- People whose cognitive symptoms were more severe than their biological Alzheimer's stage often had additional pathologies.
- Alpha-synuclein, TDP-43 signatures, and cerebral small vessel disease were common in people with discordant stages.
- The presence of co-pathologies might affect responses to drugs that target Alzheimer's pathology.
Older adults whose cognitive symptoms were more severe than their biological Alzheimer's disease stage often had additional pathologies, a cross-sectional study showed.
People with more advanced clinical impairment compared with their biomarker-based Alzheimer's stage often were positive for alpha-synuclein pathology or had higher neurofilament light (NfL) levels, a TAR DNA-binding protein 43 (TDP-43) imaging signature, or more cerebral small vessel disease than a reference group (all false discovery rate P<0.05), reported Alexa Pichet Binette, PhD, of Lund University in Sweden, and co-authors.
"Co-pathologies play an important role in symptom severity in individuals who harbor less tau-tangle pathology than expected for their clinical impairment," Pichet Binette and colleagues wrote in JAMA Neurology.
The study was driven by changes introduced in the 2024 update to the Alzheimer's criteria, which incorporated tau PET into the revised biological stages of the disease as a core biomarker.
Biological staging of Alzheimer's disease is distinct from clinical staging. Biological staging ranges from initial (amyloid-positive) to advanced (elevated amyloid and widespread tau) stages. Clinical staging is a continuum that includes no cognitive impairment in early stages, mild impairment in intermediate stages, and severe impairment in late stages.
This analysis is among the first to assess markers associated with discordance between biological and clinical staging based on the revised Alzheimer's criteria, Pichet Binette observed.
It's important to be able to understand "what are the underlying etiologies contributing to clinical impairment in individuals with lower levels of Alzheimer's disease pathology than expected, which can affect diagnosis and prognosis," Pichet Binette told MedPage Today.
"Our results provide novel evidence on the importance and high prevalence of co-pathologies and non-Alzheimer's markers in symptom severity in individuals with low levels of tau pathology compared to their clinical impairment," she noted. The overall findings are in line with the hypotheses proposed in the revised criteria, she added.
Pichet Binette and colleagues studied older adults who participated in the Swedish BioFINDER-2 and the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Among both groups, 51% were women and mean age was 73 to 74 years.
BioFINDER-2 contributed 838 participants that included cognitively normal older adults and memory clinic patients with subjective cognitive impairment, mild cognitive impairment, or dementia. ADNI contributed 380 people who were amyloid-positive, including those with normal cognition, mild cognitive impairment, or dementia. Unlike BioFINDER-2, dementia among ADNI participants was due only to Alzheimer's disease.
Data evaluated included cross-sectional measures of neurodegeneration -- cortical thickness, TDP-43 imaging signature, and NfL -- plus alpha-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics.
In the BioFINDER-2 cohort, 37.7% of the sample had congruent biological and clinical stages; this was considered the reference group. About half (51.3%) of BioFINDER-2 participants had more advanced cognitive impairment compared with their biological stage; 11.0% had the opposite. The last group had less neurodegeneration than the reference group (thicker cortex; false discovery rate P<0.001).
In the ADNI cohort, 56.1% had congruent biological and clinical stages, 36.1% had a greater clinical stage than biological, and 7.9% had a greater biological stage than clinical.
The findings are in line with neuropathology studies "showing that the presence of multiple pathologies is the norm rather than the exception with advanced age and neurodegenerative disease," Pichet Binette and colleagues noted. "These results are also important in relation to clinical trials and anti-amyloid therapies, where the presence of co-pathologies might influence (and lower) the response to drugs targeting Alzheimer's disease pathology."
A main limitation is that both cohorts were not ethnically diverse, which limited the generalizability of the findings, the researchers acknowledged. This analysis was focused on PET and future studies could assess blood-based biomarkers, they added.
The revised biological staging of Alzheimer's is still new and there are no regions or cutoffs agreed upon in the literature on how to implement it, Pichet Binette pointed out. "Our proposition is based on regions of interest and approaches previously published by our group and others, and it will be interesting to compare and contrast different implementations of the stages in the future."
Disclosures
Work at the authors' research center was supported by the European Research Council, Alzheimer's Association, GHR Foundation, Swedish Research Council, ERA PerMed, Knut and Alice Wallenberg Foundation, Strategic Research Area MultiPark at Lund University, Swedish Alzheimer Foundation, Swedish Brain Foundation, WASP (Wallenberg AI, Autonomous Systems and Software Program) and DDLS (SciLifeLab and Wallenberg National Program for Data-Driven Life Science), Parkinson Foundation of Sweden, Cure Alzheimer's Fund, Rönström Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation, Regionalt Forskningsstöd, and the Swedish federal government under the ALF agreement.
Pichet Binette reported no conflicts of interest. Co-authors reported relationships with pharmaceutical companies, other businesses, and non-profit groups.
Primary Source
JAMA Neurology
Source Reference: Pichet Binette A, et al "Evaluation of the revised criteria for biological and clinical staging of Alzheimer disease" JAMA Neurol 2025; DOI: 10.1001/jamaneurol.2025.1100.
https://www.medpagetoday.com/neurology/alzheimersdisease/115727
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