While Alzheimer’s disease accounts for about 60-70% of dementia diagnoses, the timing of these diagnoses occur late in disease progression. Identifying early signs of Alzheimer’s may allow individuals time to address potential risk factors in their lives.
“Alzheimer’s disease pathology begins years before symptoms emerge,” said Kristine Yaffe, MD, vice chair in the UCSF Department of Psychiatry and Behavioral Sciences. Yaffe and her team have spent years researching modifiable risk factors that may play a role in dementia development, including physical and cognitive activity, depression, smoking, and cardiovascular health.
A current trajectory of research into Alzheimer’s disease is focusing on ways to detect the disease early, before major symptoms manifest. Two new studies published in The Lancet present different methods for detecting Alzheimer’s disease that converge in their early detection ability.
Alzheimer’s disease is characterized by increased amounts of tau and amyloid-β plaques. Growing research indicates the importance of tau pathology and amyloid-β accumulation at initiating changes to the brain associated with Alzheimer’s disease.
“Tau is the biology most closely tied to symptoms and future decline,” said Tharick Pascoal, MD, PhD, associate professor of psychiatry and neurology at the University of Pittsburgh and a behavioral neurologist at University of Pittsburgh School of Medicine. “If we can detect tau earlier and stage it more precisely, we can make better decisions about who is truly on an Alzheimer’s trajectory, which matters for clinical trials now and could shape clinical decision-making as new therapies emerge.”
Researchers at the University of Pittsburgh led by Guilherme Povala, PhD, and Bruna Bellaver, PhD, have focused their work on brain scan imaging to detect tau both more effectively, and earlier.
The team’s recently published work compared the ability of two tracers used in non-invasive PET scans to visualize Alzheimer’s-associated tangles of tau protein. To do this, participants underwent paired tau PET scans, the first using a standard tau tracer, Flortaucipir, or a new tracer, MK6240. Within 45 days of the PET scan, participants also received an amyloid-β PET scan and detailed cognitive assessments. Of the 775 initial participants, 682 completed all of the study components.
“Because participants received both tracer scans within a short window, we’re looking at the same moment in the disease course, so differences we see reflect the tracers, not changes over time,” explained co-lead author, Guilherme Povala, PhD, postdoctoral associate at the University of Pittsburgh, about the experimental design.
Analysis showed that imaging with the MK6240 tracer detected more tau than tracing with Flortaucipir. In participants with cognitive impairment and positive amyloid-β results, MK6240 identified move than twice as many tau-positive cases, 15% compared with six percent, which was an additional 23 patients per 100. Tracing with MK6240 also identified increased tau, 28% vs. 16% with Flortaucipir, in patients with mild cognitive impairment and dementia, resulting in 15 or 21 additional cases per 100 participants scanned.
“People typically seek evaluation because they have memory concerns or other symptoms,” pointed out co-lead author, Bruna Bellaver, PhD, research assistant professor of psychiatry at the University of Pittsburgh. “Tau PET is one tool that can help clinicians stage disease biology and make more informed decisions.”
Across the country in California, researchers from University of California, San Francisco, have drawn on their experience with blood biomarkers in an effort to develop a method for detecting Alzheimer’s before major symptoms develop.
The west coast study included 1,350 participants (out of an initial 2248) who were retained in the U.S. Coronary Artery Risk Development in Young Adults (CARDIA) study. Participant blood plasma was tested from samples that were collected at project year 35 (2020-2022) and five years prior. Plasma biomarkers for amyloid-β (Aβ42 and Aβ40) and tau (p-tau217) were measured and used to calculate p-tau217-to-Aβ42 and Aβ42-to-Aβ40 ratios and then those were compared to the cognitive assessment scores that were measured at the same time period. Any participants missing materials were excluded from the initial cohort. During analysis, participants were also classified by Alzheimer’s disease neuropathy status of negative, intermediate and positive based on amyloid PET-validated cutpoints for each marker.
Results from the initial analysis showed that participants with high biomarkers also had both lower processing speeds and lower executive function in the first time point. After five years, the group that initially had high levels of biomarkers now had a 2.5 to 4 times increased risk of rapid decline in verbal memory, and three to four times the risk for rapid decline in processing speed. Together, these data suggest a connection between the observed cognitive decline and increase in biomarkers.
While brain scans, and spinal fluid tests are often used and widely available, blood tests are less invasive and relatively inexpensive, potentially enabling more patients access to diagnostics along with early detection prior to symptom development. While there is potential for measuring blood biomarkers for clinical use, senior author, Yaffe, prescribes cautious optimism. “There’s a possibility of false positives and [these markers] can only be used for Alzheimer’s, not other dementias, meaning about 60% to 70% of all dementia cases,” she said. “But for some people who discover they have the biomarkers, testing could open a window to embark on interventions that may postpone Alzheimer’s onset.” More work is still needed to clarify the utility of both early detection methods in the clinic.
Overall, both studies show significant progress in developing strategies to identify dementia, and specifically Alzheimer’s disease, earlier. Earlier diagnosis may lead to earlier intervention and potentially more positive outcomes for patients. As Yaffee concluded, “Detecting the disease early means patients can target modifiable risk factors and maybe seek other care.”
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