Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer’s Disease Mortality in Texas

Fajardo, Val A.; Fajardo, Val Andrei; LeBlanc, Paul J.; MacPherson, Rebecca E. K.

doi:10.3233/jad-170744

Cited by 62 publications

(46 citation statements)

References 65 publications

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“…Briefly, a total of 6180 water samples from public wells since 2007 were obtained from the Texas Water Development Board Groundwater Database, assessed, averaged and then log 10 ‐transformed for 234 of 254 Texas counties. As previously reported, the mean lithium concentrations in the Texas counties ranged between 0.003 and 0.539 mg/L (Fajardo, Fajardo, et al., 2018). Age‐adjusted CVD mortality (ICD‐10 codes I00‐I51) and CM mortality (ICD‐10 codes I42.0) rates from 1999 to 2016 were obtained from the Center for Disease Control Wonder's compressed mortality database.…”

Section: Methodssupporting

confidence: 63%

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Hamstra

Kurgan

Baranowski

et al. 2020

Experimental Physiology

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The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) pump is responsible for regulating calcium (Ca 2+ ) within myocytes, with SERCA2a being the dominant isoform in cardiomyocytes.Its inhibitor, phospholamban (PLN), acts by decreasing the affinity of SERCA for Ca 2+ . Changes in the SERCA2a:PLN ratio can cause Ca 2+ dysregulation often seen in patients with dilated cardiomyopathy and heart failure. The enzyme glycogen synthase kinase-3 (GSK3) is known to downregulate SERCA function by decreasing the SERCA2a:PLN ratio. In this study, we sought to determine whether feeding mice low-dose lithium, a natural GSK3 inhibitor, would improve left ventricular SERCA function by altering the SERCA2a:PLN ratio. To this end, male wildtype C57BL/6J mice were fed low-dose lithium via drinking water (10 mg kg −1 day −1 LiCl for 6 weeks) and left ventricles were harvested. GSK3 activity was significantly reduced in LiClfed versus control-fed mice. The apparent affinity of SERCA for Ca 2+ was also increased (pCa 50 ; control, 6.09 ± 0.03 versus LiCl, 6.26 ± 0.04, P < 0.0001) along with a 2.0-fold increase in SERCA2a:PLN ratio in LiCl-fed versus control-fed mice. These findings suggest that low-dose lithium supplementation can improve SERCA function by increasing the SERCA2a:PLN ratio.Future studies in murine preclinical models will determine whether GSK3 inhibition via low-dose lithium could be a potential therapeutic strategy for dilated cardiomyopathy and heart failure. K E Y W O R D Scalcium, cardiac muscle, GSK3, lithium supplementation, phospholamban, SERCA 1 wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:666-675.

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Section: Methodssupporting

confidence: 63%

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Hamstra

Kurgan

Baranowski

et al. 2020

Experimental Physiology

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“…Overall, the available evidence suggest that the neuroprotective effects of lithium found in diverse preclinical models of neurodegeneration translate into therapeutic benefits in cognitive function and reduced biomarkers in clinical trials of mild cognitively impaired amnestic and AD patients at lower lithium doses than those typically used for mood stabilization (Forlenza, Aprahamian, de Paula, & Hajek, ). Other studies also suggest that long‐term lithium treatment inhibits or slows down the core pathophysiologic features of AD in preclinical as well as in human study (Fajardo, Fajardo, LeBlanc, & MacPherson, ; Zhang et al, ). Notably, in a recent review of 28 psychiatric medications, including antipsychotics, anticonvulsants, and antidepressants, lithium had the most replicated evidence for neuroprotection in the widest range of neurodegenerative disease models (Lauterbach & Mendez, ).…”

Section: Introductionmentioning

confidence: 99%

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

Habib

Shytle

Sawmiller

et al. 2019

J of Neuroscience Research

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Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO)is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice.The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4 months of age were orally treated with low-dose LISPRO, LS, or LC for 9 months at 2.25 mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice. K E Y W O R D SAlzheimer's disease, cognitive impairment, depression, irritability, transgenic mice | 1067 HABIB et Al.

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“…8 Similarly, lithium concentrations in drinking water in several counties in Texas, USA were negatively associated with mortality rates as a result of Alzheimer's disease. 9 This body of evidence underpins the potential use of lithium as a disease-modifying therapy for Alzheimer's disease. 10 Four clinical trials have so far tested the effects of the administration of lithium salts for patients with, or at risk of, dementia.…”

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confidence: 99%

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial

et al. 2019

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BackgroundExperimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia.AimsTo determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease.MethodA total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at clinicaltrials.gov: NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25–0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale – cognitive subscale) and functional (Clinical Dementia Rating – Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0–48 months).ResultsParticipants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aβ1−42) after 36 months.ConclusionsLong-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI–Alzheimer's disease continuum.Declaration of interestNone.

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Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer’s Disease Mortality in Texas

Abstract: Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD.

Cited by 62 publications

References 65 publications

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial

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