Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, Ernstsen V, Schullehner J, Hansen B, Andersen PK, Ersbøll AK. Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. 2017 Oct 1;74(10):1005-1010. PubMed.

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  1. I find the observations intriguing. As with any correlational study, it is difficult to know whether it is the lithium or something else that correlates with lithium levels in the water, but work from this group and others supports a protective effect of lithium in bipolar patients with cognitive decline, so it is certainly plausible that lithium in the drinking water somehow protects against AD progression. If lithium is really the factor that is conferring this apparent protective effect, then the mechanism is unclear. The known direct targets of lithium are actually limited to a handful of enzymes, including GSK-3, inositol monophosphatases (IMPase), and a few other phosphomonoesterases structurally related to IMPase, but the concentrations of lithium that Kessing et al. report are 100-1,000 times lower than what is needed to inhibit these targets.

    I think it would be premature to add lithium to drinking water based on the data available so far, especially as we do not know the potential risks of chronic lithium and it is not clear yet if lithium is really the “active ingredient,” or a marker for something else. There are also plausible, theoretical concerns with lithium. Lithium at higher concentrations activates Wnt signaling, which, when uncontrolled, promotes colorectal cancer and other cancers. The concentrations they find are not high enough to do that in an acute setting, and epidemiological data so far argue long-term lithium exposure does not increase risk of cancer, but this remains a consideration, as do other potential unforeseen consequences.

    Still, it is an exciting correlation worthy of further investigation.

    View all comments by Peter Klein

  2. Linking lithium in drinking water and dementia

    Lithium, since its discovery in 1950s by John Cade, has been used as a first-line drug for bipolar disorder (Geddes et al., 2010), but with a narrow therapeutic window. Despite an uncertain mechanism of action for its therapeutic mood effect, lithium was found later to interact with key pathways in Alzheimer’s disease (Feyt et al., 2005; Nakashima et al., 2005; Caccamo et al., 2007; Phiel et al., 2003), and subsequently investigated as treatment for Alzheimer’s disease (Kessing et al., 2010; Nunes et al., 2007; Terao et al., 2006; Brinkman et al., 1984; Wingo et al., 2009; Hampel et al., 2009) and other neurodegenerative disorders (UKMND-LiCALS Study Group, 2013; Verstraete et al., 2012; Aggarwal et al., 2010) as a general neuroprotection agent. Clinical trials of lithium, however, failed to demonstrate convincing neuroprotection or clinical benefit.

    In addition to their earlier work showing that that lithium treatment was associated with a reduced rate of dementia in patients with bipolar disorder, Kessing et al. (2010) found in this new study that there is association of lithium in drinking water with the incidence of dementia. Particularly, they found that high exposure of lithium (15.1-27 μg/L) was associated with a lower incidence rate ratio (IRR) of Alzheimer’s disease (0.78 (0.73-0.81). Unusually, lower doses of lithium from water sources (5.1-10.0 µg/L) significantly increased the risk for dementia (IRR 1.22 [1.19-1.25], p<0.001).

    There are a number of serious caveats about this study:

    1. Assuming that individuals in the study drank up to three liters of water per day, the maximum intake would be about 90 µg per day from water sources. However, the intake of lithium from food sources was reported to be 0.6 to 3.1 milligrams per day in the United States in 1985 (Schrauzer, 2002). Therefore, the contribution of water-sourced lithium to the total daily intake of lithium would be marginal. This observation alone argues that the protective or hazardous effects associated with lithium intake from water sources are unlikely to be mediated by the pharmacological effect of lithium itself, but rather, mediated by some other agent in the water that co-enriches with lithium or by some other regional environmental factor.
    1. The diagnosis of dementia type (Alzheimer, vascular) was based on clinical criteria. The Alzheimer diagnosis was not confirmed with an amyloid biomarker (e.g., PET or CSF Aβ). Both vascular and Alzheimer dementia IRRs were equivalently associated with lithium in drinking water. Since tau is meant to be the pharmacological target for lithium, it is difficult to reconcile the non-specific association of lithium in drinking water with vascular dementia, where tau abnormalities are not considered to be the main culprit.
    1. The Kessing study did not report the plasma lithium levels, which are important for arguing a causal relationship between lithium intake and dementia.

