Low CSF APP refines diagnosis for p ‐tau negative Alzheimer‐like dementia

Topic: Amyloid, tau and blood-test diagnosis

Concentrations of CSF APP were significantly lower in T- compared to T+ individuals across all clinical diagnostic groups across cohorts, regardless of A± status (Figure 1). Concentrations of APP showed a positive correlation with those of CSF p-tau181 but were not associated with the Aβ42/Aβ40 ratio. APP reductions were most pronounced in T- cases clinically diagnosed with AD (AUC [95% CI]: 0.81 [0.70-0.92]). Lower CSF APP levels were associated with elevated NfL, worse Mini-Mental State Examination scores, and higher Clinical Dementia Rating-Sum of Boxes scores. In T+ individuals, APP was initially elevated in cognitively unimpaired participants but declined with disease progression, albeit from a higher baseline (Figure 2). Stratifying participants by low/high APP and p-tau revealed the highest frequency of clinical AD diagnoses in individuals with low APP and high p-tau. This group exhibited the most severe cognitive and functional impairments compared to those with high APP and/or low p-tau profiles (Figure 3). Individuals with low APP levels (APP positive) or elevated p-tau181 (p-tau181 positive) had the highest prevalence of AD-like dementia, with the risk being greatest in those positive for both markers. These results reveal a unique biological profile for T- status in clinically diagnosed AD, who are a complex and under-explored patient group, and highlight opportunities for enhancing diagnostic refinement. Given that APP influences neuronal plasticity, memory, synaptogenesis, and maintenance of neuronal iron homeostasis, our findings suggest that disruptions in APP production and processing may contribute to disease progression.

@article{chatterjee2025-41444444,
  author  = {Chatterjee, Pratishtha and Kalinowski, Paweł and Roberts, Anne Marie and Roberts, Blaine Russell and Tijms, Betty Marije and Teunissen, Charlotte Elisabeth and Bush, Ashley Ian and Ayton, Scott},
  title   = {{Low CSF APP refines diagnosis for p ‐tau negative Alzheimer‐like dementia}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70856_099406},
  pmid    = {41444444},
  url     = {https://doi.org/10.1002/alz70856_099406}
}

Key findings

• Concentrations of CSF APP were significantly lower in T- compared to T+ individuals across all clinical diagnostic groups across cohorts, regardless of A± status (Figure 1).
• Concentrations of APP showed a positive correlation with those of CSF p-tau181 but were not associated with the Aβ42/Aβ40 ratio.
• APP reductions were most pronounced in T- cases clinically diagnosed with AD (AUC [95% CI]: 0.81 [0.70-0.92]).
• Lower CSF APP levels were associated with elevated NfL, worse Mini-Mental State Examination scores, and higher Clinical Dementia Rating-Sum of Boxes scores.
• In T+ individuals, APP was initially elevated in cognitively unimpaired participants but declined with disease progression, albeit from a higher baseline (Figure 2).

Why it matters

This study found that low cerebrospinal fluid APP concentrations were most pronounced in p-tau negative cases clinically diagnosed with Alzheimer's disease, and that low APP combined with high p-tau was linked to the most severe cognitive and functional impairments. It concerns refining diagnosis rather than treating, curing or preventing Alzheimer's disease.

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Study details

• Participants384
• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70856_099406
• PubMed: 41444444
• Original source →
• Free full text: Alzheimer s & Dementia →

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