Alzheimer’s disease (AD) is a neurological condition that most commonly affects people over 65. It causes a range of symptoms including memory loss, confusion, problems with movement and even personality changes. AD can be incredibly distressing for both the patient and their families, and it is thought to affect over 800 000 people in the UK. It is a progressive illness, with symptom severity increasing over time. Intervention after onset is generally limited in its ability to improve symptoms, which means that early detection is critical in this disease for best outcome.

Considerable research efforts have been made to find markers that identify individuals who may be at risk of developing AD, in order to understand early pathological changes that may occur before clinical symptoms appear. Researchers believe that if it were possible to identify individuals who will later develop AD, intervention during the preclinical stage would have the greatest potential to delay disease onset. Investigation of brain structure has shown promising results, but brain atrophy is often a fairly late pathological event in neurodegenerative processes.

Researchers from the Department of Psychiatry, University of Cambridge in collaboration with researchers at Imperial College London, recently undertook a review of the functional neuroimaging literature in individuals at risk of developing AD, to better understand and articulate the current potential of these tools in the early detection of AD. Their paper was published earlier this year in Ageing Research Reviews.

Studies were included in the review if patients were under the age of 60 and had a genetic risk of developing AD. The review drew together findings from four distinct functional imaging techniques: positron emission tomography (PET), arterial spin labelling (ASL) magnetic resonance spectroscopy (MRS) and both task-based and resting-state functional magnetic resonance imaging (fMRI). Collating evidence from multiple techniques allowed for a deeper understanding of the physiology and processes that may be involved in altered function.

The converging narrative in this review suggests that functional changes in brain areas implicated in established AD are present in those at risk of future dementia, sometimes decades before either structural atrophy or cognitive differences are expected to manifest. For instance, PET studies that investigated amyloid deposition suggested that a build up of amyloid “plaques” could begin 15 years before expected symptom onset. Furthermore, MRS studies showed that the magnitude of decreases in metabolites in the posterior cingulate and precuneus correlated with the proximity of expected age of onset. Disruptions in the function of areas that serve memory were also consistently reported across a variety of memory and encoding tasks in fMRI studies, while no differences in these tasks were observed behaviourally. Although at present, it is unclear whether increased or decreased activation marks at-risk individuals, so interpretation of these findings is still an on-going debate.

Functional imaging techniques therefore could be able to detect changes during a preclinical stage, and this offers great clinical utility. However, it is unknown for certain, the prognostic potential of these techniques. One of the lead authors Elijah Mak commented “The majority of studies in the review were cross-sectional. Therefore, we do not know how patterns of functional changes in the brain might evolve over time with respect to disease progression. This is particularly important as some of the [genetic] risk-factors appear to have conflicting effects on brain function depending on the disease stage and age. With more longitudinal studies involving serial neuroimaging and neuropsychological assessments, we will be able to study the trajectory of functional changes in at-risk individuals until some of them develop dementia.”

We also spoke with senior author Professor John O’Brien, who concluded “The key questions remaining are a) what is the most sensitive imaging marker to detect such changes; b) how long before dementia begins can such changes be seen and c) are such changes useful for either predicting dementia in individual cases (as opposed to seeing changes at a group level) or as a surrogate outcome marker for clinical studies”.

Inspired by the findings from the review, the Cambridge team are currently working with the Universities of Edinburgh, Oxford and Imperial College London on the PREVENT Dementia study. This is a large experimental, multi-modal imaging study of several hundred middle-aged (40-59) individuals. The study hopes to address the current research gaps brought to light from this review and investigate the utility of functional imaging methods as a biomarker for Alzheimer’s disease.

Written by Siân Emma Davies

Cover image by sarcifilippo licensed under CC0 1.0