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Abstract Background Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer’s disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet. Methods Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ42, Aβ40, p-tau181, p-tau217, p-tau231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated. Results Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ42/40 + compared with Aβ42/40 − . Furthermore, Aβ42/40 − participants in C1 showed GM reduction in inferior temporal areas compared with Aβ42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time. Conclusions Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.

Category-specific impairments witnessed in patients with semantic deficits have broadly dissociated into natural and artificial kinds. However, how the category of food (more specifically, fruits and vegetables) fits into this distinction has been difficult to interpret, given a pattern of deficit that has inconsistently mapped onto either kind, despite its intuitive membership to the natural domain. The present study explores the effects of a manipulation of a visual sensory (i.e., color) or functional (i.e., orientation) feature on the consequential semantic processing of fruits and vegetables (and tools, by comparison), first at the behavioral and then at the neural level. The categorization of natural (i.e., fruits/vegetables) and artificial (i.e., utensils) entities was investigated via cross-modal priming. Reaction time analysis indicated a reduction in priming for color-modified natural entities and orientation-modified artificial entities. Standard event-related potentials (ERP) analysis was performed, in addition to linear classification. For natural entities, a N400 effect at central channel sites was observed for the color-modified condition compared relative to normal and orientation conditions, with this difference confirmed by classification analysis. Conversely, there was no significant difference between conditions for the artificial category in either analysis. These findings provide strong evidence that color is an integral property to the categorization of fruits/vegetables, thus substantiating the claim that feature-based processing guides as a function of semantic category.