Alzheimer’s disease biomarkers predict rapid cognitive decline in very old adults

Cognitive decline in very old adults has been considered for decades to be an almost inevitable consequence of aging. In clinical practice, this has contributed to many memory problems in patients over age 80 being interpreted as a natural part of aging, without further investigation into their cause. However, this view is increasingly being challenged as knowledge of neurodegenerative diseases advances and more accurate tools for their detection become available.

A study led by researchers at the Sant Pau Research Institute (IR Sant Pau) and recently published in Neurology provides new evidence on the value of Alzheimer's disease biomarkers in this age group. The study, which focused on people aged 80 and older with mild cognitive impairment, shows that the presence of Alzheimer's disease biology-determined using biomarkers in cerebrospinal fluid and blood-is not only common but is also consistently associated with a greater risk of more rapid cognitive decline and progression to dementia.

These findings challenge the still widespread belief that biomarkers have limited value at very advanced ages because of the coexistence of multiple conditions. On the contrary, the study shows that, even within this more clinically complex context, identifying the underlying pathology continues to provide relevant information about patients' progression.

"Not every memory problem after age 80 is normal, and assuming that it is can lead to the underdiagnosis of diseases such as Alzheimer's," says Dr. Ignacio Illán-Gala, a researcher with the Neurobiology of Dementias Group at IR Sant Pau, a neurologist at Sant Pau Hospital, and one of the study's authors. "We need to overcome the influence of ageism in the care of these patients and move toward a more accurate diagnosis, including at advanced ages," he adds.

Without biomarkers, clinical diagnosis is particularly inaccurate at advanced ages

One of the main challenges in addressing cognitive decline in very old adults is the limited accuracy of diagnoses based exclusively on clinical assessment. In routine practice, many patients over age 80 are evaluated without the use of biomarkers, introducing a high degree of uncertainty regarding the true cause of their symptoms. This approach, which remains widespread among clinicians, is largely justified by the high frequency of coexisting conditions at advanced ages. In this group, different neurodegenerative diseases, vascular abnormalities, and other aging-related processes commonly coexist and may simultaneously affect cognition, producing clinical presentations that are more heterogeneous and less specific than those observed at younger ages.

In addition, as age increases, differences in cognitive performance between people with and without Alzheimer's disease tend to become smaller during the early stages. Although patients with Alzheimer's disease biology perform worse, particularly on memory tests, these differences are relatively modest and overlap considerably with the results of patients without the disease. This limits the discriminatory capacity of clinical assessment, thereby contributing to diagnostic and therapeutic nihilism.

Dr. Chiara Ceriello, geriatrician at Sant Pau Hospital and first author of the articleOlder patients often have many coexisting conditions that can impact memory, and relying solely on clinical assessment may lead to inaccurate diagnoses. In fact, approximately half of the cases do not correspond to pure Alzheimer's disease, which means that, without biomarkers, it is difficult to determine what is causing the cognitive decline and to accurately anticipate its progression."

Confirming Alzheimer's disease biology reveals differences in patient outcomes

The study analyzed 167 people over age 80 with mild cognitive impairment from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort, a leading clinical cohort in neurodegenerative diseases in which patients are systematically evaluated using biomarkers. Nearly 70% had biology consistent with Alzheimer's disease, determined through the analysis of characteristic proteins in cerebrospinal fluid-such as the ratio of p-Tau181 to β-amyloid-and its blood-based correlate, p-Tau217. Although cognitive differences between patients with and without this biology were relatively subtle at baseline, their progression during follow-up was clearly different.

Specifically, patients with Alzheimer's disease biology experienced more rapid cognitive decline than those without evidence of the disease, as measured using the Mini-Mental State Examination (MMSE), a widely used scale for assessing global cognitive function. Patients with Alzheimer's disease biology showed an average decline of 0.47 points per year, compared with 0.18 points per year among those without evidence of the disease. Although this difference is moderate on an annual basis, it becomes clinically significant when considered cumulatively, as it translates into more rapid progression toward greater impairment and loss of independence. Similarly, the presence of these biomarkers was also associated with a higher risk of progressing to dementia during follow-up.

"As age increases, differences in memory performance between people with and without Alzheimer's disease tend to become smaller, making the disease more difficult to identify based solely on clinical assessment," explains Dr. Illán-Gala. "However, what does differ clearly is the course of the disease: people with this biology have a worse prognosis and more rapid progression of cognitive decline over the medium term."

In this regard, the information provided by biomarkers is particularly relevant to clinical practice in older adults. "Knowing whether these patients have Alzheimer's disease biology not only makes it possible to refine the diagnosis but also to anticipate their progression and better tailor clinical management and care planning," says Dr. Chiara Ceriello. Thus, even at advanced ages, the presence of Alzheimer's disease biology is not an incidental finding but rather a factor that significantly influences the patient's clinical trajectory and allows clinicians to anticipate its progression more accurately.

A blood-based biomarker facilitates diagnosis and clinical implementation

Beyond its prognostic value, one of the most relevant aspects of the study is the possibility of translating these findings into clinical practice through the use of blood-based biomarkers such as p-Tau217. Unlike traditional techniques, such as lumbar puncture or amyloid positron emission tomography (PET), measuring this biomarker through a blood test offers a much simpler and more broadly applicable approach.

This change is particularly relevant in geriatric care, where the systematic use of more complex procedures has historically been limited. The availability of a blood-based marker creates an opportunity to incorporate the biological assessment of Alzheimer's disease in a larger number of patients and across broader healthcare settings, facilitating a more consistent approach to diagnosis.

"The availability of a blood-based biomarker makes it much easier to incorporate this assessment into clinical practice, particularly for older patients," says Dr. Chiara Ceriello. "It allows us to obtain relevant biological information in a simpler and more practical way, and this has a direct impact on how we assess and monitor these patients." The researchers emphasize, however, that these biomarkers must always be interpreted within the patient's clinical context, considering factors such as frailty, comorbidities, and baseline functional status to determine their true clinical usefulness.

A more accurate diagnosis helps anticipate progression and improve clinical management

The study's findings challenge the practice of excluding people over age 80 from biomarker-based diagnostic strategies and point to the need for a more individualized approach. The authors emphasize that chronological age alone does not reflect the heterogeneity of this population, which includes patients with good functional status and long life expectancy for whom a more accurate diagnosis may have a significant impact.

"Precision medicine should not have an age limit," says Dr. Chiara Ceriello. "In well-preserved patients with a good quality of life, knowing whether biomarkers are present can change clinical management, prognosis, and future planning."

Beyond diagnosis, identifying Alzheimer's disease biology in older adults has direct implications for clinical practice. Determining the cause of cognitive decline makes it possible to anticipate progression, adjust follow-up, and facilitate both medical and family planning, particularly at a stage of life when these issues become increasingly important.

In this context, the arrival of new drugs capable of modifying the course of the disease reinforces the need for a more accurate diagnosis during its early stages, including in older patients. These treatments have demonstrated the ability to slow the progression of cognitive decline, making it even more significant to identify patients who could benefit from them.

"We are seeing increasing numbers of older people seeking care because they have noticed changes in their memory and want to know what is happening to them and what they can expect," says Dr. Illán-Gala. "Answering these questions is part of providing appropriate care."

Overall, the study demonstrates that Alzheimer's disease biomarkers retain significant clinical value in people aged 80 and older and that their use can help improve diagnosis and decision-making in a growing population that has so far been underrepresented in research.

Source:

Institut de Recerca Sant Pau (Sant Pau Research Institute)

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