Association of Kidney Function With Development of Alzheimer Disease and Other Dementias and Dementia-Related Blood Biomarkers

Key Points Question Is kidney function associated with Alzheimer disease (AD) or other dementias or with dementia-related blood biomarkers (neurofilament light [NfL], phosphorylated tau181 [p-tau181], and glial fibrillary acidic protein [GFAP])? Findings In this population-based cohort study of 6256 individuals, kidney function was not associated with risk of dementia diagnosis, including AD and vascular dementia subtypes, within 17 years, but was associated with blood biomarker levels of NfL and p-tau181. A sex-specific association between kidney function and GFAP levels in blood was apparent, with significant associations evident only among men. Meaning This study suggests that reduced kidney function may be associated with increased levels of dementia-related blood biomarkers but not necessarily with increased AD or dementia risk.

ESTHER participants completed standardized health questionnaires, provided blood and urine samples, and GPs provided medical information. Comprehensive monitoring of major disease incidence and mortality was conducted through participant and GP follow-up 2,5,8,11,14, and 17 years after recruitment for all participants. Furthermore, data were linked to the Saarland Cancer Registry and death certificates were obtained from local health authorities.
In order to collect information regarding dementia diagnoses throughout follow-up, questionnaires were sent to the GPs of all participants during the 14-and 17-year follow-ups.
Dementia diagnosis information was sought for all participants, including those that had died during follow-up as outlined in eFigure 1. GPs were asked to fill out questionnaires regarding the participants' dementia status (i.e. presence of dementia diagnosis, type of dementia, dementia diagnosis date, or confirmed lack of dementia diagnosis) and provide all available medical records from specialists such as neurologists or psychiatrists. All-cause dementia diagnoses include unspecified or unknown dementia. The current guidelines in Germany for The AD diagnoses were reported by the participants' own GPs and in many cases participants had been explicitly referred to neurologists according to GP reports. Due to the setting of the study in the community, many different practitioners had been involved who had employed a variety of exams (including cranial CT scans and CSF exams), which were conducted and reported to a varying degree which reflects practice in routine care. The P-tau181 measurements were completed in blood from baseline (2000-2002, 0-17 years before diagnosis) that had been frozen at -80° C until the time of measurement (2020). The AD diagnoses were made before P-tau181 was measured and GPs did not see any blood biomarker (P-tau181, NfL, GFAP) results. eFigure 1. Flow Chart of ESTHER Participants Included in the Study. Incident dementia cases included participants that received a dementia diagnosis between baseline and the 17-year follow-up. Controls included participants that remained without dementia diagnosis (GP confirmed) throughout follow-up. *P-tau181, GFAP, and NfL levels in blood plasma

Data ascertainment at baseline
The following information was ascertained at baseline through self-administered questionnaire and/or physician reports: age, sex, educational level, physical activity level, lifetime history of depression, stroke, any cancer, myocardial infarction, hypertension, congestive heart failure, body mass index (BMI), smoking status, alcohol use, and various medication use (NSAIDS (Anatomical Therapeutic Chemical Classification Codes B01AC06, N02BA01, N02BA51, N02BA71, M01A, M01BA01, M01BA03), ACE inhibitors (C09A, c09B), diuretics (C03), calcium-channel blockers (C08), beta blockers (C07, angiotensin receptors (C09C, C09D), and statins (C10AA)). Prevalent diabetes was defined as physician diagnosis, use of glucose lowering drugs or HbA1c ≥6.5% and fasting glucose ≥126 mg/dL or non-fasting glucose ≥ 200 mg/dL. Physical activity was defined as inactive: < 1 hour of physical activity/week, low: ≥ 1 hour of physical activity/week but < 2 hours of vigorous and < 2 hours of light physical activity/week, medium/high: ≥ 2 hours of light and ≥2 hours of vigorous physical activity/week. Alcohol use was defined by grams of ethanol per day with categories: abstainer, 0-19.99 g/d for women or 0-39.99 g/d for men, 20-39.99 g/d for women or 40-59.99 g/d for men, and ≥40 g/d for women or ≥60 g/d for men.

Laboratory measurements
Blood samples and urine samples taken at baseline were stored at −80°C until time of measurement. Serum creatinine measurements were performed by the kinetic Jaffe method.  Bold values denote statistical significance at the p < .05 level.