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BackgroundMRI atrophy predicts cognitive status in AD. However, this relationship has not been investigated in early-onset AD (EOAD, < 65 years) patients with a biomarker-based diagnosis.MethodsForty eight EOAD (MMSE ≥ 15; A + T + N +) and forty two age-matched healthy controls (HC; A − T − N −) from a prospective cohort underwent full neuropsychological assessment, 3T-MRI scan and lumbar puncture at baseline. Participants repeated the cognitive assessment annually. We used linear mixed models to investigate whether baseline cortical thickness (CTh) or subcortical volume predicts two-year cognitive outcomes in the EOAD group.ResultsIn EOAD, hemispheric CTh and ventricular volume at baseline were associated with global cognition, language and attentional/executive functioning 2 years later (p < 0.0028). Regional CTh was related to most cognitive outcomes (p < 0.0028), except verbal/visual memory subtests. Amygdalar volume was associated with letter fluency test (p < 0.0028). Hippocampal volume did not show significant associations.ConclusionBaseline hemispheric/regional CTh, ventricular and amygdalar volume, but not the hippocampus, predict two-year cognitive outcomes in EOAD.

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.

INTRODUCTION Recent research has suggested increased sensitivity of Alzheimer's disease (AD)‐negative neuropsychological norms; concurrently, generalized additive models for location, scale, and shape (GAMLSS) have emerged as a promising alternative to traditional norming approaches. Here, we developed amyloid β‐negative (Aβ−) next‐generation norms (NGN) for a comprehensive neuropsychological battery using GAMLSS. METHODS We included N = 987 cognitively normal (CN) individuals from a Spanish multicenter study with extensive neuropsychological data and cerebrospinal fluid AD biomarker assessment. NGN were developed using GAMLSS based on the performance of n = 774 Aβ− CN individuals aged 30–90 years. RESULTS Age‐, education‐, and sex‐adjusted z‐scores were obtained for 14 measures covering the main cognitive domains (memory, language, attention/executive, and visuospatial functions). A user‐friendly calculator for the z‐scores was made available in an open‐access ShinyApp to facilitate their application. DISCUSSION NGN may improve the detection of objective cognitive impairment in clinical and research settings. Highlights Brain amyloid β (Aβ) is associated with poorer performance in cognitively normal individuals. We provide GAMLSS‐based Aβ‐negative norms for 14 neuropsychological measures. Age, education, and often sex significantly influence cognitive performance. An online calculator for the demographically adjusted z‐scores is freely available.

INTRODUCTION We previously applied generalized additive models for location, scale, and shape to derive amyloid β–negative next‐generation norms (NGN) for a comprehensive neuropsychological battery. Here, we evaluated the accuracy of NGN in detecting cognitive impairment compared to traditional norms (TN). METHODS This multicenter study included N = 2405 participants classified as cognitively normal (CN, n = 987) or with mild cognitive impairment (MCI, n = 1418) using conventional criteria. All participants underwent neuropsychological testing and cerebrospinal fluid Alzheimer's disease (AD) biomarker assessment. We used actuarial neuropsychological criteria to reclassify all participants using TN and NGN. Diagnostic groups were compared on cognitive performance, AD biomarker positivity, and longitudinal cognitive trajectories. RESULTS Nineteen percent of TN‐classified CN participants were diagnosed with MCI by NGN, whereas 3% of TN‐classified MCI were identified as CN by NGN. NGN demonstrated stronger associations with neuropsychological performance, AD biomarkers, and progression than TN. DISCUSSION NGN enhance the detection of objective cognitive impairment, with direct implications for clinical practice and research. Highlights Next‐generation norms (NGN) reclassify one of every five cases from cognitively normal (CN) to mild cognitive impairment (MCI). This group shows poor cognitive performance and a high prevalence of amyloid β positivity. NGN‐based diagnosis of MCI predicts cognitive progression on follow‐up. Results indicate that NGN improve the detection of objective cognitive impairment. NGN can inform biomarker use, therapy indication, and clinical trial design.

INTRODUCTION We aimed to determine whether cognitively unimpaired (CU) amyloid‐ beta‐positive (Aβ+) individuals display decreased practice effects on serial neuropsychological testing. METHODS We included 209 CU participants from three research centers, 157 Aβ− controls and 52 Aβ+ individuals. Participants underwent neuropsychological assessment at baseline and annually during a 2‐year follow‐up. We used linear mixed‐effects models to analyze cognitive change over time between the two groups, including time from baseline, amyloid status, their interaction, age, sex, and years of education as fixed effects and the intercept and time as random effects. RESULTS The Aβ+ group showed reduced practice effects in verbal learning (β = −1.14, SE = 0.40, p = 0.0046) and memory function (β = −0.56, SE = 0.19, p = 0.0035), as well as in language tasks (β = −0.59, SE = 0.19, p = 0.0027). DISCUSSION Individuals with normal cognition who are in the Alzheimer's continuum show decreased practice effects over annual neuropsychological testing. Our findings could have implications for the design and interpretation of primary prevention trials. Highlights This was a multicenter study on practice effects in asymptomatic Aβ+ individuals. We used LME models to analyze cognitive trajectories across multiple domains. Practice‐effects reductions might be an indicator of subtle cognitive decline. Implications on clinical and research settings within the AD field are discussed.

