Background: Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the
clinical criteria for Alzheimer disease (AD).
Objective: The aim of this study was to test the hypothesis of misdiagnoses for these patients.
Method: Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild
cognitive impairment due to AD (AD-MCI), with normal CSF Aβ1-42, T-tau and P-tau biomarkers and clinical
follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline
(visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis.
Results: In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia
core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a
clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal
lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was
AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was
corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment,
alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had
cognitive disorders of undetermined etiology.
Conclusion: AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow-
up is particularly recommended to consider an alternative diagnosis.