There are currently no drug treatments that cure Alzheimer's disease or other common dementias. However, recent research strongly indicates leaks in the blood-brain barrier (BBB) precipitate dementia onset, offering realistic hopes that dealing with these leaks could prevent dementia onset or reverse the disease if already present. Two Israeli researchers, Daniela Kaufer and Alon Friedman, describe their pioneering work in this area in Scientific American (May 2021).
Dementia is characterised by cognitive function deterioration exceeding the usual consequences of biological ageing. Although not an inevitable consequence of ageing, dementia mainly affects older people. More than 55 million people now live with dementia worldwide and 10 million new cases arise annually. These numbers are projected to double every 20 years.
Alzheimer’s disease is the commonest form of dementia, contributing between 60 per cent and 70 per cent of cases. Dementia is the seventh leading cause of death from diseases and a major cause of disability/dependency among older people. Dementia can distress the affected person and also their carers and family. And many people greatly fear they will eventually develop dementia, becoming unable to recognise family and friends, more than they fear any other debility that may develop in old age.
BBB was discovered in the late 1800s by German physician Paul Ehrlich (1854-1915) when he injected a dye into the bloodstream of a mouse. The dye seeped into all tissues except the brain and spinal cord, demonstrating a barrier between the brain and the blood. The BBB protects the brain against pathogens, toxins and brain irritants that may be present in blood.
Small molecules
The walls of the tubes (blood vessels) that supply blood to the brain are lined by endothelial cells that pack together extremely tightly allowing only small molecules and some gases to pass passively into the brain tissue. Some larger molecules such as glucose (which the brain exclusively relies on as an energy source) are also facilitated to pass into the brain through special “doors” that are open only for them.
If the BBB is damaged, as, for example, in meningococcal disease when bacteria and other toxins enter the brain, the brain becomes inflamed which can lead to death.
Early work carried out by Kaufer and Friedman hinted that Gulf War (1990-’91) syndrome, reported by many veterans of the war, might be the result of stress-induced damage to BBB allowing the drug pyridostigmine, given to soldiers to protect against chemical weapons, to enter the brain and cause the syndrome. Gulf War syndrome is characterised by chronic fatigue, sleep problems and cognitive deterioration.
Kaufer and Friedman have carried out extensive research on mice. When put under stress, mice spring leaks in their BBB allowing blood proteins (albumins, abundant in blood) to enter the brain, initiating a cascade of changes and chaotic electrical activity similar to those seen in Alzheimer’s disease and related dementias, and in epilepsy.
Deteriorates
The BBB deteriorates anyway over the normal course of ageing and albumin levels in the brain, negligible in younger mice, rise as the mice age and the BBB deteriorates. But, most excitingly, these adverse changes can be reversed in older mice by administering a drug that prevents brain cells from being irritated by blood proteins. Older mice with inflammatory brain fog when treated with this drug begin navigating mazes like much younger mice, and abnormal electrical activity in the brain subsides.
To date the primary hypothesis as to what causes Alzheimer's disease has been the buildup of beta-amyloid protein, plaques of protein widely distributed in Alzheimer's brains. But reducing levels of this protein in the brain has not helped patients with Alzheimer's disease, nor have drugs that target beta-amyloid as outlined by Sarah Ackley and others in the British Medical Journal. The beta-amyloid hypothesis is in difficulty – and it is time to investigate other possibilities.
Unfortunately, we cannot say for sure that damage to the integrity of the BBB is the primary cause of Alzheimer’s and other dementias. It may be collateral damage caused by some other, yet unknown, primary damage event. Also, results obtained from rodents sometimes do not easily translate to humans. But, that said, there is good reason to energetically pursue this BBB hypothesis. As Kaufer and Friedman advocate, if damage to ageing BBB can initiate events that lead to dementia, and if this change can be blocked to restore health, the hypothesis is surely a line of investigation worth pursuing.
William Reville is an emeritus professor of biochemistry at UCC
