Overlapping symptoms and mixed pathologies can make it difficult to distinguish Alzheimer’s disease from dementia with Lewy bodies and other neurodegenerative conditions. But skin biopsies may offer an objective way to detect phosphorylated alpha-synuclein (P-SYN) associated with synucleinopathies, including Lewy body disease.
Todd Levine, Co-Founder and Chief Medical Officer at CND Life Sciences, discusses the potential clinical utility of this approach.
What are the biggest challenges in diagnosing Alzheimer's disease and other dementias today?
One of the main challenges in diagnosing dementia is that its many forms often have overlapping symptoms, particularly early in the disease course. Clinical presentation alone may therefore be insufficient to accurately determine the cause of a patient’s symptoms. Many patients also have mixed pathologies, with more than one condition contributing to their symptoms. Objective biomarkers can help clinicians characterize the underlying biology and support diagnostic evaluation and clinical management.
How could skin biopsies help improve the way these diseases are diagnosed?
Over the past six years, skin biopsy testing that detects the abnormal form of the synuclein protein, a hallmark of a class of neurodegenerative diseases, has been adopted in clinical practice. This test provides clinicians with information about whether cutaneous phosphorylated alpha-synuclein is detected.
A 2024 JAMA study demonstrated that P-SYN levels were correlated with measures of disease severity. Separately, we have developed an investigational digital analysis system to quantify P-SYN detected in skin biopsy specimens. This quantitative approach is currently being studied for research use.
What did the Syn-D study teach us about using skin biopsy to track changes in disease over time?
The Syn-D study provided two important insights. First, cutaneous P-SYN was detected in participants clinically characterized as having mild cognitive impairment associated with suspected dementia with Lewy bodies, before they met the clinical criteria for dementia. Because these participants were evaluated at the mild cognitive impairment stage, the findings suggest that cutaneous P-SYN can be detected before patients meet clinical criteria for dementia during that MCI stage.
Second, P-SYN levels increased over time during longitudinal follow up. Together, these findings suggest that quantitative skin biopsy may have value as a biomarker for identifying underlying pathology and evaluating changes over time, as well as potentially evaluating treatment effects in future therapeutic studies.
Your study found that some patients had both P-SYN and phosphorylated tau 217 (p-tau 217). What does this tell us about Alzheimer's disease and related dementias?
One of the main takeaways is that neurodegenerative diseases are often biologically more complex than their clinical presentation suggests. In the Syn-D study, a portion of participants had both cutaneous P-SYN and abnormal p-tau 217 biomarker findings, suggesting the potential coexistence of pathologies associated with Lewy body and Alzheimer’s disease, consistent with autopsy studies showing that mixed pathology is common. This finding reinforces the need to look beyond a single biomarker. Combining complementary measures, such as p-tau 217 and quantitative skin biopsy for P-SYN, has the potential to provide a more comprehensive picture of the underlying disease and help characterize patients who may benefit from different treatments or participation in clinical trials.
Your second study showed that P-SYN levels increased over six months. Why is it important to have a biomarker that changes over time?
One of the main challenges in developing therapies for neurodegenerative diseases is finding objective ways to determine whether a treatment affects the underlying disease process. In a study assessing patients with dementia with Lewy bodies (DLB) over six months, results suggested an estimated annualized increase of approximately 52 percent in cutaneous P-SYN from baseline to six months. These findings suggest that quantitative skin biopsy may help measure longitudinal changes in P-SYN over time. If validated in larger studies, a biomarker that changes over relatively short intervals could help characterize clinical trial participants, monitor changes in disease progression related pathology, and evaluate therapies targeting alpha-synuclein.
How could quantitative skin biopsy work alongside today's Alzheimer's tests, such as blood tests, cerebrospinal fluid testing, and brain imaging?
We view these technologies as complementary rather than competing. Blood biomarkers such as p-tau 217 provide information about Alzheimer’s disease pathology, while skin biopsy determines cutaneous phosphorylated alpha-synuclein associated with a synucleinopathy is detected. Because mixed pathologies are common, combining biomarkers may offer a more complete picture of the underlying biology. This approach could provide additional information for patient characterization in clinical care and research, particularly as more targeted therapies become available.
What would need to happen before quantitative skin biopsy could contribute to the evaluation of patients with suspected Alzheimer's disease and other dementias?
Skin biopsy testing can already identify P-SYN, and research is ongoing into semi-quantitative approaches to characterizing its deposition. This is particularly relevant because Alzheimer's disease and Lewy body pathology can coexist, potentially contributing to overlapping clinical symptoms and diagnostic complexity. Identifying evidence of synuclein pathology may provide additional information in the evaluation of patients with suspected Alzheimer's disease or other dementias, alongside established clinical assessments and biomarkers. Further research will help clarify how quantitative measurements may contribute to understanding mixed pathologies and inform future clinical applications.
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