Alzheimer’s: even when the disease is present, the brain is resilient and repairs itself

Tests indicate that there are brain changes associated with Alzheimer’s disease. But from a clinical perspective, the person in question says exactly the opposite. They show no decline in cognitive abilities, have no memory difficulties; in short, they tend not to develop symptoms of the disease. This condition occurs in around three in ten older people, and is linked to a kind of brain adaptability that makes the brain itself resilient. Today, science is shedding light on this secret that protects some people from neurodegeneration. It does so by drawing on evidence from a study by researchers at the Netherlands Institute for Neuroscience, led by Evgenia Salta (née Giorgia Tosoni), published in *Cell Stem Cell*. This form of ‘resilience’ appears to be linked to a specific population of brain cells, known as immature neurons. According to the laboratory findings, these cells may behave differently in people who show no signs or symptoms of Alzheimer’s. Rather than merely replacing damaged cells, these neurons may actually help to protect the brain from the harmful effects of the disease. This is all thanks to cognitive resilience, which enables individuals to retain their memory and cognitive abilities even when their brain shows signs of damage or pathology.

The study paves the way for an approach to the disease that is diametrically opposed to the conventional one: rather than focusing on tackling the causes of the damage, we might instead consider what helps the brain to remain healthy and functional. It all hinges on adult neurogenesis, which involves the production of new nerve cells even in adulthood and old age. This occurs in some animal species, but there is debate as to whether it can occur in humans. The experts therefore examined samples of human brain tissue donated and obtained through the Netherlands Brain Bank, comparing three groups: people with no detectable brain disorders, patients who had developed Alzheimer’s dementia, and individuals whose brains showed signs of Alzheimer’s pathology but who retained good cognitive function. They then focused on a small region within the brain’s memory centre, considered one of the few areas where new neurons might develop. ‘These cells are extremely rare, so we had to develop new methods to identify them,’ explains Salta in a press release from the Dutch organisation. ‘We focused precisely on the exact spot where we expected to find them.’

Using this method, immature neurons were found in the brains of people over the age of 80 across all the groups studied. These are cells that have not yet reached full maturity, suggesting that the ageing brain may retain cellular characteristics associated with development and adaptability. All this, even at the age of 80. But that is not all. When comparing the brains of people who had developed cognitive decline with those of people who remained mentally sharp despite having Alzheimer’s, it was found that, numerically speaking, the number of cells was not particularly higher in the latter group. It was therefore thought that it is not the quantity, but the defensive capacity of the immature cells that might make the difference. In cognitively resilient individuals, in fact, the cells showed signs of activation of biological processes associated with survival and protection against damage. ‘In resilient individuals, these cells appear to activate programmes that help them survive and cope with damage,’ notes Salta. ‘We also observe less intense signs of inflammation and cell death.’ Inflammation is part of the body’s normal defence system, but when it becomes persistent in the brain, it can contribute to damage and interfere with communication between neurons. Cell death, meanwhile, gradually disrupts the networks responsible for memory and thought. In short: immature neurons in resilient brains may be better equipped to withstand these harmful conditions and also to help the brain remain functional and ‘young’. Thus, rather than merely serving as replacements for dying neurons, immature cells could potentially help to maintain the environment surrounding existing brain cells.

Let’s be clear. For now, we are only talking about hypotheses. As fascinating as they may be, they are still just hypotheses. Far more clearly defined – albeit still evolving – is the role of biomarkers in identifying risk and tracking the course of the disease. Thanks to these tools, in the future, we may not only be able to identify those most at risk, but also to target the mechanisms responsible for the onset of the disease, through prevention strategies, personalised monitoring and, potentially, treatments capable of modifying the initial biological processes. ‘In the case of Alzheimer’s disease, for example, we do not currently have tools capable of preventing its onset with certainty, but a better understanding of the interaction between genetic predisposition and other biological factors could pave the way for new possibilities for intervention,’ comments Alessandro Padovani, past President of the Italian Society of Neurology (SIN). ‘Research is therefore focusing not only on identifying risk, but also on understanding how to effectively reduce its consequences. Among the biomarkers currently of greatest interest in neurological research are p-tau217 and beta-amyloid biomarkers, which are particularly relevant to Alzheimer’s disease, as well as light-chain neurofilaments (NfL), indicators of neuroaxonal damage, which can provide information across various neurological conditions; certain markers associated with inflammatory processes; and alpha-synuclein, which is involved in Parkinson’s disease and other related neurodegenerative conditions. This, however, is only the beginning of a rapidly evolving field of research. The ability to study thousands of proteins simultaneously, integrating this information with other biological characteristics and the potential of artificial intelligence, could profoundly transform our understanding of neurological diseases in the coming years.’

The study