Frontotemporal dementia is the leading cause of "true" A-/T+ profiles defined with Aβ_42/40 ratio

Patients with positive tauopathy but negative Aβ₄₂ (A-T+) in the cerebrospinal fluid (CSF) represent a diagnostic challenge. The Aβ_42/40 ratio supersedes Aβ₄₂ and reintegrates "false" A-T+ patients into the Alzheimer's disease spectrum. However, the biomarker and clinical characteristics of "true" and "false" A-T+ patients remain elusive.

Among the 509 T+N+ patients extracted from the databases of three memory clinics, we analyzed T+N+ patients with normal Aβ₄₂ and compared "false" A-T+ with abnormal Aβ_42/40 ratio and "true" A-T+ patients with normal Aβ_42/40 ratio, before CSF analysis and at follow-up.

24.9% of T+N+ patients had normal Aβ₄₂ levels. Among them, 42.7% were "true" A-T+. "True" A-T+ had lower CSF tau^P181 than "false" A-T+ patients. 48.0% of "true" A-T+ patients were diagnosed with frontotemporal lobar degeneration before CSF analysis and 64.0% at follow-up, as compared with 6% in the "false" A-T+ group (P < .0001).

Frontotemporal lobar degeneration is probably the main cause of "true" A-T+ profiles.