    We and others have reported that treating wild-type mice with lithium in food or drinking water, at doses equivalent to those used to treat bipolar disorder, resulted in hippocampal neuronal death, atrophy, and cognitive and behavioral dysfunction (Lei et al., 2017; Gómez-Sintes et al., 2010), in contrast to earlier beneficial effects on transgenic mice that overexpress APP or tau (Feyt et al., 2005; Nakashima et al., 2005; Caccamo et al., 2007; Phiel et al., 2003). This is because lithium suppresses brain tau expression, and, in wild-type mice (not overexpressing tau), this leads to secondary neuronal iron elevation by preventing APP trafficking (Lei et al., 2012). We further found in a clinical cohort of low-dose-lithium-treated cases (Berger et al., 2012) that the brain (nigral) iron content (measured by MRI T2* signal) was elevated during the course of treatment, which may be of concern given the association between brain iron and longitudinal cognitive decline we recently reported (Ayton et al., 2017). This is not to argue against the neuroprotective benefits of lithium in clinical practice, which are well established for bipolar disorder. We believe that mice are more sensitive to adverse neurochemical effects of lithium compared to humans.

    Taken together, we argue that the findings of Kessing et al., while intriguing, point to confounding factors associated with lithium contamination as the real biological mediator of the outcome effects observed.

    References:

    BALANCE investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010 Jan 30;375(9712):385-95. Epub 2010 Jan 19 PubMed.

    Feyt C, Kienlen-Campard P, Leroy K, N'Kuli F, Courtoy PJ, Brion JP, Octave JN. Lithium chloride increases the production of amyloid-beta peptide independently from its inhibition of glycogen synthase kinase 3. J Biol Chem. 2005 Sep 30;280(39):33220-7. Epub 2005 Jul 13 PubMed.

    Nakashima H, Ishihara T, Suguimoto P, Yokota O, Oshima E, Kugo A, Terada S, Hamamura T, Trojanowski JQ, Lee VM, Kuroda S. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 2005 Dec;110(6):547-56. Epub 2005 Oct 14 PubMed.

    Caccamo A, Oddo S, Tran LX, Laferla FM. Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol. 2007 May;170(5):1669-75. PubMed.

    Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003 May 22;423(6938):435-9. PubMed.

    Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia?. Bipolar Disord. 2010 Feb;12(1):87-94. PubMed.

    Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007 Apr;190:359-60. PubMed.

    Terao T, Nakano H, Inoue Y, Okamoto T, Nakamura J, Iwata N. Lithium and dementia: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1125-8. Epub 2006 Jun 6 PubMed.

    Brinkman SD, Pomara N, Barnett N, Block R, Domino EF, Gershon S. Lithium-induced increases in red blood cell choline and memory performance in Alzheimer-type dementia. Biol Psychiatry. 1984 Feb;19(2):157-64. PubMed.

    Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry. 2009 Nov;70(11):1588-97. Epub 2009 Aug 11 PubMed.

    Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009 Jun;70(6):922-31. PubMed.

    UKMND-LiCALS Study Group, Morrison KE, Dhariwal S, Hornabrook R, Savage L, Burn DJ, Khoo TK, Kelly J, Murphy CL, Al-Chalabi A, Dougherty A, Leigh PN, Wijesekera L, Thornhill M, Ellis CM, O'Hanlon K, Panicker J, Pate L, Ray P, Wyatt L, Young CA, Copeland L, Ealing J, Hamdalla H, Leroi I, Murphy C, O'Keeffe F, Oughton E, Partington L, Paterson P, Rog D, Sathish A, Sexton D, Smith J, Vanek H, Dodds S, Williams TL, Steen IN, Clarke J, Eziefula C, Howard R, Orrell R, Sidle K, Sylvester R, Barrett W, Merritt C, Talbot K, Turner MR, Whatley C, Williams C, Williams J, Cosby C, Hanemann CO, Iman I, Philips C, Timings L, Crawford SE, Hewamadduma C, Hibberd R, Hollinger H, McDermott C, Mils G, Rafiq M, Shaw PJ, Taylor A, Waines E, Walsh T, Addison-Jones R, Birt J, Hare M, Majid T. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013 Apr;12(4):339-45. Epub 2013 Feb 27 PubMed.

    Verstraete E, Veldink JH, Huisman MH, Draak T, Uijtendaal EV, van der Kooi AJ, Schelhaas HJ, de Visser M, van der Tweel I, van den Berg LH. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. J Neurol Neurosurg Psychiatry. 2012 May;83(5):557-64. Epub 2012 Feb 29 PubMed.

    Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M, . Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 May;9(5):481-8. PubMed.

    Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 2002 Feb;21(1):14-21. PubMed.

    Lei P, Ayton S, Appukuttan AT, Moon S, Duce JA, Volitakis I, Cherny R, Wood SJ, Greenough M, Berger G, Pantelis C, McGorry P, Yung A, Finkelstein DI, Bush AI. Lithium suppression of tau induces brain iron accumulation and neurodegeneration. Mol Psychiatry. 2016 Jul 12; PubMed.

    Gómez-Sintes R, Lucas JJ. NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy. J Clin Invest. 2010 Jul 1;120(7):2432-45. PubMed.

    Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012 Feb;18(2):291-5. PubMed.

    Berger GE, Wood SJ, Ross M, Hamer CA, Wellard RM, Pell G, Phillips L, Nelson B, Amminger GP, Yung AR, Jackson G, Velakoulis D, Pantelis C, Manji H, McGorry PD. Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study. Curr Pharm Des. 2012;18(4):570-5. PubMed.

    View all comments by Peng Lei

  3. The authors provide evidence of something we (researchers in the lithium field) were longing for. This set of data—nationwide and beautifully compiled—can only be provided by Danish/Scandinavian research groups, and Lars Kessing masters this type of work. Ten years ago, a study from his group (also addressing Danish databases) reinforced our findings of an inverse association between long-term, therapeutic lithium use (in late-life bipolar disorder) and lower prevalence of dementia (Nunes et al., 2007). 

    The present findings are also in line with the clinical and biological outcomes of a randomized, controlled clinical trial conducted in my group, indicating the potential use of low-dose lithium for the attenuation of cognitive and functional decline in patients with mild cognitive impairment (Forlenza et al., 2011). We are just about to release the continuation of this story, i.e., results from a similar intervention in a larger sample and longer duration of trial (up to four years).

    In addition, our translational studies agree with Kessing’s alleged non-linear effect of lithium on neuroprotection. In cultured neurons and animal models, many biological effects observed at micromolar and milimolar working concentrations are completely lost at higher levels, and vice-versa. That is to say, the molecular target depends on lithium doses (i.e. concentration ranges), and this way lithium can modulate distinct signaling systems, with effects that may range from neurotrophic/protective to cerebral/systemic toxicity.

     

    References:

    Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007 Apr;190:359-60. PubMed.

    Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. PubMed.

    View all comments by Orestes Forlenza

  4. The study is interesting but finds a non-linear relationship between drinking water levels of lithium and AD risk. More importantly (and emphasized in the paper), even the highest common dose (around 25 μg/L) is very small. This is relevant because the therapeutic effects of lithium for bipolar disorder occur within a relatively tight window, with optima around 0.8-1 mM (plasma concentration). In terms of mass (grams), the dosage is around 1,000 mg per day (usually split between two or three doses, depending on formulation). It’s not thought that constant, low-level amounts in drinking water cause tissue accumulation as lithium is a highly soluble salt.

    In terms of biological effect on GSK3 (as raised in the editorial), there’s some good data on lithium and GSK3 (an enzyme implicated in hyperphosphorylation of tau, APP processing, etc.) that 25 percent inhibition in mice caused by reducing the gene dosage of the GSK3 by that amount induces behavioral changes similar to treating mice with the equivalent of 1 mM lithium (i.e., in testing animal endophenotypes designed as surrogates for depression). A concentration of 1 mM causes about 25 percent inhibition of activity of this protein kinase. In other words, only partial inhibition of GSK3 is likely sufficient to drive an effect. However, the amounts in drinking water are much, much lower than any of these studies. I am assuming that biological effects of lithium in terms of GSK3 inhibition are similar for BPD and AD and note that most of the data on GSK3 in these disorders is largely correlative and biochemical. We still do not know if inhibiting GSK3 is useful for either disease and lithium has many effects in cells.

    Looking at the Danish study, my opinion is that there is very likely an insufficient amount of lithium in drinking water to significantly impact GSK3 (or several of the other known targets of the ion which have Ki's in a similar range). Moreover, if levels were raised to even sub-therapeutic doses, this would mean a much larger dose than occurs naturally (orders of magnitude) and would be likely be rejected by public health policy makers. For example, fluoride is typically added to drinking water at less than 1 mg/L (equivalent to about 50 μM) and even that is contentious.

    The authors do cite two studies on PLA2 in rats treated with “low” doses of lithium, so it’s possible there are some targets that are affected, but that “low” dose was 125 mg/L in water, at least 4,000 times the amount in the Danish water systems. The question then is whether people at risk of AD or with early stages of AD might be treated with lithium.  As the authors note, these studies have yielded mixed or disappointing results—possibly due to the disease being too far along for therapeutic intervention (as has been the case for other drugs).

