Throughout the world, nitrogen (N) losses from intensive agricultural production may end up as undesirably high concentrations of nitrate in groundwater with a long-term impact on groundwater quality. This has human and environmental health consequences, due to the use of groundwater as a drinking water resource, and causes eutrophication of groundwater-dependent ecosystems such as wetlands, rivers and near-coastal areas. At national scale, the measured nitrate concentrations and trends in Danish oxic groundwater in the last 70 years correlate well with the annual agricultural N surpluses. We also show that the N use efficiency of agriculture is related to the groundwater nitrate concentrations. We demonstrate an inverted U-shape of annual nitrate concentrations as a function of economic growth from 1948 to 2014. Our analyses evidence a clear trend of a reversal at the beginning of the 1980s towards a more sustainable agricultural N management. This appears to be primarily driven by societal demand for groundwater protection linked to economic prosperity and an increased environmental awareness. However, the environmental and human health thresholds are still exceeded in many locations. Groundwater protection is of fundamental global importance, and this calls for further development of environmentally and economically sustainable N management in agriculture worldwide.

Dementia is the leading cause of dependence and disability in the elderly population worldwide.^1,2 As the mean life expectancy increases, the prevalence of dementia³ and associated monetary costs are expected to increase exponentially.⁴ The pathogenesis of Alzheimer disease is highly complex and likely to be multifactorial, including deregulated amyloid-β, phosphorylated τ, and glycogen synthase kinase 3, as well as inflammation, mitochondrial dysfunction, and calcium dyshomeostasis, suggesting that combination therapy or multitarget drugs might be effective.⁵ Lithium is a multitarget drug that seems to possess neuroprotective abilities by modulating a large array of intracellular cascades and pathways involved in oxidative stress, inflammation, mitochondrial dysfunction, membrane homeostasis, and inhibitory effects on glycogen synthase kinase 3.^5-8 Animal studies^9,10 have found that long-term lithium treatment improves learning and memory, and human observational studies^11,12 suggest that continued treatment with lithium may reduce the risk of dementia among patients with bipolar disorder. In bipolar disorder, treatment with lithium in usual therapeutic daily doses (600-2400 mg) for mood stabilization increases the risk of chronic kidney disease in the elderly population.¹³ In accordance with this finding, lower doses have been used in trials investigating the effects of lithium on cognition among older individuals.^14,15 A placebo-controlled, randomized 2-year trial suggested that long-term treatment with daily low-milligram doses of lithium (150-600 mg) may decrease the rate of developing Alzheimer disease and cerebrospinal fluid concentrations of phosphorylated τ among individuals with mild cognitive impairment.¹⁴ Furthermore, in a 15-month, placebo-controlled randomized clinical trial, a microdose of 300 µg/d of lithium stabilized cognitive impairment in patients with Alzheimer disease.¹⁵ We investigated whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water, hypothesizing that higher long-term lithium exposure may be associated with a lower incidence of dementia.