-CRP and IL-6 levels. These findings remained after controlling for various lifestyles, medical comorbidities, and practice effects known to affect cognitive functioning. Until now, studies on handgrip strength asymmetry in cognitive impairment have been limited to cross-sectional or longitudinal examinations with a short follow-up. We filled these gaps by identifying the relationship between the risk of cognitive impairment and handgrip strength over seven years.

We extended previous studies [24] on the relationship between handgrip strength and cognition by conducting a longitudinal analysis and investigating the association between handgrip strength asymmetry and cognition. While many studies have examined the impact of handgrip strength asymmetry on various outcomes [9,25], only a few have specifically focused on its influence on cognitive outcomes. Chen et al. [14] found that the risk of developing neurodegenerative disorders (e.g., Parkinson’s disease, brain atrophy, or dementia) among older Chinese adults is linked to handgrip strength asymmetry. Nevertheless, they did not conduct a subgroup analysis for each disorder. In a cross-sectional study, decreased handgrip strength (not asymmetry) was associated with reduced cognitive function and mobility [13]. Furthermore, consistent with our findings, a longitudinal panel study by McGrath et al. revealed a positive correlation between handgrip strength asymmetry and lower cognitive function in aging Americans during a single follow-up [11]. Our longitudinal analysis, featuring three repeated cognitive tests, reaffirmed that the link between handgrip strength asymmetry and cognitive impairment is primarily observed in men. In addition, these associations are particularly pronounced among participants with higher inflammatory markers (hs-CRP and IL-6). Inflammation, as indicated by elevated levels of IL-6 and hs-CRP, can contribute to the loss of muscle mass and function [26] and may also directly impact brain health and cognitive impairment [27,28]. The effects of IL-6 and hs-CRP are thought to be related to inflammatory processes that can affect both grip strength and cognitive function in aging individuals. Our results provide preliminary evidence and imply that participants with higher IL-6 and hs-CRP, such as those with chronic diseases (cardiovascular disease, diabetes, and frailty) [29], might be better suited to utilize handgrip strength asymmetry as a predictor of cognitive impairment.

Our studies also particularly focus on specific domains of cognitive impairment rather than global cognition only. We found that associations of the co-existence of low handgrip strength and handgrip strength asymmetry with cognitive impairment in global cognition, executive function, and attention were significant in men but not in women. McGrath et al.’s longitudinal study [11] revealed a positive association between handgrip strength and global cognitive function. Kim et al.’s population-based cohort study on older Korean adults [19] found that higher handgrip strength was linked to a reduced subsequent risk of cognitive impairment. However, a fundamental limitation across these prior studies is that these associations are mainly based on research on global cognition. Additionally, there is a need for longitudinal studies to assess the relationship between low handgrip strength and handgrip strength asymmetry with specific cognitive domains. In older American men over the age of 60, grip strength is positively associated with acquiring new vocabulary information and verbal fluency, while no such relationship was observed in older women [30]. Similarly, in another Chinese study, better handgrip strength in men was associated with better language and memory performance, with no such correlations noted in older women [31]. However, two of the aforementioned studies were conducted using a cross-sectional design and without discussing handgrip strength asymmetry. The discrepancy between our results and the studies mentioned above may be partly due to differences in the cognitive assessment tools, sample population characteristics, the temporal stages of decline in various cognitive domains, and the duration of the follow-up period [32]. Together, the group analysis in our study provides additional information on the relationship between handgrip strength/asymmetry and cognitive impairment. Previous literature [33] has shown that there are many ways to measure and calculate grip strength. Our intention is not to replace grip strength with grip asymmetry but to offer a complementary and additional method. Many grip strength protocols traditionally measure grip strength for both the left and right hands, but those measures have yet to be studied and used effectively. Furthermore, cognitive impairment has various domains [34], and separate and combined grip strength and asymmetry are associated with different cognitive domains. Our study results confirmed the above information and underscored the novelty of our research being focused on specific cognitive domains.

