Hydrate to keep the amyloid away

Abstract

Despite older adults being more susceptible to dehydration, the relation between hydration and Alzheimer's disease and related dementias (ADRD) remains largely unexplored. A recent study by Jee Wook Kim and colleagues examined the association between daily fluid intake and ADRD neuroimaging biomarkers in 287 cognitively normal older adults. They found that lower daily fluid intake was associated with greater brain Aβ deposition and cerebrovascular injury. Here, we discuss the strengths and limitations of this study. We further highlight the potential for reverse causality and how hydration may play a role in the clinic and future ADRD research studies.

Whereas lifestyle factors from physical exercise to dietary habits have garnered significant attention as preventive strategies in Alzheimer's disease (AD) and related dementias (ADRD), ¹ the role of hydration has remained largely unexplored. As thirst sensitivity decreases with aging, older adults are more susceptible to dehydration, which has been associated with increased mortality and poor health outcomes including decreased cognitive function and increased risk of ischemic stroke.^2–5 In preclinical animal studies, water deprivation or osmotic stressors in rats markedly increased the levels of amyloid-β protein precursor in neurons, while water deprivation in mice resulted in cerebrovascular dysfunction associated with oxidative stress and cognitive deficits.^6,7 Collectively, these studies suggest that dehydration may be a significant risk factor for age-related dementias including AD and vascular dementia; however, little is known about the associations between hydration and ADRD risk in older adults.

In their article entitled, “Daily Fluid Intake and Brain Amyloid Deposition: A Cohort Study,” Jee Wook Kim and colleagues sought to explore the association between daily fluid intake and AD pathology and cerebrovascular injury in a well-characterized cohort of 287 cognitively normal older adults (55–90 years old) from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). ⁸ KBASE participants underwent comprehensive clinical evaluations, including daily fluid intake measurements using the Mini Nutritional Assessment (MNA), and multimodal brain imaging, including positron emission tomography (PET) to assess Aβ and tau deposition and cerebral glucose metabolism, and magnetic resonance imaging (MRI) scans with T1-weighted images to evaluate cortical thicknesses and fluid-attenuated inversion recovery (FLAIR) to evaluate cerebrovascular injury by white matter hyperintensity (WMH) volumes. Participants were stratified into two groups: high daily fluid intake (more than 5 cups) and low daily fluid intake (5 cups or less). Cross-sectional and longitudinal assessments over 2 years were performed while adjusting for multiple confounders, including demographic and clinical variables, APOE genotype, physical activity, dietary habits, and metabolic markers such as fasting glucose, insulin, and cholesterol levels.

A significant association between low daily fluid intake and greater brain Aβ deposition, as assessed by PET imaging, was found in both the cross-sectional (global Aβ retention) and longitudinal analyses (change in global Aβ retention at 2 years). Notably, this association was observed only in APOE4-negative individuals. Low daily fluid intake was also associated with greater WMH volumes in cross-sectional analyses, although no significant associations were seen in the longitudinal analyses. However, there were no significant associations between daily fluid intake and any of the other neuroimaging measures including brain tau deposition, cerebral glucose metabolism, and cortical thicknesses.

This study should be commended as one of the first to comprehensively explore the potential impact of daily fluid intake on ADRD neuroimaging biomarkers in cognitively normal older adults. Strengths of this study include the use of a well-characterized cohort (KBASE) with baseline and follow-up data including multimodal brain imaging. Additionally, the authors carefully consider a wide range of potential confounding factors in their analyses. Moreover, to ensure that the findings were not due to poor general nutritional status, sensitivity analyses restricted to well-nourished participants were also conducted, which yielded similar results as the analyses conducted in the entire cohort.

Although the study has many strengths, several limitations must be noted. The most important consideration being the measurement of hydration status. The reliance on self-reported data to record daily fluid intake can introduce recall bias, particularly among older adults. Furthermore, daily fluid intake was recorded only once at the baseline visit and therefore did not account for changes that may occur over time, which may be particularly important in the longitudinal analyses. The dichotomization of participants into “high” and “low” daily fluid intake categories based on intake of more or less than 5 cups of fluid may also oversimplify hydration status. Adding additional measures of hydration status such as laboratory tests (e.g., hematocrit, serum sodium, serum osmolarity, etc.) could help further strengthen these findings. Other study limitations include the relatively short follow-up period of 2 years that may have been insufficient to capture long-term effects of hydration on AD pathology, cerebrovascular injury, and the development of dementia. Additionally, only a small subset of participants underwent tau PET scans (74 at baseline and 44 at 2-year follow-up), which likely underpowered the analyses investigating the associations between daily fluid intake and brain tau deposition. Finally, as the study was conducted entirely in Korea, it is not known how generalizable these findings will be in other populations without studies in additional cohorts.

An intriguing finding from this study is that the negative association between daily fluid intake and brain Aβ deposition was only seen in APOE4-negative individuals. The reasons for this are not clear. One possible explanation relates to the glymphatic system, a fluid transport system that facilitates the clearance of metabolites, including Aβ, from the brain. ⁹ It has been hypothesized that APOE4 may play a role in the premature narrowing of meningeal lymphatic vessels leading to abnormal meningeal lymphatic clearance and the pathological accumulation of Aβ in the brain. ¹⁰ Therefore, in APOE4 individuals, this impairment in glymphatic flow may limit any additional deleterious effects of dehydration on Aβ accumulation. Meanwhile, APOE3 individuals, who generally maintain more efficient glymphatic function, might be more susceptible to disruptions in Aβ clearance due to poor hydration. To clarify this finding, additional clinical studies in other cohorts to verify these results and mechanistic studies exploring how APOE may interact with hydration status to promote Aβ pathology will be needed.

Importantly, while the authors suggest that low daily fluid intake is promoting the brain Aβ pathology, the possibility of reverse causality should be considered. For instance, individuals with early brain Aβ deposition in the preclinical stage of AD might reduce their fluid intake due to subtle cognitive or behavioral changes. Prior research has identified that Aβ pathology in the hypothalamus can affect body weight regulation.^11,12 It is therefore plausible that Aβ pathology may similarly cause dysregulation of the brain circuits involved in thirst sensation or fluid homeostasis, leading to decreased fluid intake.

Despite these limitations, this study underscores the importance of examining hydration in older adults and the need to investigate in clinical trials whether reducing dehydration prevents or delays ADRD. If dehydration in older adults can be verified and validated as a modifiable risk factor for ADRD, ensuring adequate daily fluid intake could become a clinically meaningful, cost-effective strategy for preventing or delaying ADRD. Along with measures of other modifiable ADRD risk factors such as body weight, blood pressure, and blood sugar levels, clinicians could incorporate hydration assessments into routine evaluations. Education campaigns targeting older adults and caregivers could emphasize the cognitive and cerebrovascular benefits of adequate hydration, while addressing barriers such as reduced thirst sensitivity and limited access to fluids.