Background and Objectives Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort. Methods All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included. Results Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value. Discussion Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics. Classification of Evidence This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

Objectives: Early‐ and late‐onset Alzheimer's disease (EOAD and LOAD) share the same neuropathological traits but show distinct cognitive features. We aimed to explore baseline and longitudinal outcomes of global and domain‐specific cognitive function in a well characterized cohort of patients with a biomarker‐based diagnosis.Methods: In this retrospective cohort study, 195 participants were included and classified according to their age, clinical status, and CSF AD biomarker profile: 89 EOAD, 37 LOAD, 46 young healthy controls (age ≤ 65 years), and 23 old healthy controls (>65 years). All subjects underwent clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture.Results: We found distinct neuropsychological profiles between EOAD and LOAD at the time of diagnosis. Both groups showed similar performances on memory and language domains, but the EOAD patients displayed worsened deficits in visual perception, praxis, and executive tasks (p < 0.05). Longitudinally, cognitive decline in EOAD was more pronounced than LOAD in the global outcomes at the expense of these non‐amnestic domains. We found that years of education significantly influenced the decline in most of the neuropsychological tests. Besides, the APOE ε4 status showed a significant effect on the decline of memory‐related tasks within the EOAD cohort (p < 0.05).Interpretation: Age of onset is a main factor shaping the cognitive trajectories in AD patients, with younger age driving to a steeper decline of the non‐memory domains. Years of education are related to a transversal decline in all cognitive domains and APOE ε4 status to a specific decline in memory performance in EOAD.

Both authors contributed equally. Background: Self-reported and informant-reported subjective cognitive decline (SCD) may be useful in the detection of preclinical Alzheimer’s disease (Pre-AD) and cognitive impairment related to abnormal amyloid-β (A

Background: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer’s disease (preAD). Objectives: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging. Methods: 68 cognitively normal older adults were classified as controls ( n = 52) or preAD ( n = 16) according to amyloid-β (Aβ) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available. Results: Four SCD-Q factors were extracted: EM-factor (episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p = 0.014) and A-factor (F(1) = 4.04; p = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks ( Sig-items. ) Significant discriminative powers for Aβ-positivity were found for L-factor (AUC = 0.75; p = 0.003) and A-factor (AUC = 0.74; p = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig-items . A significant time × group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year. Conclusions: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed.

NIA-AA diagnostic criteria include volumetric or visual rating measures of hippocampal atrophy (HA) as a diagnostic biomarker of Alzheimer's disease (AD). We aimed to determine its utility as a diagnostic biomarker for early onset Alzheimer's disease (EOAD) by assessing Medial Temporal Atrophy (MTA) and hippocampal volume (HV) determination. MTA score and HV quantified by FreeSurfer were assessed in 140 (aged ≤65) subjects with biomarker supported diagnosis: 38 amnesic (A-EOAD), 20 non-amnesic (NA-EOAD), 30 late onset AD (LOAD), 20 fronto-temporal dementia (FTD) and 32 healthy controls (HC). The results showed that the proportion of MTA ≥ 1.5 was higher on LOAD and FTD than EOAD and HC but none of the MTA thresholds (≥1, ≥1.5 and ≥ 2) showed acceptable diagnostic accuracy. LOAD had lower HV than the other groups. A-EOAD HV was lower than NA-EOAD and HC but equal to FTD. The 6258 mm3 cut-off showed good diagnostic accuracy between A-EOAD and HC. Both tools showed a moderate inverse correlation. In conclusion, MTA has a limited diagnostic utility as an EOAD biomarker as it does not discriminate AD from FTD or HC in initial symptomatic stages. HV may discriminate A-EOAD from HC but not from FTD.