The Sant Pau Research Institute (IR Sant Pau) has led a multicenter project that redefines what is considered normal cognitive performance. The work, carried out in collaboration with Hospital Clínic de Barcelona, Hospital Universitario Marqués de Valdecilla in Santander, and the CITA-Alzheimer Foundation in San Sebastián, has resulted in two complementary scientific articles published in the journal Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM), which establish new cognitive reference standards based exclusively on individuals without amyloid pathology and demonstrate their ability to improve early diagnosis.
This initiative emerges at a pivotal moment for clinical practice. The arrival of disease-modifying therapies requires increasingly precise identification of patients who are in very early stages, when intervention is most effective and safest. However, traditional neuropsychology faces a fundamental challenge: determining what “normal performance” truly means in older adults, given that part of age-related decline can be confused with changes inherent to the preclinical phase of Alzheimer’s disease. The project addresses this need by redefining cognitive reference standards using advanced tools and data from rigorously selected populations, allowing for a more accurate delineation of the threshold between healthy aging and true cognitive decline.
In the first part of the project, neuropsychological reference standards based exclusively on individuals without Alzheimer’s disease biomarkers were developed for the first time, using advanced statistical models that take age, educational level, and sex into account. This combination, which until now had only been applied partially in certain specific tests, is used for the first time simultaneously and across such a broad battery of neuropsychological assessments, representing a significant methodological advance at the international level. This approach allows for a more precise definition of what can be considered truly normal cognitive performance in aging. By excluding individuals who already show amyloid pathology in the preclinical phase—still without symptoms—it prevents the mild decline associated with the disease from being mistaken for healthy aging.
The development of these new reference standards was based on a cohort of nearly 800 cognitively healthy adults and on advanced statistical models capable of describing in detail how age, education, and biological sex influence each cognitive domain. This approach made it possible to identify subtle but relevant differences between men and women, as well as nonlinear effects of age and education that previous methods could not detect, substantially increasing the precision of cognitive assessments.
In parallel, the team developed a clinical calculator that allows for rapid and accurate calculation of adjusted scores, facilitating individualized interpretation of each case in memory clinics. Although it is not intended for the public, the tool is designed so that all professionals who assess patients with suspected cognitive impairment can use it as diagnostic support, promoting consistent application of the new reference values in clinical practice.
As explained by Dr. Sara Rubio-Guerra, researcher in the Neurobiology of Dementias group, neurologist at the Sant Pau Memory Unit, and first author of the study, “a key part of diagnosis is clearly defining what we mean by cognitive normality. If this reference point is not accurate, we may overlook very early alterations or, conversely, raise concerns in completely healthy individuals. These new norms allow us to interpret performance more precisely and better distinguish between healthy aging and the earliest changes associated with the disease.”
In the second part of the study, an analysis was conducted in a sample of more than 2,400 individuals without dementia, demonstrating that application of these new reference standards substantially improves the ability to identify very mild cognitive alterations. The new standards make it possible to detect earlier one in five cases of incipient cognitive impairment that previously went unnoticed.
The data confirm that this group does not represent cognitive variability inherent to aging. These individuals show high rates of Alzheimer’s disease biomarkers and a faster cognitive decline in longitudinal analyses, indicating that they are indeed in an early stage of the disease. Earlier detection allows for more precise guidance of the diagnostic workup and helps determine when further evaluation with biomarkers is warranted.
By contrast, the number of individuals whom the new norms would classify as impaired in the absence of biological evidence of disease is small, around 3%, and in most of these cases biomarkers are negative. This minimizes the risk of overdiagnosis and avoids subjecting healthy individuals to unnecessary testing.
According to Dr. Ignacio Illán-Gala, researcher in the Neurobiology of Dementias group at IR Sant Pau, neurologist at the Sant Pau Memory Unit, and senior author of the study, “early diagnosis is key in the era of new disease-modifying therapies. Detecting these incipient cases earlier means being able to offer therapies at the time when they are most effective and safest.” The neurologist emphasizes that neuropsychology acts as “a gateway to the diagnostic workup,” especially when memory complaints are very subtle and the decision to request biomarkers requires knowing with precision whether true cognitive decline is present. “With more accurate reference values, we can better determine who needs further evaluation and who can be reassured, avoiding both overdiagnosis and missed therapeutic opportunities,” he adds.
Overall, the project consolidates IR Sant Pau’s leadership in the development of biomarkers and precision tools and lays the groundwork for future improvements as markers for other neurodegenerative diseases in preclinical stages are identified.
