If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, ChinaSchool of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, ChinaSchool of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
Address correspondence to Zhendong Liu, MD, Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwuweiqi Road, Jinan, Shandong 250021, China.
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, ChinaSchool of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
To investigate excessive dietary salt intake as an independent risk factor of cognitive impairment and dementia in older adults.
Design
Prospective, population-based cohort study.
Settings and Participants
Two thousand forty-one community residents aged ≥60 years were recruited between April 2007 and August 2009 from the Shandong area of China.
Measurements
Participants were classified into low, mild, moderate, and high salt intake groups according to urinary sodium measurements for 7 consecutive days. Global cognitive function was assessed at baseline and biennially thereafter using the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Dementia Rating Scale (DRS), and Informant Questionnaire on Cognitive Decline in the Elderly. Demographics and apolipoprotein E (APOE) genotype were also obtained for each participant. Participants were monitored for 11.4 ± 2.0 years.
Results
During follow-up, MMSE, MoCA, and DRS scores decreased progressively faster with increasing salt intake (Padjustment < 0.05 among all intake groups). In total, 319 participants (13.74 per 1000 person-years) developed cognitive impairment. Compared with the low salt intake group, cognitive impairment risk was increased by 75% in the mild group (Padjustment = 0.027), 180% in the moderate group (Padjustment < 0.001), and 330% in the high group (Padjustment < 0.001) after adjustment for age, education, mean, and variability in visit-to-visit systolic and diastolic blood pressure, and APOE genotype. The hazard ratio for cognitive impairment increased by 1.59 (95% CI 1.40-1.79) with each 1-SD increment in salt intake after confounder adjustment (Padjustment < 0.001).
Conclusions and Implications
Excessive dietary salt impairs cognitive function and increases cognitive impairment risk in older adults independently of known risk factors, including hypertension and APOE genotype.
Dementia is a clinically heterogenous condition that frequently includes memory deficits, impulsivity, poor communication skills, apathy, hallucinations, and motor dysfunction, impairments that collectively diminish functional independence and quality of life, and place enormous burdens on family caregivers and health care systems.
GBD 2013 Mortality and Causes of Death Collaborators Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013.
It is thus critical to identify risk factors for dementia in order to facilitate the development of preventive and therapeutic measures.
Table salt (sodium chloride) is an essential nutrient and major food additive, but excessive dietary salt intake is known to induce hypertension, neurotoxicity, and endothelial dysfunction, reduce cerebral blood flow, increase cerebral small vessel disease risk, and disrupt gut-initiated adaptive immune responses, effects that can lead to cognitive impairment and numerous additional health effects.
However, the influence of excessive dietary salt consumption on cognitive impairment and dementia risk in older adults remains unclear.
The main goal of the current study was to investigate the effects of salt intake on emergent cognitive impairment and dementia risk in a large cohort of healthy community-dwelling older adults.
Methods
Participants
A total of 2041 individuals aged ≥60 years were randomly selected from a prospective study cohort recruited between April 2007 and August 2009 in the Shandong area of China (ChiCTR-EOC-17013598).
The original cohort consisted of 21,000 individuals aged ≥15 years who had no plans to leave the study area within 5 years. Exclusion criteria were as follows: failure to complete a 7-day salt intake assessment, changes in salt intake style during follow-up, failure to complete global cognitive function assessments, no determination of apolipoprotein E (APOE) genotype, diagnosed with dementia and/or cognitive impairment or psychosis at baseline, unwillingness to provide informed consent, or history of stroke or transient ischemic attack, head injury, drug or alcohol abuse, congestive heart failure, myocardial infarction, liver dysfunction, renal dysfunction, or malignancy. During follow-up, we also planned to drop participants for a change in salt intake group in order to reduce the confounding effects of diet–health status covariance. This study was approved by the Research Ethics committee of the Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China, and all participants provided their written informed consent.
Salt Intake Estimation
Twenty-four-hour urine collection is widely regarded as the gold standard method for assessment of salt intake and is endorsed by the World Health Organization (WHO).
In this study, we used 24-hour urine samples collected over 7 consecutive days to estimate salt intake in the spring and autumn at baseline. Participants were asked to record sweating and maintain daily dietary habit logs during 24-hour urine collection. The urinary Na+ concentration was measured using a DSI-905 electrolyte analyzer (Xunda Medical Instrument Co, Ltd, Shanghai, China) and results used to estimate salt intake according to the following formula: salt intake (g/d) = [concentration of Na+ (mmol/L)/17 (mmol/g)] × urine volume (L/d). Twenty-four-hour urine creatinine excretion was used to monitor the urine collection. Participants were classified into low (≤6 g/d), mild (>6 but ≤9 g/d), moderate (>9 but <12 g/d), and high salt intake (≥12 g/d) groups in accordance with the Dietary Guidelines for Chinese Residents.
