Scientists have found a way to predict the development of early dementia

A decrease in the thickness of gray matter in several areas of the brain can indicate how quickly a person with early Alzheimer's disease will move from mild cognitive impairment to dementia and begin to lose independence. Scientists have developed an MRI biomarker that evaluates the disease-specific pattern of atrophy and complements the prognosis based on the patient's current symptoms. About how the new "signature" of the brain works, how accurate such a forecast is and when the method can enter clinical practice — in the material of Izvestia.

Illness before the age of 65

Early Alzheimer's disease differs from the most common form by the age of onset of symptoms: memory, speech, thinking, or visual-spatial perception disorders occur before the age of 65. According to the US National Institute of Aging, these cases account for less than 10% of all Alzheimer's disease diagnoses.

However, the early onset of the disease does not mean that it is necessarily inherited. Rare changes in the APP, PSEN1, and PSEN2 genes are indeed capable of directly causing the disease, but most early cases are sporadic. The authors of the new study studied patients without an identified hereditary mutation that causes Alzheimer's disease.

Where mild disorders end and dementia begins

The study participants were at the stage of mild cognitive impairment. During this period, memory and thinking problems already go beyond the usual age-related changes, but a person is still able to cope with most everyday tasks on their own.

The transition to dementia is fixed when cognitive impairments begin to significantly interfere with daily life. It becomes more difficult for a person to work, manage finances, cook meals, take medications, navigate an unfamiliar environment, or perform other familiar activities without outside help.

The duration of the intermediate stage varies significantly. One patient can remain independent for several years, while the other's condition worsens much faster. A clinical examination makes it possible to assess the severity of the symptoms at the moment, but it is difficult to determine the further rate of change.

What scientists have called a brain signature

The developed method is called the "signature of early Alzheimer's disease." This is not a separate formation that can be seen in the image, but a map of the areas of the cortex that are especially vulnerable in the early form of the disease.

The basis of the biomarker was laid in the previous work of the same group. Then scientists found that in patients with early Alzheimer's disease, atrophy is especially noticeable in the lower part of the parietal lobe, the posterior cingulate cortex, the preclinium and the posterior temporal cortex. The study showed that this pattern is reproduced in different groups of patients and is associated with the severity of cognitive impairment.

This pattern differs from typical late-onset Alzheimer's disease, in which damage to the medial parts of the temporal lobe, including structures closely related to memory, is particularly noticeable. In younger patients, neurodegeneration may more broadly affect the parietal and posterior temporal regions, which are responsible not only for memorization, but also for speech, attention, reasoning, and processing of visual-spatial information.

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How was the study conducted?

The researchers analyzed data from 130 people aged 40 to 64 years. All had mild cognitive impairments associated with biomarker-confirmed early Alzheimer's disease, but they remained independent at the time of inclusion in the study. The control group consisted of 97 cognitively healthy people of comparable age.

Each volunteer underwent an MRI scan at the beginning of the study. The participants then underwent at least one repeated annual examination. The average follow-up period was about two years. The researchers measured the thickness of the cortex in eight areas related to memory, speech and thinking. These included the medial and lateral parietal cortex, as well as the posterior part of the lateral temporal cortex. The obtained values were combined into a general indicator of the severity of atrophy.

Not only the absolute thickness of the crust was used for calculations. The scores of each participant were compared with those of a healthy control group and adjusted for age and gender. This allowed us to determine how much the brain condition of a particular patient deviated from the expected level.

Such an analysis cannot be equated with a regular visual MRI scan. In the study, the images were subjected to quantitative processing, during which the program measured predefined areas and formed a summary estimate. Therefore, the presence of a standard MRI report does not mean that a new signature has been automatically calculated for the patient.

What has been shown by two years of observations

During the study, 84 out of 130 patients, or approximately 65%, transitioned from mild cognitive impairment to dementia. In people with more pronounced cortical thinning, this transition occurred faster on average. For each standard deviation towards more severe atrophy, there was a 1.24-fold increase in the relative risk of developing dementia. In other words, with a more pronounced decrease in cortical thickness, the instantaneous risk of deterioration during the follow-up period was approximately 24% higher.

It is important to interpret this figure carefully. This does not mean that dementia will necessarily develop in an additional 24% of patients. The indicator also does not allow one snapshot to determine a specific month or year when a person will lose independence. We are talking about the statistical difference in the rate of disease development between people with different degrees of atrophy.

The addition of an MRI signature improved the prediction model, which already took into account age, gender, and the initial severity of cognitive impairment. Consequently, the condition of certain areas of the cortex contained additional information that could not be obtained from the evaluation of symptoms alone.

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Can a biomarker be considered a "clock"

The biomarker is compared with a timer that can indicate the speed of approaching dementia. Such a metaphor helps to explain the idea of the study, but it should not be taken literally yet. The method distributes patients according to the likely rate of progression, rather than starting an individual countdown. Two people with similar MRI results may experience different disease dynamics due to their health, education level, comorbidities, lifestyle, and other biological factors.

In addition, the study assessed the association of initial atrophy with subsequent deterioration over an average of two years. Longer-term observations will be required to calculate long-term forecasts.

What limitations have the scientists found?

The results obtained cannot yet be transferred to all patients with early Alzheimer's disease. The biomarker was developed and tested on a single research group, most of whose participants belonged to the white population of non-Hispanic origin. It is unknown how accurately the algorithm will work in other ethnic and social groups.

In most of the participants, the impairments primarily affected memory. Meanwhile, early Alzheimer's disease can begin with speech, behavioral, or visual-spatial problems. The authors admit that for such variants of the disease, the map of vulnerable areas of the brain and its prognostic accuracy may differ.

The sample was also formed according to strict criteria. The participants underwent an extended examination, did not have a number of other neurological diseases, and were monitored in specialized research centers. In everyday clinical practice, patients usually differ more in their state of health.

The study did not show whether the signature could predict other significant events, such as the need for permanent care, moving to a specialized institution, or life expectancy. This requires separate and longer-term observations. Finally, the scientists will have to conduct an external verification of the algorithm — apply it to an independent group of patients who were not used in the development of the model. Only then will it be possible to assess the method's readiness for widespread clinical use.