Study Underscores Importance of Considering Copathologies in Individuals with Alzheimer’s

A study published in JAMA Neurology has shown that individuals with clinical symptoms more severe than their biological Alzheimer disease (AD) stage (clinical > biological) often have additional brain pathologies, including α-synucleinopathy, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebrovascular disease. These findings underscore the importance of considering non-AD biomarkers when clinical impairment exceeds what would be expected from AD pathology alone.

The 2-cohort study analyzed data from participants in the Swedish BioFINDER-2 study (NCT03174938) (n=838) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n=380). Participants spanned the AD continuum—from cognitively normal older adults to those with dementia—and were included if they were amyloid-β positive and had undergone tau-positron emission tomography (PET) imaging. Clinical staging was based on a 1-to-6 severity scale, while biological staging included the spatial extent of tau-PET signal, following the revised 2024 AD criteria. Key metrics included neurodegeneration markers (cortical thickness, neurofilament light chain [NfL]), copathologies (α-synuclein, TDP-43 MRI signature), vascular lesions, comorbidities, and demographics.

Among the BioFINDER-2 cohort, researchers found:

• 37.7% of participants were concordant between clinical and biological staging  (reference group)
• 51.3% were at a clinical stage more advanced than their biological stage
• 11% of participants were at a biological stage greater than their clinical stage 

Among the ADNI cohort:

• 56.1% of participants had concordant clinical and biological stages (reference group)
• 36.1% were at a clinical stage greater than their biological stage
• 7.9% of participants were at a biological stage greater than their clinical stage

Researchers found that those who had greater clinical stages of AD compared with biological stages had higher rates of α-synuclein pathology, elevated NfL levels, greater TDP-43-like atrophy visualized on MRI, and increased cerebral small vessel disease compared with the reference groups. Conversely, those with more advanced biological than clinical stage showed less neurodegeneration. 

The researchers conclude that copathologies are a major contributor to cognitive impairment in individuals with less tau pathology than expected for their clinical presentation. The authors advocate for the routine assessment of non-AD biomarkers in patients whose clinical symptoms outpace their biological AD stage, as this may impact both diagnosis and management strategies.