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Objective We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)‐derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)‐related syndromes, Alzheimer’s disease (AD), and healthy controls. Methods We included 214 participants with CSF available recruited at two centers: 93 with FTLD‐related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1‐42, Aβ1‐40, Aβ1‐38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP‐derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain‐specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP‐derived peptides, and regional gene expression profile using a brain‐wide regional gene expression data in combination with gene set enrichment analysis. Results The CSF levels of Aβ1‐40, Aβ1‐38, and sAPPβ were lower in the FTLD‐related syndromes group than in the AD and healthy controls group. CSF levels of all APP‐derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD‐related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP‐derived peptides, we found a reduced expression of genes related to synaptic function. Interpretation APP‐derived peptides in CSF may reflect FTLD‐related neurodegeneration. This observation has important implications as Aβ1‐42 levels are considered an indirect biomarker of cerebral amyloidosis.

INTRODUCTION Self‐reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear. METHODS We analyzed 394 genetic‐FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI‐based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes. We used the residuals of linear regression models, which predict each participant's cognitive and behavioral performance levels relative to cortical thickness, as a proxy for reserve. We then modeled sex differences in longitudinal trajectories with linear mixed‐effects models. RESULTS Symptomatic females with genetic FTD had lower frontal cortical thickness than males, and the C9orf72 subgroup showed lower‐than‐expected frontal cortical thickness for a given level of executive functioning. Differences in cognitive reserve between sexes peaked near symptom onset but diminished thereafter. DISCUSSION Females with genetic FTD showed higher cognitive reserve than males, suggesting that self‐reported sex modulates resilience to frontotemporal neurodegeneration. Highlights Females with genetic FTD showed higher cognitive reserve than males. Those differences were particularly pronounced in the C9orf72 and GRN subgroups. The higher cognitive reserve in females declined as the disease progressed.

Background/Aims: Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular and cerebrovascular disease, and it has also been proposed as an independent risk factor for dementia and Alzheimer’s disease (AD). Its relationship with cognitive impairment, however, remains unclear. We aimed to determine the relationship of tHcy levels with clinical diagnoses and cognitive performance in a sample of outpatients with cognitive impairment. Methods: Plasma tHcy, folate, vitamin B12 and creatinine levels were assessed in individuals evaluated at the Memory Disorder Unit. Diagnoses included subjective memory complaints (SMC, n = 27), mild cognitive impairment (MCI, n = 142), AD (n = 139) and vascular dementia (VD, n = 17). All patients underwent extensive neuropsychological testing to evaluate attention, memory, language, and visuoconstructional and executive functions, as well as depression and impairments of daily living activities. Results: tHcy levels did not differ between patients with SMC, MCI, AD or VD. Increased tHcy was associated with worse performance in geometric figure copy and clock drawing tests. Conclusions: tHcy levels did not discriminate between diagnostic groups of patients with cognitive impairments. Elevated tHcy levels in these patients appear to have a detrimental effect on visuoconstructional performance.

Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular and cerebrovascular disease, and it has also been proposed as an independent risk factor for dementia and Alzheimer's disease (AD). Its relationship with cognitive impairment, however, remains unclear. We aimed to determine the relationship of tHcy levels with clinical diagnoses and cognitive performance in a sample of outpatients with cognitive impairment. Plasma tHcy, folate, vitamin B12 and creatinine levels were assessed in individuals evaluated at the Memory Disorder Unit. Diagnoses included subjective memory complaints (SMC, n = 27), mild cognitive impairment (MCI, n = 142), AD (n = 139) and vascular dementia (VD, n = 17). All patients underwent extensive neuropsychological testing to evaluate attention, memory, language, and visuoconstructional and executive functions, as well as depression and impairments of daily living activities. tHcy levels did not differ between patients with SMC, MCI, AD or VD. Increased tHcy was associated with worse performance in geometric figure copy and clock drawing tests. tHcy levels did not discriminate between diagnostic groups of patients with cognitive impairments. Elevated tHcy levels in these patients appear to have a detrimental effect on visuoconstructional performance.

