What Can Skin Reveal About Dementia?

Detecting phosphorylated alpha-synuclein could add biological context when symptoms and pathologies overlap

By
Jessica Allerton
October 16, 2026
5 min

The Pathologist

Overview

Skin biopsy can detect cutaneous phosphorylated alpha-synuclein (P-SYN), a biomarker associated with synucleinopathies, and may provide information complementary to Alzheimer’s disease biomarkers. Interview-reported Syn-D findings include P-SYN detection during mild cognitive impairment associated with suspected dementia with Lewy bodies and increasing P-SYN levels during follow-up; the source describes quantitative analysis as investigational and under study.

Background

Dementia syndromes can have overlapping clinical features, particularly early in their course, and more than one pathology may contribute to a patient’s symptoms. The DLB Consortium report notes that mixed Alzheimer’s disease pathology is common in DLB and can complicate differential diagnosis. Clinical assessment and biomarkers therefore provide different kinds of information about underlying disease biology. The article describes skin biopsy as a way to assess cutaneous P-SYN associated with synucleinopathies, alongside measures such as blood p-tau 217.

Data Highlights

Evidence	Reported findings	Context
JAMA multicenter skin-biopsy study (2024)	Among 343 participants in the primary analysis, cutaneous P-SYN was detected in 92.7% of Parkinson disease, 96.0% of DLB, 98.2% of multiple system atrophy, and 100% of pure autonomic failure cases, versus 3.3% of controls.	Thirty-site, blinded, cross-sectional study; authors called for external validation in unselected clinical populations.
Syn-D findings described in the interview	P-SYN was detected in participants clinically characterized as having mild cognitive impairment associated with suspected DLB, before they met clinical criteria for dementia. P-SYN levels increased during longitudinal follow-up.	The supplied article does not report sample size or numerical estimates for these findings.
Six-month DLB study described in the interview	Estimated annualized increase in cutaneous P-SYN was approximately 52% from baseline to six months.	The interview states that larger studies are needed to validate the approach.

Key Findings

The article identifies overlapping symptoms and mixed pathologies as challenges in distinguishing Alzheimer’s disease, DLB, and other neurodegenerative conditions.
Skin biopsy testing detects whether cutaneous P-SYN is present; the interview describes a separate digital system for quantifying P-SYN as investigational and being studied for research use.
In the Syn-D study as described by the interviewee, cutaneous P-SYN was detected in participants with mild cognitive impairment associated with suspected DLB before they met clinical criteria for dementia.
The interview reports that P-SYN levels increased over longitudinal follow-up, including an estimated annualized increase of approximately 52% in a six-month DLB study.
Some Syn-D participants had both cutaneous P-SYN and abnormal p-tau 217 findings, which the interview presents as evidence consistent with possible coexisting Lewy body and Alzheimer’s disease pathologies.
The 2024 JAMA study reported cutaneous P-SYN detection in 92.7% of Parkinson disease, 96.0% of DLB, 98.2% of multiple system atrophy, and 100% of pure autonomic failure cases, compared with 3.3% of controls; its authors noted the need for external validation in unselected clinical populations.

Clinical Implications

The interview presents skin biopsy for P-SYN and Alzheimer’s disease biomarkers such as p-tau 217 as complementary measures that may help characterize coexisting pathologies. Quantitative skin-biopsy analysis is described as investigational, and the interview states that larger studies are needed to validate its potential use in tracking disease-related changes or evaluating therapies.

Conclusion

The supplied material describes cutaneous P-SYN testing as a potential source of information about synucleinopathy in patients with cognitive impairment, including those with possible mixed pathology. Its quantitative and longitudinal applications remain under study.