Every year on September 21st, the World Alzheimer’s Day raises awareness about a neurodegenerative disease that primarily affects memory and other cognitive functions.

In this regard, we interviewed Prof. Massimo Filippi, director of the Neurology Unit, the Neurophysiology service, and the Neurorehabilitation Unit, as well as full professor in Neurology at the Vita-Salute San Raffaele University (UniSR), and Prof. Federica Agosta, Group Leader of the Neuroimaging of Neurodegenerative Diseases lab and associate professor in Neurology at UniSR, to delve deeper into the topic of biomarkers in the early diagnosis of this disease.

Beyond clinical symptoms: the biology of Alzheimer’s disease

Alzheimer’s disease is characterized by specific biological markers, the most well-known of which are the abnormal accumulation of beta-amyloid protein aggregates and the formation of tau protein neurofibrillary tangles in the brain. These deposits progressively impair communication between neurons, eventually leading to their death.

These biological alterations give rise to the typical clinical symptoms, such as memory loss and other cognitive deficits. “It is increasingly clear that clinical symptoms cannot be considered separately from the biological processes that characterize the disease, which necessarily precede its onset,” explains Professor Filippi.

“When a person shows the first cognitive impairments attributable to Alzheimer’s, we are facing an initial clinical phase, but not necessarily an early biological phase of the disease,” comments Professor Filippi. Biological changes in the brain can indeed begin decades before symptoms appear.

A Blood Test to diagnose Alzheimer’s

Recognizing biological changes at an early stage is essential in order to intervene promptly and slow down the progression of the disease and the onset of clinical symptoms.
A biomarker is a measurable indicator of a biological process, detectable through laboratory analyses or imaging techniques, which provides information about the presence or progression of a disease. In the case of Alzheimer’s, the most studied biomarkers used to inform diagnosis concern the alterations of beta-amyloid and tau proteins responsible for the deposits and tangles observed in the brain.

Since the early 2000s, the first biomarkers have been introduced to identify Alzheimer’s disease in people with suspicious clinical symptoms. Today, diagnosis is based on a combination of factors: the patient’s clinical and family history, analysis of reported symptoms, neurological examination including neuropsychological tests, and the detection of biomarkers.

The latter are investigated through nuclear medicine exams such as PET scans, which show the presence of amyloid plaques in the brain, and lumbar puncture (spinal tap), which allows quantification of altered forms of beta-amyloid and tau in the cerebrospinal fluid.
However, PET scans and lumbar punctures can be costly and relatively invasive for the patient. For this reason, research has focused on developing alternative diagnostic methods capable of detecting Alzheimer’s biomarkers in a less invasive, more affordable way and applicable on a large scale, while maintaining the same reliability and accuracy.
One of the most promising solutions is blood sampling, which allows measurement of the pathological forms of beta-amyloid and tau associated with the disease.

As the FDA states, the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test measures the levels of two proteins – pTau217 and β-amyloid 1-42 – in human plasma and calculates their ratio. This ratio is closely associated with the presence or absence of amyloid plaques in the brain, offering a less invasive alternative to PET scans.

As part of its assessment of the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test, the FDA evaluated evidence from a study involving cognitive impairment in 499 adults who were evaluated at multiple sites. The samples were tested using the Lumipulse test, and these results were compared to amyloid PET and/or cerebrospinal fluid results.

In the study, 91.7% of the individuals who tested positive with the Lumipulse assay tested positive for amyloid plaques based on the PET or CSF result. And 97.3% of participants with a negative test result with the Lumipulse test had no detectable amyloid plaques based on the PET or CSF result. Fewer than 20% of the 499 participants had indeterminate results based on the Lumipulse testing.

The primary potential risks with the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test are the false positive and false negative results. A false positive result can lead to an improper diagnosis of Alzheimer's disease, with subsequent emotional distress and side effects. A false negative may conversely result in delayed diagnosis and treatment.

“The hope is that, in the future, general practitioners could use blood tests to screen at-risk individuals, such as those with a family history of Alzheimer’s, even before symptoms appear,” states Professor Agosta.

While not yet suitable for use in the general asymptomatic population, these tests may eventually reduce the need for more invasive and costly procedures and promote more personalized treatment approaches.

A new era of treatment

Until recently, Alzheimer’s had no truly effective therapies that could modify the underlying biology.

“Nowadays, there are disease-modifying drugs that can be administered to selected patients who are in the early phases of Alzheimer’s. I’m talking about monoclonal antibodies like lecanemab and donanemab, which recognize and remove beta-amyloid plaques in the brain, helping to slow down cognitive impairment. In this context, a biological diagnosis based on biomarker detection is increasingly becoming necessary, but not sufficient, to access treatment with such antibodies,” says Professor Agosta.

“As a result, biological diagnosis will be indispensable for all patients who meet the criteria for receiving this type of therapy.”

However, while blood-based biomarkers are accurate in detecting the biological presence of the disease, they cannot yet predict with certainty if or when symptoms will appear.
Having biological changes means the disease is present, but it does not necessarily mean that clinical symptoms will develop.

Prevention and modifiable risk factors

Although it is not yet possible to prevent Alzheimer’s disease in the strict sense, some preventive strategies focus on reducing the overall risk of cognitive decline by targeting certain modifiable risk factors. According to the latest evaluation by the Lancet Commission (2024), about 45% of dementia cases could be prevented or delayed by addressing fourteen modifiable factors throughout life. These include insufficient education (before age 20), hypertension, obesity (in adulthood), untreated hearing and vision loss, depressive symptoms, physical inactivity, diabetes, high LDL cholesterol, smoking, excessive alcohol consumption, air pollution, head trauma, and social isolation.
Addressing these factors can significantly contribute to reducing the incidence of dementia in the general population.
In particular, the Commission highlights the central role of an active lifestyle, both physically and cognitively. Maintaining a mentally stimulating life—through activities such as reading, lifelong learning, logic games, or social interaction—is one of the most recommended measures to preserve cognitive functions.

A disease that must be recognized

Alzheimer’s is not an inevitable consequence of aging. While aging increases the risk, cognitive decline is not a normal part of growing old.

It is a disease, and as such, it must be recognized, diagnosed, and treated as early as possible.

“Confusing Alzheimer’s with normal aging only perpetuates stigma and delays intervention,” conclude the professors.
“We need a cultural shift: Alzheimer’s must be seen like any other disease — where early diagnosis is essential.”