Background Bilingualism has been proposed as a cognitively enriching factor that delays dementia onset by an average of four years. Understanding how bilingualism may drive variation in cognitive decline—whether by conferring resilience or resistance to Alzheimer's disease (AD) pathology—is critical for its therapeutic potential. Approaching the issue from a biological perspective is essential, however few studies have examined its underlying mechanisms. This study investigates the relationship between bilingual status, cognitive decline, and cerebrospinal fluid (CSF) biomarkers reflecting key AD pathophysiological processes. Method We analyzed data from 567 participants with biomarker‐confirmed, memory‐predominant AD in the Sant Pau Initiative on Neurodegeneration (SPIN) cohort. All participants underwent neurologic and neuropsychological evaluations, CSF biomarker testing, and language‐use assessments. They were categorized into active bilinguals (frequent Catalan and Spanish use) and passive bilinguals (Spanish speakers with passive Catalan exposure). Robust and generalized linear models were used to determine whether bilingualism protects against cognitive decline and, if so, whether this reflects a mechanism consistent with resilience (better cognitive performance despite similar levels of pathology) or resistance (lower CSF biomarker levels reflecting amyloid‐beta (Aβ42) and tau accumulation (phospho‐tau, total‐tau), neurodegeneration (neurofilament light, NFL), and neuroinflammation (GFAP, YKL‐40). Result Active and passive bilinguals were similar in age, sex, APOE genotype distribution, and proportion of participants in the MCI/dementia stage, though active bilinguals had more years of education (Table 1). Controlling for education, its interaction with bilingual status, and age, we found evidence of resilience: active bilingualism was consistently associated with better performance on the Trail Making Test A, CERAD figure copy, and Boston Naming Test. Evidence of resistance was more limited: active bilingualism was linked to lower levels of YKL‐40. This effect was present only in low‐ and mid‐education participants, as evidenced by the significant interaction between bilingual status and education. No significant associations were found with the other biomarkers. Conclusion Active bilingualism appears to protect against cognitive decline in individuals with biomarker‐confirmed AD, primarily through resilience rather than resistance to AD pathology. Preliminary findings suggest a potential effect of resistance to neuroinflammation is limited to people with AD with low and mid‐education levels, which requires further investigation in larger datasets.

Background Patients with neurodegenerative diseases can display early behavioral changes during the clinical assessment that can be captured with the Social Behavior Observer Checklist (SBOC). Nevertheless, the incremental diagnostic utility of this structured observational instrument, when used in conjunction with conventional neuropsychological assessments, has not been ascertained across diverse cultural contexts. We aimed to determine the diagnostic value of the SBOC in large biomarker supported cohort of patients with different neurodegenerative diseases. Method Participants from the SPIN cohort underwent extensive diagnostic protocols, including neuropsychological evaluation and cerebrospinal fluid biomarker analysis. Diagnostic categories were assigned based on consensus criteria. We derived cognitive composites (memory, language, executive function, and visuospatial function) by averaging scaled scores measuring parallel neuropsychological constructs. A total SBOC score and three subscale scores (disorganized, reactive, and insensitive subscales) were calculated. We explored the correlation between SBOC scores and cognitive domains. We studied the diagnostic accuracy of SBOC measures by calculating the Area Under the Receiver Operating Curve (AUROC). We compared the AUROC of SBOC‐derived scores and cognitive composites with the DeLong’s test. Result The cohort included 572 participants: 126 cognitively healthy controls (HC), 166 with Frontotemporal Lobar Degeneration Syndromes (FTLD‐S), and 280 with Alzheimer’s disease (AD). FTLD‐S encompassed 95 with behavioral variant frontotemporal dementia (bvFTD), 26 non‐fluent/agrammatic, 8 semantic variant primary progressive aphasias, and 37 progressive supranuclear palsy‐corticobasal degeneration spectrum disorders. SBOC scores exhibited modest correlations with executive functions. FTLD‐S patients had higher SBOC scores than HC and AD, with bvFTD patients showing the greatest elevations. The diagnostic accuracy of the SBOC was high for distinguishing FTLD‐S from HC (AUROC = 0.91 for total and 0.94 for disorganized scores) and bvFTD from HC (AUROC = 0.90 for total and 0.92 for disorganized scores), matching the accuracy of cognitive composites. However, SBOC scores did not differentiate between FTLD‐S and AD (AUROC = 0.61) or between FTLD‐S subtypes. Conclusion The SBOC is a useful scale that can complement the information obtained from formal neuropsychological testing and help identifying prototypical behaviors associated with different neurodegenerative diseases.

Patients with neurodegenerative diseases can display early behavioral changes during the clinical assessment that can be captured with the Social Behavior Observer Checklist (SBOC). Nevertheless, the incremental diagnostic utility of this structured observational instrument, when used in conjunction with conventional neuropsychological assessments, has not been ascertained across diverse cultural contexts. We aimed to determine the diagnostic value of the SBOC in large biomarker supported cohort of patients with different neurodegenerative diseases. Participants from the SPIN cohort underwent extensive diagnostic protocols, including neuropsychological evaluation and cerebrospinal fluid biomarker analysis. Diagnostic categories were assigned based on consensus criteria. We derived cognitive composites (memory, language, executive function, and visuospatial function) by averaging scaled scores measuring parallel neuropsychological constructs. A total SBOC score and three subscale scores (disorganized, reactive, and insensitive subscales) were calculated. We explored the correlation between SBOC scores and cognitive domains. We studied the diagnostic accuracy of SBOC measures by calculating the Area Under the Receiver Operating Curve (AUROC). We compared the AUROC of SBOC-derived scores and cognitive composites with the DeLong's test. The cohort included 572 participants: 126 cognitively healthy controls (HC), 166 with Frontotemporal Lobar Degeneration Syndromes (FTLD-S), and 280 with Alzheimer's disease (AD). FTLD-S encompassed 95 with behavioral variant frontotemporal dementia (bvFTD), 26 non-fluent/agrammatic, 8 semantic variant primary progressive aphasias, and 37 progressive supranuclear palsy-corticobasal degeneration spectrum disorders. SBOC scores exhibited modest correlations with executive functions. FTLD-S patients had higher SBOC scores than HC and AD, with bvFTD patients showing the greatest elevations. The diagnostic accuracy of the SBOC was high for distinguishing FTLD-S from HC (AUROC = 0.91 for total and 0.94 for disorganized scores) and bvFTD from HC (AUROC = 0.90 for total and 0.92 for disorganized scores), matching the accuracy of cognitive composites. However, SBOC scores did not differentiate between FTLD-S and AD (AUROC = 0.61) or between FTLD-S subtypes. The SBOC is a useful scale that can complement the information obtained from formal neuropsychological testing and help identifying prototypical behaviors associated with different neurodegenerative diseases.