We used the Chinese version of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Mattis Dementia Rating Scale (DRS) to assess global cognitive function as described.
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
All tests were administered by experienced neuropsychology research assistants blinded to salt intake, clinical and laboratory data, and APOE genotype. The interobserver coefficients of variation were 0.90 for the MMSE, 0.91 for the MoCA, and 0.89 for the DRS score in random testing of 30 participants. Global cognitive functions were then assessed biennially after the baseline survey.
Assessment of the Informant Questionnaire on Cognitive Decline in the Elderly
We used a shortened Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
to further support progressive cognitive impairment among participants exhibiting reduced MMSE, MoCA, and DRS scores during the follow-up period. The IQCODE rates the changes in cognitive function from 10 years earlier and is used throughout the world as an informant (proxy)-rated complementary screening tool for dementia. The IQCODE was completed independently by spouses, friends, relatives, or caregivers able to assess the participant's cognitive capacity 10 years earlier.
APOE Genotyping
The APOE genotype was identified based on the presence of single-nucleotide polymorphisms rs7412 and rs429358 by polymerase chain reaction using the TaqMan genotyping Kit (Applied Biosystems). Participants were categorized as ε4 carriers, carrying at least one ε4 allele, or non–ε4 carriers.
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
Effect of low-dose statins and apolipoprotein E genotype on cerebral small vessel disease in older hypertensive patients: a subgroup analysis of a randomized clinical trial.
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
The cutoff of the MMSE for cognitive impairment was ≤23 points or a decline ≥3 points between any 2 follow-up visits or MoCA <20 points, DRS <120 points, and the IQCODE ≥3.38.
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
Secondary outcomes were the changes in MMSE, MoCA, and DRS scores during follow-up.
Statistical Analysis
Continuous variables are expressed as mean with SDs or median with interquartile range (25th to 75th percentile) depending on normality of the distribution according to the Kolmogorov-Smirnov test, whereas categorical data are presented as frequency with percentage. Normally distributed continuous variables were compared between 2 groups by independent samples t test and among more than 2 groups by 1-way analysis of variance (ANOVA) with post hoc Bonferroni tests for pairwise comparisons, whereas nonnormally distributed continuous variables were compared between 2 groups by Mann-Whitney U test and among more than 2 groups by Kruskal-Wallis test with post hoc Bonferroni tests for pairwise comparisons. Categorical variables were compared by χ2 test. Cumulative incidence of cognitive impairment was estimated using the Kaplan-Meier method and compared among groups by log-rank test. Hazard ratios (HRs) with 95% CIs was assessed using Cox proportional hazards models. A linear mixed model was used to compare the changes in MMSE, MoCA, and DRS scores during follow-up among salt intake groups. Model 1 was unadjusted, whereas model 2 was adjusted for age, sex, smoking status, drinking, and education. Model 3 was adjusted for the confounders in model 2 as well as baseline body mass index, blood pressure, fasting plasma glucose, and plasma lipids; histories of hypertension, diabetes, and dyslipidemia; use of antihypertensive, glucose-lowering, antidyslipidemic, and antiplatelet medications; and APOE genotype. Model 4 was adjusted for confounders in model 3 and the changes in mean visit-to-visit systolic and diastolic blood pressure. Chained equations were used for imputing missing data for variables. All statistical analyses were performed using SPSS, version 26.0 (SPSS Inc), and graphs were created using GraphPad Prism, version 9.1.0 (GraphPad Software). A 2-sided P < .05 was considered statistically significant for all tests.
Results
Baseline Demographic and Clinical Characteristics of the Study Population
Figure 1 presents a summary flowchart of this study, whereas Table 1 and Supplementary Table 1 summarize demographic and clinical characteristics of the participants and excluded subjects at baseline, respectively. There were no significant differences in demographic or clinical characteristics among salt intake groups. Further, there were no significant differences between included and excluded participants, indicating that exclusion criteria did not introduce any substantial bias.
Changes in Global Cognitive Function During Follow-up
Scores on the MMSE, MoCA, and DRS decreased in all 4 salt intake groups during the follow-up period (Figure 2), but the magnitudes of these decreases differed significantly among groups even after adjustment for the mean and visit-to-visit variability in systolic blood pressure (Padjustment < 0.001). Decreases in MMSE, MoCA, and DRS scores were significantly greater in the high salt intake group than the low, mild, and moderate groups, significantly greater in the moderate group compared to the low and mild groups, and greater in the mild group than in the low group (all Padjustment < 0.05). Thus, greater dietary salt intake was strongly associated with an accelerated decline in global cognition.
Fig. 2Changes in global cognitive function and cumulative hazard of cognitive impairment in older adults stratified by salt intake. (A-C) Changes in MMSE score (A), MoCA score (B), and DRS score (C) during study follow-up for each salt intake group. (D) Cumulative hazard of cognitive impairment for each salt intake group. Note that the decreases in global cognitive function assessment scores during follow-up were accelerated by greater salt intake.
Associations of Salt Intake With Cognitive Impairment and Dementia Risk
Over an average 11.4 ± 2.0 years of follow-up, 319 participants (13.74 per 1000 person-years) developed cognitive impairment. Among them, 21 (5.34 per 1000 person-years) were in the low salt intake group, 63 (9.52 per 1000 person-years) in the mild group, 100 (14.94 per 1000 person-years) in the moderate group, and 135 (22.61 per 1000 person-years) in the high salt intake group. After adjustment for confounders including the mean and visit-to-visit variation (SD) in systolic blood pressure, the HR for cognitive impairment was 1.75 (95% CI 1.07-2.88) in the mild salt intake group (Padjustment = 0.027), 2.80 (95% CI 1.74-4.50) in the moderate group (Padjustment < 0.001), and 4.30 (95% CI 2.70-6.83) in the high group (Padjustment < 0.001) compared to the low salt intake group (Figure 2 and Supplementary Table 3). The risk of cognitive impairment increased 1.59 (95% CI 1.40-1.79) per 1-SD rise in salt intake across the entire follow-up period (Padjustment < 0.001, Supplementary Table 4).
Discussion
Excessive dietary salt intake significantly accelerated the progression of cognitive impairment and increased the risk of dementia in a cohort of community-dwelling older adults independently of other important risk factors. The Chinese National Total Diet Survey reported an average daily salt intake of 12 g/person in 2000,
more than double that recommend by the WHO (5 g/d). Therefore, excessive salt intake may exacerbate the expected increase in dementia rates due to population aging.
Excessive salt intake has a detrimental effect on cardiovascular and cerebrovascular functions that may ultimately lead to cognitive deficits and dementia.
In mice, a high-salt diet was found to induce hyperphosphorylation of tau protein and cerebral endothelial dysfunction, both of which are associated with local neurodegeneration and ensuing cognitive dysfunction.
Excessive salt intake also induces an imbalance in gut-initiated adaptive immune responses mediated by immunomodulatory Th17 cells, which in turn is associated with cognitive dysfunction.
However, few studies have examined the association of salt intake with cognitive impairment in otherwise healthy aging (community-dwelling) individuals. In this study, we found that the risk of dementia as well as the progression of cognitive impairment increased progressively with salt intake, even after adjustment for confounders such as hypertension.
Hypertension and blood pressure variation are major risk factors for dementia.
Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial.
Excessive variability in systolic blood pressure that is self-measured at home exacerbates the progression of brain white matter lesions and cognitive impairment in the oldest old.
High sodium intake increases blood pressure and risk of kidney disease. From the Science of Salt: A regularly updated systematic review of salt and health outcomes (August 2016 to March 2017).
To assess the effect of salt intake on dementia risk independent of hypertension, we adjusted not only for baseline systolic and diastolic blood pressure but also the mean and visit-to-visit variation in both systolic and diastolic blood pressure using Cox proportional hazards models. This analysis revealed a 75% increase in risk among subjects consuming only 6 to 9 g of salt per day compared with those consuming <6 g/d (around the WHO recommendation), a substantial increase in risk among those consuming 9 to 12 g/d, which is still at or below the average intake in China, and a dramatic increase of 330% among individuals consuming more than 12 g/d. These increases correspond to a 58.5% rise in dementia risk for every 1-SD increment in salt intake compared with the low intake group independent of changes in blood pressure. In addition to current hypertension, we also adjusted for age
Thus, high salt intake is a strong independent risk factor for dementia among community-dwelling older adults in China.
The major strength of this study is that risk models were adjusted for mean and visit-to-visit variability in blood pressure during the follow-up period as well as baseline blood pressure. Alternatively, a major limitation of this study is that other critical dietary risk factors for disease, such as total caloric intake, fat intake, and potassium intake were not recorded.
Conclusion and Implications
We conclude that excessive salt intake is an independent risk factor for emergent dementia and cognitive impairment in initially healthy older adults. Further studies are needed to validate these findings in other populations, including other ethnicities, and to identify possible prevention and intervention strategies.
Acknowledgments
The authors thank the patients, general practitioners, and nurses who took part in this study.
Supplementary Material
Results
Changes in Blood Pressure Across the Follow-up Duration
We assessed the changes in blood pressure during the follow-up period in this study, because high blood pressure and excessive variability in blood pressure have been demonstrated to be closely associated with a higher risk of dementia.
The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial.
Excessive variability in systolic blood pressure that is self-measured at home exacerbates the progression of brain white matter lesions and cognitive impairment in the oldest old.
Supplementary Figure 1 and Supplementary Table 2 detailed the changes in systolic and diastolic blood pressure in the 4 groups. The mean and SD in visit-to-visit systolic blood pressure were significantly greater in the high salt intake group than those in the low, mild, and moderate groups, and in the moderate group than those in the low and mild groups (all Padjustment < 0.05).
Supplementary Figure 1Changes in blood pressure across the follow-up duration. (A) Changes in systolic blood pressure. (B) Changes in diastolic blood pressure.
Supplementary Table 3Cumulative Hazards of Cognitive Impairment in the Mild, Moderate, and High Groups Compared With Low Group
Beta
SE
Wald
HR
95% CI
P Value
Model 1
Low group (ref)
1.000
Mild group
0.606
0.252
5.783
1.833
1.119-3.004
.016
Moderate group
1.084
0.240
20.381
2.957
1.847-4.734
<.001
High group
1.509
0.235
41.299
4.521
2.854-7.163
<.001
Model 2
Low group (ref)
1.000
Mild group
0.599
0.252
5.646
1.821
1.111-2.984
.017
Moderate group
1.069
0.240
19.772
2.912
1.818-4.665
<.001
High group
1.496
0.235
40.500
4.465
2.816-7.078
<.001
Model 3
Low group (ref)
1.000
Mild group
0.573
0.254
5.102
1.773
1.079-2.915
.024
Moderate group
1.030
0.242
18.122
2.801
1.743-4.501
<.001
High group
1.466
0.237
38.203
4.334
2.722-6.900
<.001
Model 4
Low group (ref)
1.000
Mild group
0.561
0.253
4.899
1.752
1.066-2.879
.027
Moderate group
1.030
0.242
18.137
2.801
1.744-4.499
<.001
High group
1.458
0.236
38.035
4.299
2.704-6.833
<.001
Model 1 was adjusted for no confounders. Model 2 was adjusted for age, sex, smoking, drinking, and education. Model 3 was adjusted for confounders in model 2 and baseline body mass index, blood pressure, fasting plasma glucose, and plasma lipids; history of hypertension, diabetes, and dyslipidemia; use of antihypertensive, glucose-lowering, antidyslipidemic, and antiplatelet medications; and APOE genotype. Model 4 was adjusted for confounders in model 3 and the mean and SD in visit-to-visit systolic and diastolic blood pressure.
Supplementary Table 4Cumulative Hazards of Cognitive Impairment With Each 1-SD Increment in Salt Intake During the Follow-up Period
Beta
SE
Wald
HR
95% CI
P Value
Model 1
0.468
0.061
58.155
1.597
1.416-1.802
<.001
Model 2
0.465
0.062
56.662
1.592
1.410-1.797
<.001
Model 3
0.461
0.063
54.009
1.586
1.402-1.793
<.001
Model 4
0.461
0.062
54.643
1.585
1.403-1.791
<.001
Model 1 was adjusted for no confounders. Model 2 was adjusted for age, sex, smoking, drinking, and education. Model 3 was adjusted for confounders in model 2 and baseline body mass index, blood pressure, fasting plasma glucose, and plasma lipids; history of hypertension, diabetes, and dyslipidemia; use of antihypertensive, glucose-lowering, antidyslipidemic, and antiplatelet medications; and APOE genotype. Model 4 was adjusted for confounders in model 3 and the mean and SD in visit-to-visit systolic and diastolic blood pressure.
GBD 2013 Mortality and Causes of Death Collaborators
Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013.
Telmisartan and rosuvastatin synergistically ameliorate dementia and cognitive impairment in older hypertensive patients with apolipoprotein E genotype.
Effect of low-dose statins and apolipoprotein E genotype on cerebral small vessel disease in older hypertensive patients: a subgroup analysis of a randomized clinical trial.
The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial.
Excessive variability in systolic blood pressure that is self-measured at home exacerbates the progression of brain white matter lesions and cognitive impairment in the oldest old.
High sodium intake increases blood pressure and risk of kidney disease. From the Science of Salt: A regularly updated systematic review of salt and health outcomes (August 2016 to March 2017).
Funding sources: This work was supported by the National Natural Science Foundation of China grants 81973139, 81870281, and 81670432; the Zhejiang Provincial Natural Science Foundation of China grants LY18H020011 and LQ19H020005; the Medical and Health Science and Technology Development Plan Project of Shandong, China grants 202103010686, the Innovation Project of Shandong Academy of Medical Sciences, and the Academic Promotion Program of Shandong First Medical University.
00782-4&id=gr1.jpg){kind=link}
00782-4&id=gr2.jpg){kind=link}
00782-4&id=fx1.jpg){kind=link}