    When differences between known therapeutic doses (for bipolar disorder) and natural sources are 4,000- to 10,000-fold, one has to wonder about mechanism of action/causality. While these are not “homeopathic” doses (they are measurable!), I wonder if the variances in natural levels in water are surrogates for some other difference that accounts for the variation in incidence. 

    View all comments by Jim Woodgett

  5. This is a very interesting finding that reinforces the therapeutic potential of lithium. Like any medication, lithium has a therapeutic window. What is not in dispute is that at high doses used to treat bipolar disorder, the effect of lithium on neurons is powerful and occurs within approximately seven days; what remains elusive is how low we can go with lithium to achieve any putative measurable improvement in long-term neuronal health.

    A significant number of plausible hypotheses exist about the candidate therapeutic targets of lithium. They include, my own opinion, that lithium, being a small ion that can fit into magnesium-sensitive biological targets, can influence neuronal calcium signaling, specifically by targeting NMDA receptors and inositol monophosphatase (Wallace, 2014). They include also my hypothesis that by potentially modulating calcium signaling before the onset of dementia, lithium might influence neuronal hyperactivity upstream of measurable amyloid accumulations—possibly default-mode-network hyperactivity, which in turn might influence amyloidogeneis, amyloid accumulations, and the onset of dementia.

    There is evidence that lithium targets hyperexcitable neurons (Mertens et al., 2015; Stern et al., 2017), and that lithium may reduce rates of dementia when it is administered at high doses to treat bipolar disorder years before the onset of dementia (Gerhard et al., 2015). How low we can go with lithium dosing to influence and cause any possible measurable decrease in neuronal hyperactivity remains an intriguing question. 

    In the quest to better understand lithium and better quantify lithium dosing, it might be worthwhile to focus on the measurable effects of lithium on neurons, such as neuronal hyperactivity modulation as one example; and possible correlations between lithium dosing, measurable changes to neuronal activity, amyloidogenesis, measurable quantities of amyloid accumulations, measurable changes in cognition, and the onset of dementia. 

    References:

    Gerhard T, Devanand DP, Huang C, Crystal S, Olfson M. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study*†. Br J Psychiatry. 2015 Jul;207(1):46-51. Epub 2015 Jan 22 PubMed.

    Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Ødegaard KJ, McCarthy MJ, Zandi PP, Alda M, Alba M, Nievergelt CM, Pharmacogenomics of Bipolar Disorder Study, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015 Nov 5;527(7576):95-9. Epub 2015 Oct 28 PubMed.

    Stern S, Santos R, Marchetto MC, Mendes AP, Rouleau GA, Biesmans S, Wang QW, Yao J, Charnay P, Bang AG, Alda M, Gage FH. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. Mol Psychiatry. 2017 Feb 28; PubMed.

    Wallace J. Calcium dysregulation, and lithium treatment to forestall Alzheimer's disease - a merging of hypotheses. Cell Calcium. 2014 Mar;55(3):175-81. Epub 2014 Feb 22 PubMed.

    View all comments by James Wallace

  6. We would like to signal our interest and our enthusiasm for the comprehensive study of Kessing et al. which was recently published in JAMA regarding the potential benefits rendered by drinking water with high lithium concentrations. This situation will be akin to the clinical administration of lithium at “microdoses,” a concept pioneered by Forlenza and collaborators. We would like to add to the discussion that our recent publication in Translational Psychiatry (Wilson et al., 2017) provides additional scientific support to that concept in vivo. In this report, we applied a new nanoencapsulated lithum formulation in a rat transgenic model of the Alzheimer’s-like amyloid pathology, at doses equivalent to 1/100 to 1/400 of the dosage applied conventionally for mood disorders. This study illustrated that “nano-lithium” application at early AD-like stages is able to diminish the amyloid pathology by restoring BACE1 activity to normal levels, restoring hippocampal neurogenesis, inhibiting GSK3β activity and preventing, foremost, the consequential cognitive impairment resulting from CNS amyloid pathology. 

    References:

    Wilson EN, Do Carmo S, Iulita MF, Hall H, Ducatenzeiler A, Marks AR, Allard S, Jia DT, Windheim J, Cuello AC. BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology. Transl Psychiatry. 2017 Aug 1;7(8):e1190. PubMed.

    View all comments by A. Claudio Cuello

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  1. Does Lithium in Tap Water Keep Dementia at Bay?