Background Phosphorylated tau at threonine 217 (p‐tau217) is a highly specific blood‐based biomarker for Alzheimer's disease (AD) pathology, with high diagnostic accuracy and reproducible cut‐offs across cohorts. However, the prognostic utility of plasma p‐tau217 has not been assessed across the clinical stages of AD. The objectives of this study were to evaluate the prognostic utility of a commercially available immunoassay for plasma p‐tau217 in predicting clinical and functional decline across the clinical stages of AD in a cohort with up to 10 years of follow‐up. Method This cohort study analyzed data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort, including baseline visits conducted between March 2011 and November 2022. Participants included individuals with and without cognitive impairment, classified into clinical stages 1–6 based on AD pathology status in cerebrospinal fluid (CSF), determined by the p‐tau181/Aβ1‐42 ratio. Plasma p‐tau217 concentrations were measured using a commercially available immunoassay (ALZpath pTau217 assay). Cognitive and functional decline were assessed via changes in the Mini‐Mental State Examination (MMSE) and progression to stage 4. Longitudinal plasma p‐tau217 changes were also analyzed according to baseline AD pathology status. Result The study included 731 participants (mean [SD] age, 71.5 [10.1] years; 442 females [60%], 289 males [40%]). Among individuals with AD pathology, plasma p‐tau217 levels (but not CSF p‐tau181) increased with advancing clinical stages, and longitudinal changes in plasma p‐tau217 exhibited greater annual increases than CSF p‐tau181. Both plasma p‐tau217 levels and CSF p‐tau181 correlated with cognitive measures and predicted faster cognitive decline. Based on established cut‐offs, participants with negative or intermediate p‐tau217 levels experienced slower cognitive and functional decline than those with positive plasma p‐tau217 levels. In non‐demented participants, plasma p‐tau217 (but not CSF p‐tau181) was independently associated with accelerated progression to the dementia stage. Conclusion Plasma p‐tau217, measured using a commercially available immunoassay, was associated with cognitive and functional decline in AD. These findings highlight the potential of plasma p‐tau217 for use in routine clinical practice to monitor and prognosticate AD progression.

Background Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are severe neurodegenerative disorders lacking disease‐modifying treatments and validated biomarkers. Clinical trials face challenges due to phenotypic overlap and imperfect clinicopathological correlations. MRI‐derived models have shown to accurately predict PSP and CBD pathology in a large autopsy‐confirmed cohort (Illán‐Gala et al., JAMA Network Open, 2022). This study examines how participant selection based on MRI models and imaging outcomes impacts sample size estimations in hypothetical clinical trials. Method Eighty‐four participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) with baseline and longitudinal MRI data and clinical assessments were included. Diagnoses comprised Richardson syndrome (RS, 61%) and corticobasal syndrome (CBS, 30%) without Alzheimer's disease. MRI‐derived models predicted PSP, CBD, or other pathologies (MRI‐PSP, MRI‐CBD, MRI‐Other) according to baseline MRI. Cortical thickness and volume measures were derived from MRI data using Freesurfer and employed to identify an optimal MRI‐signature of regions showing the highest effect size on atrophy over 12 months using linear mixed‐effects models. Disease progression was also measured with PSP Rating Scale (PSPRS). Sample sizes required to detect a 30% reduction in mean change at 12 months were calculated for hypothetical clinical trials. Result MRI predicted PSP, CBD, and other pathologies in 46%, 26%, and 27% of participants, respectively. Among RS diagnoses, 31 (61%) were classified as MRI‐PSP; among CBS, 6 (24%) were MRI‐CBD. MRI‐signature regions for PSP progression included midbrain, superior‐temporal, and rostral‐middle‐frontal thickness. For CBD, key regions included midbrain and pons volumes, superior‐frontal, and entorhinal thickness. In a hypothetical PSP trial, selection criteria based on clinical diagnosis required 336 participants using PSPRS as outcome, while MRI‐based diagnosis with MRI‐signature as outcome reduced the sample size to 121 (64% decrease). For a CBS trial, the sample size reduced from 1301 participants if inclusion was based on clinical diagnosis to 160 using MRI‐based selection and outcomes. Conclusion Selecting participants with increased diagnostic certainty for PSP and CBD based on baseline MRI, combined with using MRI measures as outcomes could enhance the efficiency of future phase 2 clinical trials for 4R tauopathies. We plan to replicate these results in the Davunetide trial cohort.