Climate change and Alzheimer's disease: the role of the hypothalamus

Project Summary:

Climate change and demographic shifts are driving a dramatic global rise in dementia, disproportionately affecting low- and middle-income countries and Latin America. Dehydration—exacerbated by higher temperatures and reduced access to potable water—is a recognised risk factor for cognitive decline, particularly in older adults whose renal water conservation is impaired and thirst responses blunted. This project tests a novel hypothesis linking lifetime inadequate hydration to Alzheimer’s disease (AD) via sustained activation of hypothalamic magnocellular neurons (MCNs). MCNs synthesise vasopressin to regulate body water and, despite being relatively spared from AD neurodegeneration, paradoxically express high levels of amyloid precursor protein (APP). We propose that chronic MCN activation increases APP expression and secretion, promoting amyloid plaque formation in hippocampal and other cognition-relevant regions, thereby driving AD onset and progression. Using complementary strengths from the University of Bristol and UNIFESP, we will apply state-of-the-art brain gene transfer techniques in rat and mouse models—including animals carrying AD-linked mutations—to chronically activate MCNs or upregulate APP specifically in these cells. Behavioural assays across lifespan cohorts will assess memory and cognitive decline; neuropathological, transcriptomic and proteomic analyses will evaluate classical AD hallmarks. Parallel human studies will leverage brain bank samples from Bristol and São Paulo, employing single-cell and spatial transcriptomics combined with neuronal tracing to relate animal findings to human pathology. Comparative analyses across UK and Brazilian cohorts will explore how differing risk landscapes (genetic/sex factors versus socioeconomic and educational determinants) intersect with MCN-related mechanisms. Outcomes will clarify the molecular and cellular role of hypothalamic MCNs in AD, assess the impact of hydration across ageing, and inform non-pharmacological prevention strategies such as assisted hydration. The programme will also strengthen UK–Brazil research links, train early-career researchers, and support larger joint funding bids addressing the intersection of climate, hydration and neurodegeneration. Gambling is a fast-growing global industry worth $540 billion.  However, around 450 million people around the world now suffer from gambling related harm and 80 million have a gambling disorder. Gambling is associated not only with financial losses and the risk of financial ruin, but with relationship and family breakdown; heightened risk of domestic violence; increased crime against property and people; and physical and mental health problems.  It is a serious public health issue. 

Visitor Biography:

Dr Andrew Mecawi holds a degree in Veterinary Medicine from the Federal Rural University of Rio de Janeiro (2009), an MSc and PhD in Physiology from the University of São Paulo (2012), and completed postdoctoral fellowships at the University of São Paulo (2012–2013) and the University of Bristol, UK (2014). He has been an Assistant Professor in the Department of Biophysics at the Federal University of São Paulo (UNIFESP) since 2018. His research focuses on Physiology and Biophysics, emphasising neurodevelopment, brain ageing and neurodegenerative diseases. He uses artificial intelligence and bioinformatics to analyse genomic, transcriptomic and proteomic data in both bulk and single-cell approaches applied to the central nervous system. Current projects investigate the role of hypothalamic magnocellular vasopressin-producing neurons in the development of pre-eclampsia, in neurodegenerative responses related to Alzheimer’s disease, and in behavioural control including sleep–wake cycles, anxiety and memory.