Renal Dysfunction Contributes to Episodic Memory Deficits and Medial Temporal Atrophy in Alzheimer's Disease: A Pilot Study

To the Editor: Cognitive impairment and dementia is present in 30% to 40% of individuals with renal disease, but the mechanism of dementia in these individuals is poorly understood.1, 2 Cognitive impairment is not limited to individuals with advance renal disease but is also recognized in the mild to moderate stages of kidney disease.3, 4 Medial temporal atrophy (MTA) is the neuroimaging hallmark of Alzheimer's disease (AD) and other types of dementia. Investigating the association between renal dysfunction and MTA may provide insights into the pathogenesis of dementia in individuals with renal impairment. To further understanding of the role of renal disease in the pathogenesis of AD, the influence of serum creatinine and estimated glomerular filtration rate (eGFR) on MTA was investigated in a cohort of individuals with early-stage dementia. It was hypothesized that individuals with renal impairment would have greater MTA and poorer performance on episodic memory and executive function. This was a case–control study of individuals recruited from a tertiary hospital. Individuals with a diagnosis of mild dementia having brain magnetic resonance imaging (MRI) performed within 6 months of recruitment and having at least 6 years of education were included. Mild AD was diagnosed based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. Participants had a Clinical Dementia Rating (CDR) score of 0.5 to 1.0. The centralized institutional review board in Singapore approved this study. Serum creatinine, 25-hydroxy vitamin D3, serum glucose, and serum insulin were measured. eGFR was calculated using the Modification of Diet in Renal Disease equation: 186 × (serum creatinine/88.4)−1.154 × age−0.203 × (0.742 if female) × (1.210 if African American). Participants were classified as having normal renal function (serum creatinine 40–75 μmol/L) or impaired renal function (serum creatinine >75 μmol/L). Cognitive evaluation included the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Alzheimer's Disease Assessment Scale–Cognitive (ADAS-cog). Two independent raters blinded to all clinical and cognitive data quantified MTA and white matter hyperintensity (WMH) on brain MRI using the Scheltens's scale and modified Fazekas's scale. Logistic regression and correlational analyses was performed using SPSS Statistics version 21 (IBM Corp., Armonk, NY). Sixty-four individuals with mild dementia were recruited. Their mean age was 72.5 ± 7.5, and they had a mean 7.7 ± 5.3 years of education. Mean serum creatinine for the whole cohort was 82.4 ± 40.1 μmol/L (range 42.0–319.0 μmol/L) and mean eGFR was 78.5 ± 22.4 mL/min per 1.73 m2 (range 12.3–127.8 mL/min per 1.73 m2). Mean MMSE score was 24 ± 5 and mean MoCA score was 22 ± 5. Thirty-two participants were identified as having renal dysfunction (Table 1). Mean serum creatinine for participants with renal dysfunction was 104.9 ± 46.9 μmol/L (range 76.0–319.0 μmol/L) and mean eGFR was 64.2 ± 16.6 mL/min per 1.73 m2 (range 12.3–87.2 mL/min per 1.73 m2). Participants with renal dysfunction had significantly higher medial temporal atrophy (3.6 vs 1.9, P = .01). Univariate regression analyses demonstrated that, with increasing creatinine levels, the odds ratio associated with MTA was 8.1 (95% confidence interval (CI) = 1.4–46.9, P = .02). On multivariate analyses after correcting for age and serum vitamin D level, the OR was 12.6 (95% CI = 1.2–134.3, P = .04). High serum creatinine level (coefficient of determination (R2) = 0.084, P = .004) and low eGFR (R2 = 0.06, P = .02) were significantly associated with poor episodic memory, the cognitive hallmark of Alzheimer's disease. This cross-sectional pilot study demonstrated that renal dysfunction measured according to serum creatinine levels and eGFR was associated with medial temporal atrophy in individuals with mild dementia. It further demonstrated a significant negative relationship between creatinine levels and episodic memory and between eGFR and episodic memory. Several factors such as vitamin D deficiency, hyperglycemia, and insulin resistance previously implicated in the pathogenesis of dementia may be exerting their effects on cognition through a common mechanism, namely renal impairment.5-7 Despite comparable global cognition between subjects with and without renal impairment, subjects with renal impairment had significantly greater MTA, suggesting a role for MTA in the diagnosis of impending dementia.8, 9 It was further demonstrated that increasing creatinine levels and lower eGFR are negatively correlated with episodic memory performance. This strengthens the hypothesis that renal dysfunction plays a major role in the pathogenesis of dementia. The finding of adverse relationship between renal dysfunction, cognition, and medial temporal atrophy even in the early stages of dementia supports the hypothesis that renal dysfunction and its metabolic consequences may have a causative role in the development of dementia. Further prospective longitudinal studies involving individuals at different stages of dementia and examining biomarkers of amyloid-tau pathology and different levels of chronic kidney disease are required. The Singhealth Foundation, Singapore, supported this study. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Aloysius Ng, Yasmin Idu Jion, Nur Hani Zainal, and Nagaendran Kandiah had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were responsible for the design and execution of the study; logistic arrangements; cognitive evaluation; collection, management, analysis, and interpretation of data; and preparation, review, and approval of the manuscript. Sponsor's Role: None.

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