A simple test of how well someone navigates a virtual maze could spot Alzheimer’s disease years before memory loss begins. Current diagnostic tools fail at early detection. Pen-and-paper cognitive tests are unreliable across different languages and education levels, while brain scans and spinal fluid tests are too expensive and invasive for widespread use. The disease’s earliest damage targets the entorhinal cortex and hippocampus—brain regions that handle spatial navigation and memory. The researchers have already shown that middle-aged people at genetic risk for Alzheimer’s perform worse on spatial tests even when other cognitive skills remain normal, and that these tests outperform the best existing cognitive assessments for detecting early-stage disease. If successful, this project would give GPs a cheap, non-invasive screening tool—delivered as a smartphone app or augmented reality headset—that works equally well across cultures and languages. It would also allow clinicians to track how Alzheimer’s spreads through the brain by testing different components of the spatial memory circuit, bridging a critical gap between laboratory studies of molecular pathology and real-world patient care. The ultimate goal is to detect the disease early enough for treatments to delay or prevent dementia.
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We will address one of the greatest unmet needs in global healthcare, namely the ability to detect Alzheimer s disease (AD) in its very earliest presymptomatic stages, when therapeutic interventions have the greatest chance of delaying or preventing progression to dementia. Current tests do not meet this need; legacy cognitive tests lack sensitivity and specificity for early AD and are afflicted by educational and linguistic confounds, while PET- and CSF-based biomarker tests are expensive, invasive and unsuited to deployment at scale. Our ability to detect AD at outset derives from usage of tests of spatial navigation and memory, representing functions of the entorhinal cortex (EC) and the hippocampus, the first regions exhibiting neurodegeneration in AD. We have already shown alterations of these spatial behaviours in middle-aged asymptomatic individuals at risk of AD, in the absence of impairment in other cognitive domains, and also that spatial tests have higher diagnostic sensitivity and specificity for prodromal AD than current best-in-class cognitive tests. Our aim now is to translate this superior diagnostic capability to usage in routine clinical practice. In probing natural behaviours common to all humankind, spatial tests not only have an ecological validity absent from pen-and-paper tests but are also usable in different communities independent of culture and language differences, thus meeting the need for inclusivity and diversity in next generation cognitive testing. Furthermore, our approach yields two additional critical benefits, neither of which can be delivered by any competitor method. First, we will bridge the translational divide between lab-based research into disease mechanisms and studies of the human condition. In using tests based on the spatially-related firing activity of EC and hippocampal neurons, our approach helps address the crucial knowledge gap between lab-based research examining the effect of AD molecular pathology on cellular function and the onset of the clinical disorder in the human. This knowledge gap represents arguably the biggest impediment to the discovery of effective therapies for AD. Second, we can track AD as its spreads from disease outset. This is achievable by our use of spatial tests testing the function of different components of the EC-hippocampal synaptic circuit, allowing us to measure the behavioural outcomes associated with AD pathological spread within this circuit. For implementation at scale in routine clinical practice, we will adapt our spatial tests to run on low-burden devices, developing augmented reality (AR) and smartphone app versions of our current VR- and tablet-based tests respectively. By working with design engineers, public-patient consortia and primary care practitioners we will maximise usability and acceptability from service user and service provider perspectives. To ensure fitness for purpose we will trial our new tests in asymptomatic and symptomatic cohorts with early AD, validating against molecular and imaging biomarkers of AD. Spatial tests have an unequalled ability to transform diagnosis of early AD and bridge the divide between basic science research and clinical practice. The imperative now is to deliver these advantages to the benefit of people worldwide at risk of dementia.
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