Print This PostWith any disease, we typically see changes first on a molecular and cellular level, followed by changes in the tissue that these cells make up. These changes then affect the function of the organ and organ system of these tissues. Ageing is a biological process which impacts on our cells and tissues in the same order. We first see molecular and cellular changes, which over time impacts on tissue structure and organ function. This is what occurs in the brain as we age. But brain ageing is not a disease, so why might the processes be similar? In this blog, I discuss whether the brain diseases which cause dementia can be considered a form of accelerated brain ageing.
The process of ageing results in changes on a molecular, cellular, tissue, and organ level, which results in either degeneration of the organ, or a reduced ability for it to regenerate. In the brain, we see this as mitochondrial dysfunction, oxidative stress, impaired DNA repair mechanisms, changes in cell signalling, accumulation of misfolded proteins, signs of neuroinflammation, and reduced brain volume due to loss of neurons. These changes don’t happen equally everywhere in the brain, but instead affect some regions more than others. These changes are also key hallmarks linked to neurodegeneration, and almost all aged brains show these changes to some extent. In the brains of older people with no history of neurological or neurodegenerative disease, we also see evidence, to varying degrees, of amyloid plaques and tau tangles (pathologies associated with Alzheimer’s disease), and also Lewy bodies (associated with Dementia with Lewy bodies and Parkinson’s disease). This means that these characteristic pathological changes are not exclusively present in the brains of people with neurodegenerative diseases, but also in older people with no associated cognitive or motor impairments. It’s possible that these pathologies may be a precursor to dementia, as we know that pathological changes develop and progress in the brain many years before clinical symptoms are present. But what’s clear is the need to uncouple brain pathologies and clinical symptoms, as they often don’t correlate.
Research has shown that there are very few people over the age of 80 who lack any of the pathological features described which are associated with neurodegenerative diseases. For example, one study analysed the brains of people over the age of 90 and reported that almost half either met the neuropathological diagnostic criteria for Alzheimer’s disease, or had mixed pathologies, despite having no clinical diagnosis of dementia during life. Of those who did have a diagnosis of dementia, most did have evidence of neurodegenerative disease pathologies, but 12% of the sample didn’t. So if it’s common for older people to have neurodegenerative disease pathology, regardless of whether they have the associated cognitive or motor impairments, an interesting approach to explain why this might be the case is to think of typical brain ageing as being on a continuum with neurodegeneration. Here, biological ageing results in neurodegenerative disease eventually, with the type(s) determined by genetic and environmental factors for each person. However, biological age doesn’t necessarily correlate with chronological age, meaning there’s the possibility that some people will experience faster biological ageing relative to their chronological age. Those who do experience accelerated brain ageing, and develop neurodegenerative pathologies at a relatively younger age, will typically be those who also experience cognitive and/or motor symptoms, and receive a clinical diagnosis on this basis. Those whose biological and chronological age are more closely aligned may still develop neurodegenerative pathologies, but these will be evident at a much older age and will be unlikely to be associated with any impairment. Accelerated biological ageing is not a purely theoretical concept; people who are affected by rare genetic conditions known as progeroid syndromes undergo premature biological ageing processes. So aside from these relative rare cases, why might some people experience accelerated brain ageing, and others not?
We know that various risk factors for dementia have been identified. It’s possible that someone’s exposure to these risk factors can determine the speed of biological ageing, triggering the mechanisms leading to the development and progression of neurodegenerative pathologies. In addition, some people may have protective factors or compensatory mechanisms which mean they’re able to maintain typical brain ageing, or at least unimpaired cognition, as the development of neurodegenerative pathologies progresses.
If the gap between biological age and chronological age can be influenced by various risk and protective factors, the timepoint in someone’s life in which these exposures occur can be important in determining long-term health outcomes. For example, experiencing a traumatic brain injury (TBI) is associated with an increased risk of developing dementia in later life, but we don’t fully understand why. Controlling for all other factors, experiencing a TBI at an earlier timepoint in someone’s life would mean a longer time course for the development and progression of neuropathologies, and therefore an increasingly larger gap between biological and chronological age than someone who might have experienced a TBI later in life. Brain ageing is therefore heterogenous because across the lifespan everyone will experience variable levels of risk exposure, potentially causing different degrees of cumulative damage that impacts on the rate of biological brain ageing.
A lot of progress has been made in developing new drugs to treat the brain diseases that cause dementia, but we also need tests which are specific and sensitive enough for early diagnosis, so these treatments can be delivered when they will be most effective. If we accept that dementia, and the brain diseases which cause it, are a consequence of accelerated brain ageing, is brain age something we can measure to predict whether someone will develop dementia in later life, as an early diagnostic tool? Studies have shown that it’s possible to predict brain age using neuroimaging, like MRI. One possible use of measuring brain age would be for predicting whether people with mild cognitive impairment (MCI) will eventually develop dementia. MCI is characterised by problems in thinking and memory. It may not necessarily be caused by the brain diseases underlying dementia, but around 1 in 10 people with MCI will go on to develop dementia each year. One study has shown that a greater gap between biological and chronological brain age can be used as a predictor for whether someone with MCI will develop dementia. This could potentially enable early access to treatment that would slow cognitive decline in people likely to develop dementia.
More research is needed to understand healthy brain ageing if we want to effectively treat diseases and conditions which cause cognitive impairment, like dementia.
However, as we see a significant amount of research funding directed towards fluid-based biomarkers for diagnosing diseases like Alzheimer’s, we need to be cautious about the poor correlation between brain pathologies and clinical symptoms. We should strive to diagnose people as early as possible so that treatments can be given when they’re most effective, but this shouldn’t be at the expense of potentially diagnosing and treating individuals with positive tests for β-amyloid or tau, for example, if they are cognitively unimpaired and may never go on to develop dementia. An additional measure, such as brain age, could be a useful predictor for determining whether the presence of neurodegenerative pathologies will convert to the cognitive impairment we see in dementia.
Dr Kamar Ameen-Ali
Author
Dr Kamar Ameen-Ali is a Lecturer in Biomedical Science at Teesside University & Affiliate Researcher at Glasgow University. In addition to teaching, Kamar is exploring how neuroinflammation following traumatic brain injury contributes to the progression of neurodegenerative diseases that lead to dementia. Having first pursued a career as an NHS Psychologist, Kamar went back to University in Durham to look at rodent behavioural tasks to completed her PhD, and then worked as a regional Programme Manager for NC3Rs.
Dementia Researcher
NIHR
Thank you, Dr. Kamar, for the clear explanation. The idea of measuring brain age is important for better understanding dementia and helping with early diagnosis.