Plausible mechanisms linking handgrip strength asymmetry to cognitive impairment involve hemispheric specialization [35], with dominant hand efficiency in spatial attention processes [36]. Cognitive impairment may lead to a compensatory mechanism of lateral shifting between brain hemispheres to counteract losses in one hemisphere [37]. Brain structure evidence supports these findings, showing a slightly greater rate of volume reduction in the right subfields than in the left subfields among individuals with Alzheimer’s disease compared with the general population [38]. In addition, the dominant and nondominant hands have complementary roles in motor performance, relying on different cognitive domains. The dominant right hand/left hemisphere relies more on visual feedback for movement, while the nondominant left hand/right hemisphere is more skillful at utilizing proprioceptive information [39]. However, with cognitive decline, this coordinated mechanism becomes less efficient [37] and might result in handgrip strength asymmetry. These mechanisms may explain the observed variation in the association between handgrip strength asymmetry and various domains of cognitive impairment.

Early diagnosis of cognitive decline and dementia is crucial for effective management and intervention planning. Employing public health approaches in the early stages has demonstrated improvement in cognitive functioning, potentially delaying underlying degenerative processes and slowing the disease course [2]. However, these strategies often require considerable workforce and material resources. Furthermore, many emerging dementia cases have been from developing countries or underserved areas with limited medical resources [40]. Handgrip strength is an inexpensive, noninvasive, and widely available assessment in the clinical setting and can easily applied to community settings. Our results showed that reduced handgrip strength and handgrip strength asymmetry increased the risk of cognitive impairment across various domains. This confirmed the role of handgrip strength asymmetry as an effective assessment tool for the early diagnosis, detection, or identification of cognitive impairment. We can implement handgrip strength asymmetry in regular clinical practice in screening methods when diagnosing cognitive impairment or massive screening in communities. It helps healthcare providers identify patients at risk and prioritize them for more in-depth assessments. If a patient has handgrip strength asymmetry, healthcare providers can recommend timely interventions [2,41], such as specific exercises, dietary changes, or mental activities to maintain or improve cognitive function.

This study has several strengths worth noting. First, four cognitive domains (including memory, attention, verbal fluency, and executive function) were evaluated using a battery of cognitive tests, which may have captured more subtle changes regarding these domains. Second, the repeated face-to-face cognitive assessment data enable us to better understand how handgrip strength relates to changes in cognitive function over time. Third, evaluating associations in a relatively healthy population in our study enhances the generalizability of the findings to community population screening because early detection and intervention at a silent preclinical stage is crucial. Fourth, this study underlines the value of exploring neglected aspects of inflammation markers and sex differences.

Nevertheless, the current study has some limitations that should be acknowledged. First, only cognitive tests are used to define cognitive impairment, and they cannot confirm the underlying brain pathology change. Nevertheless, these clinical tests of cognition have been validated and strongly correlate with cognitive impairment. Second, we could not divide the population into subgroups based on dominant and nondominant handgrip strength asymmetry due to the small sample size in the nondominant handgrip strength asymmetry group. However, right-handed individuals were shown to exhibit significantly greater strength in their dominant hand, while no significant difference in strength between sides was observed among left-handed individuals [20]. Third, the potential exists for a learning effect to have influenced the results as participants became more familiar with repeated cognitive testing. However, we account for this effect when applying the statistical analysis method.

5. Conclusions

Older adults with isolated instances or co-existence of low handgrip strength and handgrip strength asymmetry have an increased risk of different domains of cognitive impairment. This relationship seems more prominent in men than in women. Incorporating these simple assessments into regular clinical practice improves the allocation of limited screening resources and timely clinical interventions in older adults.

Author’s contributions

Study design: Tao-Chun Peng, Jen-Hau Chen, Yen-Ching Chen.

Data collection: Tao-Chun Peng, Jen-Hau Chen, Yen-Ching Chen.

Data analysis: Tao-Chun Peng, Jeng-Min Chiou, Jen-Hau Chen.

Drafting of the manuscript: Tao-Chun Peng, Yen-Ching Chen.

All authors read and approved the final version of the manuscript.

Financial support

This study was supported by the Ministry of Science and Technology in Taiwan (100-2314-B-002-103, 101-2314-B-002-126-MY3, 103-2314-B-002-033-MY3, 104-2314-B-002-038-MY3, 107-2314-B-002-186-MY3, 107-2314-B-002-230, 108-2314-B-002-128-MY2, 110-2118-M-001-002-MY3, 110-2314-B-002-068, 110-2314-B-002-129-MY3, and 111-2314-B-002-090-MY3).

Sponsor’s role

The sponsors had no role in the design, methods, participant recruitment, data collection, analysis, and article preparation.

Conflict of interest

No potential conflicts of interest were disclosed.

Appendix A. Supplementary data

The following is Supplementary data to this article: