Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer's Disease Neuroimaging Initiative cohort.

BACKGROUND: Chronic kidney disease (CKD) is associated with cognitive impairment and dementia. We examined whether this relationship hold true in older adults, who have a higher prevalence of both CKD and dementia. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We conducted a cross-sectional secondary analysis of an established observational cohort. We analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an NIH funded, multicenter longitudinal observational study, which includes participants with normal and impaired cognition and assesses cognition with a comprehensive battery of neuropsychological tests. We included a non-probability sample of all ADNI participants with serum creatinine measurements at baseline (N = 1181). Using multivariable linear regression analysis, we related the CKD Epidemiology Collaboration equation eGFR with validated composite scores for memory (ADNI-mem) and executive function (ADNI-EF).
RESULTS: For the 1181 ADNI participants, the mean age was 73.7 ± 7.1 years. Mean estimated glomerular filtration rate (eGFR) was 76.4 ± 19.7; 6% had eGFR<45, 22% had eGFR of 45 to <60, 51% had eGFR of 60-90 and 21% had eGFR>90 ml/min/1.73 m2. The mean ADNI-Mem score was 0.241 ± 0.874 and mean ADNI-EF score was 0.160 ± 1.026. In separate multivariable linear regression models, adjusted for age, sex, race education and BMI, there was no association between each 10 ml/ min/1.73 m2 higher eGFR and ADNI-Mem (β -0.02, 95% CI -0.04, 0.02, p = 0.56) or ADNI-EF (β 0.01, 95% CI -0.03, 0.05, p = 0.69) scores.
CONCLUSION: We did not observe an association between eGFR and cognition in the older ADNI participants.

Introduction

Cognitive impairment and dementia negatively affect activities of daily living, quality of life, sense of well-being, morbidity and mortality [1-4]. Age is an independent risk factor for both cognitive impairment and chronic kidney disease (CKD) and increase in life expectancy has fueled an unprecedented growth in the prevalence of both conditions [5-7]. With the current threshold of glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for CKD approximately one-half of older adults >70 years have CKD [7]. The impact of a lower GFR in older adults is controversial [8-11] as lower GFR in older adults is associated with different renal pathology [12, 13] as well as clinical outcomes [14-18] when compared to younger persons. Age associated decline in GFR is less likely to progress to end stage kidney disease (ESKD), and most older people with CKD die with CKD rather than from it [18].

In older adults, the association of eGFR and cognition remains contentious. While some studies report absence of cognitive impairment at eGFR of >30 mL/min/1.73 m2 [19-22], others report incremental risk of cognitive impairment with declining eGFR [23-25]. Baseline differences in age and comorbidities or use of tests designed for screening and not detection of severity of cognitive impairment make the results difficult to interpret. For example, in The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study [23] the mean age of participants with CKD was 71 years compared to 64 years in controls. With an individual’s risk of developing dementia doubling every 5 years after age 65, matching for age at baseline is important. There were also baseline differences in other confounding variables such as sex, education, and comorbidities. Similar baseline differences were present in the Chronic Renal Insufficiency Cohort Cognitive Study (CRIC-COG) [25]. In fact, a prospective cohort study indicated association of dementia and low eGFR in unadjusted analysis, but this association was lost after adjustment for confounding variables, highlighting the importance of these baseline confounders [26]. Another study in older men [27] did not show an association of lower eGFR with cognition after adjusting for differences in age, race and education. In the Health, Aging, and Body Composition (Health ABC) Study [28] after stratification by age, there was no association between eGFR and cognition in the older half of the participants indicating an interaction of age in this association. Some other studies included patients with moderate to severe CKD [24] and not mild CKD, which is more common in older adults.

Thus, it remains unclear if the association between lower GFR and cognitive impairment holds true for the older adults with CKD, where estimation of kidney function may be less accurate and the implications of a lower GFR may be different. With paucity of data on cognitive outcomes with a lower GFR in older adults, risk estimation and guidelines for management, counselling and education on cognitive impairment and dementia for older patients are lacking. Overestimation of risk of cognitive impairment can lead to unnecessary anxiety and over utilization of health resources while underestimation can lead to less aggressive preventative management and increase in rates of dementia.

To better understand the association between mild-moderate CKD and cognition, we conducted a post hoc analysis of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is an NIH supported multicenter, longitudinal, prospective, observational study of normal cognitive aging, mild cognitive impairment (MCI), and early dementia. We chose the ADNI cohort for this analysis as the ADNI has an older population with a mean age of 74 years without a significant burden of medical issues, since that was an exclusion criterion for the ADNI. Moreover, the ADNI provided comprehensive neuropsychological testing with detailed evaluation of memory and executive function, two domains of cognition preferentially affected in kidney disease [29].

Materials and methods

Participants

Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu/). The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging, positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early Alzheimer’s disease. The ADNI includes men and women with normal cognition, MCI and dementia between the ages of 55 and 90 from 63 sites in the United States and Canada. The ADNI excluded participants with significant systemic illness, unstable medical conditions, major depression and baseline brain imaging with focal lesions or multiple lacunae and thus comprised of a healthier cohort of older adults without underlying comorbidities other than cognitive impairment. The ADNI began in October 2004 and recruited participants in phases; ADNI-1 had 800 participants; 200 with Alzheimer’s disease, 400 with MCI, and 200 with normal cognition. ADNI-GO had 200 participants with early amnestic MCI. ADNI 2 had another 650 participants. All ADNI participants from different phases of the ADNI study, (ADNI-1, ADNI-GO, and ADNI-2) with a baseline serum creatinine measurement were included in this analysis. Participants from ADNI-3 were excluded as they did not have a serum creatinine measurement.

We grouped participants with MCI [30] and dementia together as the group with cognitive impairment. Per the ADNI protocol, participants in this group with cognitive impairment had a) a subjective memory concern as reported by the participant, study partner, or clinician b) an abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II Subscale, and c) Clinical Dementia Rating (CDR) ≥ 0.5 [31]. Participants in the control group had to be free of memory complaints (verified by a study partner) beyond what one would expect for age, have normal memory function documented by scoring above education adjusted cutoffs on the Logical Memory II subscale and a CDR score of 0 with a memory box score of 0.

Measurement of kidney function (Independent variable)

Participating centers collected baseline serum creatinine measurement from all participants. We calculated the eGFR using the CKD Epidemiology Collaboration (CKD-EPI) equation [32] since CKD-EPI is more selective in classifying persons as having CKD and more accurately predicts the risk of vascular events, mortality and end-stage kidney disease [33, 34]. We categories participants by eGFR in the following groups; eGFR <45, 45–60, 61–90 and >90 ml/ min/ 1.73 m2. For sensitivity analysis, we used the Modification of Diet in Renal Disease Study equation (MDRD) [35] since MDRD is the most widely used equation for estimating eGFR in clinics and most clinical laboratories automatically report eGFR calculated by MDRD [36].

Assessment of cognition (Outcome)

The ADNI uses a comprehensive battery of standard neuropsychological tests for the assessment of cognition. We used previously developed and validated composite scores for memory (ADNI-Mem) [37] and executive function (ADNI-EF) [38] for our analysis. ADNI-Mem is derived from Rey Auditory Verbal Learning Test (RAVLT, 2 versions), AD Assessment Schedule—Cognition (ADAS-Cog, 3 versions), Mini-Mental State Examination (MMSE), and Logical Memory data. ADNI-EF is derived from WAIS-R Digit Symbol Substitution, Digit Span Backwards, Trails A and B, Category Fluency, and Clock Drawing. We used the two composite scores as they incorporate all indicators of memory or executive function, maximizing measurement precision and account for version effects in some of the individual tests used in the ADNI. Moreover, these composite scores have linear scaling properties, tested validity and a good prediction of who would progress to MCI or dementia.

Other variables

Baseline demographics; age, sex, race, ethnicity, marital status, years of education, body mass index (BMI), functional Activities Questionnaire (FAQ) score [39] and handedness were also obtained from the ADNI database.

Statistical analysis

We evaluated baseline participant clinical and sociodemographic characteristics using descriptive statistics. We tested differences in baseline characteristics by eGFR categories (<45, 45–60, 61–90 and >90 ml/min/1.73 m2) using linear trend tests for continuous variables and chi-square tests for categorical variables. We used the spearman correlations and scatterplots to describe the unadjusted association between eGFR (as a continuous variable) and ADNI-mem and ADNI-EF scores. After confirming normal distribution of ADNI-Mem and ADNI-EF scores, we ran multivariable linear regression models predicting cognition measured by ADNI-Mem and ADNI-EF scores as outcome variables and eGFR, age, sex, race, education and BMI as exposure variables (based on current literature on factors affecting cognition) to assess the adjusted association of eGFR (as a categorial variable and as a continuous variable) with cognition. We also performed a similar multivariable linear regression for participants with and without CKD defines as eGFR <60 ml/min/1.73 m2. Since the majority of participants were either Caucasians or African Americans, we grouped race into Caucasian, African American and other races for the multivariable linear regression.

To avoid confounding by baseline cognitive impairment status, we did sub-group analysis by grouping participants into groups with and without cognitive impairment. Baseline characteristics were compared using student’s t-test and chi-square tests as appropriate. We analyzed the distribution of ADNI-mem and ADNI-EF scores in the two groups by eGFR categories described above. We repeated the multivariable linear regression analysis above in these subgroups. We also performed a sub-group analysis for ages <75 and ≥75, men and women and Caucasians and non-Caucasians among participants with and without cognitive impairment. For sensitivity analysis with used eGFR calculated with the MDRD equation and repeated the multivariable linear regression analysis in the entire cohort and in groups with and without cognitive impairment [40, 41].

All analyses were done with SAS 9.4 (Cary, NC) with a p-value of 0.05 marking statistical significance.

Results

The analysis included 1181 ADNI participants with baseline serum creatinine values available, 6% with eGFR<45, 22% with eGFR 45–60, 51% with eGFR 60–90 and 21% with eGFR>90 ml/min/1.73 m2. Baseline characteristics are summarized in . There was no difference in age, ethnicity, years of education, BMI, FAQ score or handedness across the different categories of eGFR. More participants with lower eGFR were Caucasians and were widowed. More participants with a higher eGFR had cognitive impairment based on subjective complains, logical Memory II score and CDR score as described above. Lower eGFR groups did not have lower ADNI-Mem or ADMI-EF scores.

Unadjusted correlation analysis showed a weak negative association between eGFR and ADNI-Mem scores and a statistically non-significant weak negative association between eGFR and ADNI-EF scores with correlation coefficients of -0.105 (p = 0.001) and -0.02, p = 0.43) respectively (. Multivariable linear regression analysis ( showed an inverse relationship of age with ADNI-EF scores. Female sex was associated with higher ADNI-Mem scores and a higher education was associated with higher ADNI-Mem and ADNI-EF scores. There was no association between eGFR and ADNI-Mem or ADNI-EF scores. S1 Table of shows the same analysis comparing participants with and without CKD (eGFR <60 ml/ min/1.73 m2 and eGFR ≥60 ml/ min/1.73 m2) with similar results.

Scatterplot showing unadjusted correlation for a) ADNI-mem and b) ADNI-EF scores (y axis) and GFR (x-axis).

When categorized by cognitive impairment (with and without cognitive impairment) (S2 Table of , the mean eGFR was higher in the group with cognitive impairment. The distribution of eGFR was similar in both groups (S1 Fig of ADNI-Mem and ADNI-EF scores were similar across the eGFR categories in both groups (S3 Table of No significant correlation was seen between eGFR and ADNI-Mem or ADNI-EF scores in participants with cognitive impairment. In participants without cognitive impairment, a weak negative correlation was seen between eGFR and ADNI-mem scores while no significant correlation was seen between eGFR and ADNI-EF scores (S2 Fig of Separate multivariable linear regression analysis in the groups with and without cognitive impairment (S4 Table of showed similar associations for age, sex, and education and eGFR with ADNI-Mem and ADNI-EF scores. There was no association between eGFR and ADNI-Mem or ADNI-EF scores, even after stratification by age, sex and race (S5 Table of . Our results remained consistent when we used eGFR calculated with MDRD instead of CKD-EPI equation (S6 Table of .

Discussion

We aimed to assess the association between eGFR and cognition in ADNI participants. We showed that modestly low eGFR was not associated with lower memory or executive function in the older adults from the ADNI cohort. In adjusted analysis, male sex was associated with lower memory scores while older age was associated with lower executive function scores. Lower education was associated with both lower memory and executive function scores. Lower eGFR was not associated with either memory or executive function.

Using the ADNI cohort had the advantage of a detailed evaluation of cognition with a comprehensive battery of standard neuropsychological tests and validated composite scores for memory and executive function, the two main domains of cognition typically affected in kidney disease [29]. We used validated composite scores for memory and executive function rather than results from individual neuropsychological tests to conserve the statistical power by reducing the number of potential comparisons and to reduce measurement error. In addition, these composite scores were built with consideration for the variation in results that may be present due to use of different versions of some neuropsychological tests used in the ADNI [37].

Moreover, the ADNI had relatively healthy older adults. Lower eGFR in older adults may have different implications than in younger adults. Among persons with eGFR levels <45 ml/min/1.73 m2 at baseline, older adults are less likely (than their younger counterparts) to experience an annual decline in eGFR of >3 ml/min/1.73 m2 [14] or progression to ESKD [15]. The development of ESKD is a much rarer event in older compared with younger patients with an eGFR of 30 to 59 mL/min/1.73 m2 [16]. Similarly, biopsy studies indicate that unlike progressive glomerulosclerosis in the young, age associated glomerulosclerosis does not contribute to progressive CKD [17]. Although there is a high prevalence of cognitive impairment in CKD [42, 43], this association may not be applicable to older adults [44]. This difference may be secondary to age related decline in eGFR in the absence of an actual kidney ‘disease’ pathology or inaccurate categorization of older adults as CKD due to imperfect estimation of GFR by commonly used serum creatinine-based equations.

Our results are consistent with the results from the BRain IN Kidney disease (BRINK) study where eGFR >30 mL/min per 1.73 m2 was not associated with cognitive impairment [19]. Although smaller, this study like the ADNI, used a comprehensive battery of neuropsychological tests to assess memory and executive function. The Health ABC study [28] did not show an association between eGFR and cognition (odds ratio 1.10, 95% CI, 0.80 to 1.51) in participants >73 years supporting the results of our study. Similarly, the French 3C study [20], the Norwegian HUNT study [21] or the Australian Sydney Memory and Ageing Study [22] did not show an detrimental association between lower eGFR and cognitive decline or dementia.

Some other studies have shown a graded decrease in cognition with lower GFR. Although these studies are meritorious in their own right, there are some important differences between these studies and our study that may account for the contrasting results. Some studies included patients with severe kidney disease with lower eGFR and/or younger participants [23–25, 44] while others had inadequate matching at baseline and/or limited neuropsychological testing with use of tests meant for screening to assess global cognition. The single center study by Kurella et al. [24] compared patients with CKD and ESKD to published normative values matched for age and education. The study population was younger (mean age 62±14.3 years) and had more severe kidney disease (mean serum creatinine 3.1 ± 1.9 mg/dl and mean eGFR 18.7 ± 35.3 mL/min per 1.73 m2) than our cohort. The REGARDS study [23] used a 6- item cognitive screening test incorporated into the baseline telephone interview. Although easier to perform in a large study such as REGARDS with over 20,000 participants, screening tests especially when over phone may lack the specificity of comprehensive neuropsychological tests. In addition, screening tests assess global cognition and not specific domains of cognition such as memory and executive function that are preferentially affected in CKD. Phone based cognitive tests can be affected by hearing loss in older adults. Moreover, baseline differences in age and vascular disease with CKD patients being older and with greater burden of comorbidities than controls. Since age and comorbid conditions are risk factors for cognitive impairment, these differences can lead to positive confounding. Similarly, the CRIC-COG study [25] also had differences in baseline characteristics where participants with lower eGFR had lower education and greater burden of comorbidities. Another study from the Third National Health and Nutrition Examination Survey (NHAHES) [45] had younger participants with a mean age of 36; the results may thus not be extrapolatable to older adults.

Our study has limitations. We performed a cross-sectional analysis, and therefore causality or directionality cannot be inferred. The ADNI data did not have serial measurements of kidney function. Only 6% of the participants had an eGFR of <45 mL/min/1.73m2. This was expected as severe CKD was an exclusion criterion for the study. However, since we wanted to explore the association between eGFR and cognition in older adults without known progressive intrinsic kidney disease, this cohort was well suited for our study as age associated decline in eGFR is not expected to cause severe CKD with eGFR <45 mL/min/1.73m2. We used serum creatinine based eGFR measurements. Although serum creatinine-based calculation of eGFR is standard clinical practice, changes in muscle mass rather than kidney function can change eGFR and eGFR may not correlate well with measured GFR in persons with normal kidney function. Also, sarcopenia is associated with both cognitive impairment and CKD and cause confounding. This may explain the higher eGFR in the group with cognitive impairment in our study. Although we did not have results from the gold standard dual-energy X-ray absorptiometry for measurement of muscle mass, we did compare BMIs across the eGFR groups and did not find any differences.

In conclusion, we showed that mild-moderate CKD in older adults (likely attributable to physiological aging) is not associated with cognitive impairment. With almost half of the population over age 70 years with CKD [7], our findings have important clinical implications and provide clinically useful information for physicians that can guide management and education of older patients at highest risk of dementia.

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13 Aug 2020

PONE-D-20-20489

Mild to moderate CKD is not associated with cognitive impairment in the elderly

PLOS ONE

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Two experts raised important issues.  Normal vs declined eGFR should be analyzed.  Also you claimed this article is focus on aged cohort but the cohort selection is not clearly described in regards of age.

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Reviewer #1: To examine whether the relationship between CKD and dementia hold true in the elderly, the authors conducted a cross-sectional secondary analysis of an established observational cohort of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including a non-probability sample of all ADNI participants with serum creatinine measurements at baseline. The authors showed that modestly low eGFR was not associated with lower memory or executive function in the elderly population of the ADNI cohort using multivariable linear regression analysis.

The theme of this study is intriguing and the manuscript is well-written; however, there are some concerns to be addressed.

1. It is considered that eGFR correlates with the measured GFR in patients with renal dysfunction, while it is doubtful that the same correlation is shown in patients with normal renal function. How would you describe that point?

2. BMI should be entered into all multivariable models.

3. I wonder whether the decorrelation between eGFR and cognition in the multivariable linear regression analysis would be maintained when stratified by eGFR (eGFR<60 or eGFR ≥60). The authors should show the results stratified by eGFR.

4. The authors describe “Unadjusted correlation analysis showed weak negative associations of ADNI-Mem scores and ADNI-EF scores with eGFR with correlation coefficients of -0.105 (p=0.001) and -0.02, p=0.43) respectively (Figure 1)” in Page 8 and “Weak correlation between eGFR and ADNI-Mem and ADNI-EF scores were again seen (Supplementary Figure 2)” in Page 10 in the Results section. These descriptions are incorrect because some of these associations are not significant. The authors should revise these descriptions.

Reviewer #2: This is a well done study examining the association of eGFR with cognitive impairment from the Alzheimers Disease Neuroimaging initiative. I have only a few minor suggestions for improvement.

Could the authors include more details on entry criteria for the parent study, I don't see age criteria mentioned, perhaps include age range to clarify whether the cohort was restricted to older adults or not? Much of the rationale for why the authors chose to conduct this study in this particular cohort does not come out until the discussion. I believe the argument is that this is an older cohort without much underlying comorbidity other than dementia or mild cognitive impairment for some? Presenting this in the introduction could provide a stronger rationale for why the authors chose to conduct this study in this particular cohort.

In the introduction, it would be good to present more detail on the demographic characteristics of study populations in which the association between eGFR and cognitive function has been measured. The introduction makes it sound like there have been no prior studies of cognitive impairment and eGFR in older populations? My sense is that some prior studies have been conducted in older adults, so summarizing those studies and their results would be helpful then highlighting original contribution of this study (it sounds like the contribution of this study is that it included mostly healthy older adults?)

Consider less sweeping title, the authors found no association of eGFR in this particular cohort, but I am not sure this justifies the statement that there is no association in "the elderly." Maybe no association in older adults enrolled in the Alzheimers Disease Neuroimaging initiative?

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Reviewer #2: Yes: ann ohare

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27 Aug 2020

We thank the editors and the reviewers for their thoughtful feedback. We are also thankful for their suggestions which we believe have improved the manuscript. Our response to each concern is outlined below.

Editors:

1) Normal vs declined eGFR should be analyzed.

Response: We have added another multivariable linear regression analysis with this stratification of eGFR (Supplementary Table 1).

2) You claimed this article is focus on aged cohort but the cohort selection is not clearly described in regards of age.

Response: We agree. We have clarified the age under methods and described the cohort in more detail under introduction in the revised manuscript.

Reviewer #1

1) It is considered that eGFR correlates with the measured GFR in patients with renal dysfunction, while it is doubtful that the same correlation is shown in patients with normal renal function. How would you describe that point?

Response: We agree and have clarified this further in our limitations. Obtaining measured GFR is cumbersome and impractical, eGFR is often used in both research and clinical practice. Since our study is essentially a null study and there is no association between any level of eGFR and cognition (Figure 1, Table 2), this does not alter our results or conclusion.

2) BMI should be entered into all multivariable models.

Response: We have added BMI in the multivariate models.

3) I wonder whether the decorrelation between eGFR and cognition in the multivariable linear regression analysis would be maintained when stratified by eGFR (eGFR<60 or eGFR ≥60). The authors should show the results stratified by eGFR.

Response: We have added this stratification of eGFR (Supplementary Table 1).

4) The authors describe “Unadjusted correlation analysis showed weak negative associations of ADNI-Mem scores and ADNI-EF scores with eGFR with correlation coefficients of -0.105 (p=0.001) and -0.02, p=0.43) respectively (Figure 1)” in Page 8 and “Weak correlation between eGFR and ADNI-Mem and ADNI-EF scores were again seen (Supplementary Figure 2)” in Page 10 in the Results section. These descriptions are incorrect because some of these associations are not significant. The authors should revise these descriptions.

Response: Thank you for pointing this out. We have revised the descriptions as suggested.

Reviewer #2:

1) Could the authors include more details on entry criteria for the parent study, I don't see age criteria mentioned, perhaps include age range to clarify whether the cohort was restricted to older adults or not?

Response: We have added the mean age (74) in ADNI in the introduction and the age range (55-90) in the methods section where we describe the ADNI cohort. For ADNI 2 the minimum age for the normal control group and the significant memory concern group was 65 years.

2) Much of the rationale for why the authors chose to conduct this study in this particular cohort does not come out until the discussion. I believe the argument is that this is an older cohort without much underlying comorbidity other than dementia or mild cognitive impairment for some? Presenting this in the introduction could provide a stronger rationale for why the authors chose to conduct this study in this particular cohort.

Response: We agree. We have added this detail in the last paragraph of the introduction in the revised manuscript.

3) In the introduction, it would be good to present more detail on the demographic characteristics of study populations in which the association between eGFR and cognitive function has been measured. The introduction makes it sound like there have been no prior studies of cognitive impairment and eGFR in older populations? My sense is that some prior studies have been conducted in older adults, so summarizing those studies and their results would be helpful then highlighting original contribution of this study (it sounds like the contribution of this study is that it included mostly healthy older adults?)

Response: We agree and have added more detail about other published studies as suggested.

4) Consider less sweeping title, the authors found no association of eGFR in this particular cohort, but I am not sure this justifies the statement that there is no association in "the elderly." Maybe no association in older adults enrolled in the Alzheimer’s Disease Neuroimaging initiative?

Response: Thank you for this suggestion. We have changed the title to ‘Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort’ to more accurately describe this study.

Submitted filename: Response to Reviewers (PONE-D-20-20489).docx

Click here for additional data file.

15 Sep 2020

Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort

PONE-D-20-20489R1

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29 Sep 2020

PONE-D-20-20489R1

Mild-moderate CKD is not associated with cognitive impairment in older adults in the Alzheimer’s Disease Neuroimaging Initiative cohort

Dear Dr. Gupta:

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Table 1

Baseline characteristics of included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants in different ranges of estimated glomerular filtration rate.

Data are presented as mean and standard deviation for continuous variables and n (%) for categorical variables.

	Total Sample (N = 1181)	eGFR (ml/min/1.73 m2)				p Value
		<45(n = 68)	45–60(n = 264)	61–90(n = 599)	>90(n = 250)
Age in years, mean ± SD	73.7 ± 7.1	73.2 ± 7.3	73.7 ± 6.8	74.0 ± 7.0	73.4 ± 7.7	0.79
Male, n (%)	665 (56.3)	16 (23.5)	72 (27.3)	367 (61.3)	210 (84.0)	<0.001
Ethnicity (%)						0.22
Not Hispanic/Latino	1146 (97.0)	67 (98.5)	252 (95.5)	582 (97.2)	245 (98.0)
Hispanic/Latino	29 (2.5)	1 (1.5)	8 (3.0)	15 (2.5)	5 (2.0)
Unknown	6 (0.5)	0 (0.0)	4 (1.5)	2 (0.3)	0 (0.0)
Race n (%)						0.001
Caucasian	1097 (92.9)	66 (97.1)	252 (95.5)	559 (93.3)	220 (88.0)
African American	48 (4.1)	1 (1.5)	4 (1.5)	19 (3.2)	24 (9.6)
American Indian/ Alaskan Native	3 (0.3)	0 (0.0)	2 (0.8)	1 (0.2)	0 (0.0)
Asian	20 (1.7)	0 (0.0)	2 (0.8)	13 (2.2)	5(2.0)
Native Hawaiian/ Other Pacific Islander	2 (0.2)	0 (0.0)	1 (0.4)	1 (0.2)	0 (0.0)
More than one race	11 (0.9)	1 (1.5)	3 (1.1)	6 (1.0)	1 (0.4)
Marital status n (%)						0.005
Married	896 (75.9)	46 (67.6)	182 (68.9)	467 (78.0)	201 (80.4)
Widowed	150 (12.7)	16 (23.5)	44 (16.7)	67 (11.2)	23 (9.2)
Divorced	98 (8.3)	5 (7.4)	26 (9.8)	49 (8.2)	18 (7.2)
Never Married	35 (3.0)	1 (1.5)	12 (4.5)	16 (2.7)	6 (2.4)
Unknown	2 (0.2)	0 (0.0)	0 (0.0)	0 (0.0)	2 (0.8)
Years of education, mean ± SD	15.9 ± 2.9	15.7 ± 2.9	15.8 ± 2.8	15.9 ± 2.9	16.1 ± 2.9	0.28
BMI, mean ± SD	26.6 ± 4.2	27.8 ± 6.2	26.5 ± 4.6	26.4 ± 3.9	26.9 ± 4.0	0.30
FAQ score, mean ± SD	4.7 ± 7.1	5.9 ± 8.6	5.1 ± 7.7	4.5 ± 7.0	4.6 ± 6.2	0.11
Right-handed	1082 (91.6)	62 (91.2)	245 (92.8)	548 (91.5)	227 (90.8)	0.89
Cognitive Impairment, n (%)	805 (68.2)	42 (61.8)	169 (64.0)	398 (66.4)	196 (78.4)	0.001
ADNI-mem score, mean ± SD	0.241 ± 0.874	0.390 ± 0.909	0.337 ± 0.935	0.250 ± 0.882	0.075 ± 0.750	0.004
ADNI-EF score, mean ± SD	0.160 ± 1.026	0.238 ± 1.040	0.213 ± 0.983	0.132 ± 1.053	0.151 ± 1.004	0.423
Serum creatinine, mean ± SD	1.00 ± 0.3	1.6 ± 0.3	1.2 ± 0.2	1.00 ± 0.1	0.7 ± 0.1	<0.001
eGFR (CKD-EPI), mean ± SD	76.4 ± 19.7	40.1 ± 7.6	58.5 ± 8.8	77.8 ± 11.7	101.7 ± 7.6	<0.001
eGFR (MDRD), mean ± SD	69.3 ± 17.4	35.9 ± 5.6	50.9 ± 5.0	71.9 ± 8.9	91.4 ± 6.8	<0.001

BMI; body mass index (kg/m2), FAQ; functional activities questionnaire, eGFR; estimated glomerular filtration rate, CKD EPI; Chronic Kidney Disease Epidemiology Collaboration, MDRD; The Modification of Diet in Renal Disease; ADNI-mem; composite memory score, ADNI-EF; composite executive function score.

Table 2

Multivariable linear regression model predicting ADNI-Mem score and ADNI-EF scores.

A. With eGFR as a categorical variable. Participants with eGFR <45, 45–60 and >90 are compared to participants with eGFR 61–90 ml/ min/1.73 m2 taken as the reference group. B. With eGFR as a continuous variable.

	Beta estimate for ADNI-Mem score	95% confidence interval	p value	Beta estimate for ADNI-EF score	95% confidence interval	p value
A
Age (+10)	-0.07	-0.16, 0.03	0.17	-0.24	-0.35, -0.13	<0.0001
Female sex	0.36	0.20, 0.51	<0.0001	0.17	-0.01, 0.35	0.27
AA race	0.25	-0.10, 0.60	0.16	-0.20	-0.60, -0.20	0.32
Other race	-0.06	-0.50, 0.37	0.77	0.02	-0.49, 0.52	0.95
Years of education (+1)	0.08	0.06, 0.10	<0.0001	0.11	0.08, 0.13	<0.0001
BMI (+1)	0.01	0, 0.03	0.08	0.01	-0.01, 0.03	0.23
GFR <45	-0.09	-0.42, 0.25	0.61	0.03	-0.36, 0.42	0.88
GFR 45–60	0.08	-0.10, 0.26	0.40	0.10	-0.11, 0.31	0.33
GFR >90	-0.06	-0.24, 0.12	0.51	0.11	-0.1, 0.31	0.32
B
Age (+10)	-0.06	-0.16,0.03	0.19	-0.25	-0.36, -0.14	<0.0001
Female sex	0.37	0.22, 0.53	<0.0001	0.20	0.02, 0.37	0.03
AA race	0.24	-0.11, 0.58	0.18	-0.19	-0.59, 0.21	0.35
Other race	-0.07	-0.5, 0.37	0.77	0.02	-0.48, 0.52	0.95
Years of education (+1)	0.08	0.06, 0.10	<0.0001	0.11	0.08, 0.13	<0.0001
BMI (+1)	0.01	0,0.03	0.09	0.01	-0.01, 0.03	0.21
eGFR (+10)	-0.01	-0.04, 0.02	0.56	0.01	-0.03, 0.05	0.69

ADNI-Mem; ADNI composite memory score, ADNI-EF; ADNI composite executive function score, AA; African American, BMI; body mass index (kg/m2), eGFR; estimated glomerular filtration rate (ml/min/1.73 m2). For race, African American race and other races were compared with Caucasian race.