The new holy grail in the fight against Alzheimer’s, the most common neurodegenerative disease, is the ability to detect it earlier and earlier, even before symptoms appear. Two studies published this week are steps toward that possibility, and raise controversial questions as to whether early screening should be made available to the general population to look for the disease’s first molecular signs. That would allow for the identification of individuals who are at the highest risk. But it would also generate a large number of false positives that could overwhelm healthcare services.

One of the studies focuses on measuring markers in the blood of middle-aged individuals who show no signs of dementia. A team of U.S. doctors and scientists used an approved blood test to gauge the accumulation of two proteins associated with Alzheimer’s — variants of beta-amyloid and tau — in 1,350 people between the age of 56 and 69, who have been followed for at least 35 years, and who were apparently free of cognitive disorder.

Their results showed that around 6% of all participants had some molecular marker associated with Alzheimer’s, and were already showing symptoms of mild cognitive impairment.

The study is led by Kristine Yaffe from the University of California, San Francisco. Her team focused on the fact that 30% of the risk of dementia can be avoided through simple interventions, like leading a healthy lifestyle and exercising. In light of their results, which were published by the medical journal The Lancet, researchers point out that the new blood tests “might enable timely prevention and intervention in midlife adults” through aforementioned measures and newly available pharmaceuticals. These drugs, Lecanemab and Donanemab, do not cure the health condition, but can moderately slow its advance.

Results showed that patients with two molecular markers (Aβ42/40 and p-tau217/Aβ42) have much higher risk of suffering from problems associated with verbal memory and cognitive processing, compared with people who do not display accumulation of these proteins in the blood. The marker Aβ42/40, for example, is associated with more than a fourfold risk increase for verbal memory issues, and that p-tau217/Aβ42 is linked to nearly the same increase in regards to cognitive speed. Among those testing positive for the first marker, risk increases from three out of 100 of suffering from the condition to 12 out of 100, for example.

Researchers did not find that such patients had diagnosable generalized cognitive decline; that is to say, the first signs of something that could progress towards the appearance of Alzheimer’s, or not. Having the molecules in the blood does not mean that one is 100% sure to suffer from dementia: there is still a level of uncertainty in these tests that continues to complicate early diagnosis before the appearance of clear signs of cognitive decline.

A second study published on Friday in The Lancet explores another path to early diagnosis. In current clinical practice, biomarkers of Alzheimer’s are detected through brain scan or lumbar spinal tap to extract cerebrospinal fluid. Those are reliable methods, but costly — which is where the utility of blood tests comes in. This second study analyzes a new technique for detecting Alzheimer’s proteins by using a positron emission tomography (PET) scanner. The study was carried out in the United States and Canada with nearly 700 participants. Among cognitively unimpaired individuals between 50 and 89 years of age who already displayed an accumulation of the amyloid protein, the new experimental MK6240 method, produced by the U.S. company Lantheus, detected proteins associated with Alzheimer’s before standard diagnostic methods, allowing for earlier diagnoses.

The Spanish Society of Neurology (SEN) estimates that more than 50% of mild cases of Alzheimer’s are undiagnosed. With current methods, the period between the onset of the first symptoms and official diagnosis ranges from two to three years. That makes early diagnosis through increasingly simple methods a fundamental part of the application of new pharmaceuticals in treating the disease, which have been proven to slow its development by 27% over 18 months. These new drugs only work if they are administered in the initial phases of the disease. To put it another way, Alzheimer’s affects 50 million people around the world, but the new drugs, at their current rates of prescription, would only help 5% of them, according to SEN. There are two drugs of this kind that have been approved in Europe and the United States, Lecanemab and Donanemab, though both are awaiting reports on their cost (currently just shy of $30,000 a year, not including diagnostic tests) and effectiveness.

Drugs and screenings

One of the first study’s most important contributions is its analysis of Alzheimer’s biomarkers in a middle-aged sector of the population who have no apparent sign of cognitive issues, something that very few prior investigations have focused on, according to comments on the study from Anna Rosenberg and Tiiia Ngandu of the Finnish Institute for Health and Welfare. However, they warn that the predictive power of these markers is smaller among younger patients. That is why they warn that “they are not appropriate as large-scale screenings in the general population.” The primary issue at the moment is that it is unknown whether people with high markers will or will not develop dementia. That should be the next step in this area of study, they add.

For example, in the semaglutide trials for the thinning molecule present in new drugs like Ozempic, the treatment has been seen to reduce the tau protein in cerebrospinal fluid, but not in the blood, point out the two authors.

Pascual Sánchez Juan, an expert on dementia and scientific director of the CIEN Foundation, underlines the value of these studies in the field, but warns that it is too soon for their therapeutic application. The primary value of the first study is having focused on “a population with an average age of 61, which is very young for a study on Alzheimer’s.” It is “probable” that the 6% of people who already show some sign of cognitive decline will develop the disease, he explains. But due to the low prevalence, the value of carrying out general screening on the healthy population would have low predictive value. “Since at the moment, there are no drugs that can reverse the disease’s course [only delay its arrival], this kind of test would not be justified beyond the study, and no one should worry about getting it done if they do not have recognizable cognitive symptoms,” he says.

Juan Fortea, a neurologist at Barcelona’s Hospital Sant Pau, is the co-author of the second study. The doctor says that the tau protein on which it focused is currently “the best predictor” of a patient’s status, which is to say, in which phase of the disease they are in. That is why early detection can help.

The researcher believes that neurology is currently in a crucial moment when it comes to establishing blood tests and rolling out new drugs against Alzheimer’s. At the moment, there are two opposing viewpoints, one held by the International Working Group, which says that in order to diagnose Alzheimer’s, the existence of symptoms are required in addition to biological markers. The other, held by patients’ associations, holds that the mere presence of these markers should be considered Alzheimer’s. The doctor thinks it’s still too soon to carry out population-wide screening, but “that could change in a few years.”

Companies that have developed the new drugs against Alzheimer’s are carrying out trials with people who do not yet demonstrate symptoms, but do show an accumulation of these proteins. This analysis could demonstrate the effectiveness of intervention prior to diagnosis. If that is proven, and reliable “risk calculators” of Alzheimer’s are developed, such as those that already exist for cardiovascular diseases, it would be viable to conduct generalized tests, Fortea argues. It would be similar to those already being carried out for cholesterol and some cancers, like colon and breast.

Raquel Sánchez-Valle, coordinator of Spanish Society of Neurology’s Study Group for Behavior and Dementias, sees both advances and risks in these new studies. “In the field of research, [these tests] allow for the selection of participants for intervention studies, pharmacological and non-pharmacological, some of which are already in progress, which could give relevant results in a few years. It would be then that we would have a response as to whether or not population-level screening should be recommended,” she says. “Another thing is that the availability of plasma markers are leading health people to ask for them privately. It will be complicated to manage the possibility of false positives, because the information you can give from the individual, predictive perspective is very sparse, and because intervention studies that are being proposed have little to no individual-level evidence at this time,” warns the expert.

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