Background Sleep alterations are common in Alzheimer's disease (AD) and may be related to the early degeneration of the neuromodulatory subcortical systems (NNS). The Apolipoprotein E‐ϵ4 (APOE4) allele is the major genetic risk factor of sporadic AD and has been associated with a faster rate of cognitive decline. Our aim was to study objective measures of sleep fragmentation and the NNS nuclei integrity in a sample of AD patients according to their APOE4 status. Method We included 54 patients with a biomarker‐based diagnosis of AD, classified as APOE4 non‐carriers (n = 25) and carriers (n = 29). Participants underwent clinical and neuropsychological evaluation, CSF extraction, blood sampling, 2‐week actigraphy (Motion Wath 8 device; CamNTech), and magnetic resonance imaging to measure NNS integrity. Analysis of variance (ANOVA) adjusted by age were used to compare the actigraphy measures and the NNS nuclei integrity between APOE4 carriers and non‐carriers. In a subsample (n = 35), we run Repeated Measures ANOVA adjusted by age to explore longitudinal (1‐year follow‐up) neuropsychological performance among groups. Results There were no significant differences between APOE4 carriers and non‐carriers in terms of age, years of education, CSF AD biomarker levels or Mini‐Mental State Examination (MMSE) score (all p>0.05; Table 1). Compared to non‐carriers, APOE4 carriers showed a higher sleep fragmentation index (F[1,41]=5.12; p <0.05), increased body movement (F[1,41]=4.61; p <0.05) and decreased total sleep time (F[1,36]=4.79; p <0.05) as measured by actigraphy (Figure 1). APOE4 carriers presented lower integrity (Figure 2) of the preoptic area and paraventricular nucleus (PVN) (F[1,40]=4.65; p <0.05), nucleus accumbens (F[1,40]=5.17; p <0.05), hypothalamus (F[1,40]=9.12; p <0.01), and the right basal forebrain (F[1,40]=6.10; p <0.05). On the contrary, APOE4 carriers showed higher locus coeruleus integrity (F[1,40]=5.12; p <0.05). While there were no between‐group differences in the neuropsychological scores at baseline, APOE4 carriers displayed a higher decline in verbal learning measures at the 1‐year follow‐up (F[1,29]=4.50; p <0.05). Conclusion APOE4 carriers present higher sleep fragmentation and a higher vulnerability of several NSS nuclei when compared with non‐carriers. Further longitudinal research is called for to assess the relevance of the current findings as prognostic markers of the disease.

Background Alzheimer's disease (AD) features a complex interplay of factors influencing cognitive decline. While CSF and plasma biomarkers have widely demonstrated their diagnostic utility, whether they may add prognostic value remains unrevealed. With this longitudinal study we aim to address this knowledge gap by evaluating the predictive value of several fluid biomarkers over cognitive decline in a cohort of biomarker‐confirmed AD individuals. Method We included 139 participants with biologically‐confirmed AD (A+T+N+). Four cerebrospinal fluid (CSF) biomarkers (Amyloid‐Beta1‐42 [Aβ1‐42], tau phosphorylated at threonine 181 [p‐tau181], total tau [t‐tau], and neurofilament light chain [NfL]) were determined with enzyme immunoassay, and three plasma biomarkers (p‐tau181, NfL and glial fibrillary acidic protein [GFAP]) were determined with single‐molecule array. Biomarkers were stratified into tertiles. Comprehensive neuropsychological assessments were administered at baseline (n=139) and annually (Year 1 n=108, Year 2 n=78, Year 3 n=25, Year 4 n=3 and Year 5 n=3; mean follow‐up time 1.7 years [SD 0.3]). Mixed Models for Repeated Measures explored the effectof CSF and blood biomarkers on Mini‐Mental State Examination (MMSE) score progression. Result Participants had a mean age at onset of 65.7 (SD 6.4) years, 17% were non‐amnestic, 58% were APOEε4 carriers. Higher baseline plasma p‐tau181 and GFAP concentrations correlated with MMSE score decline (p=0.009 and p=0.002, respectively) (Table 1, Table 2, Figure 1). Conversely, no significant associations were observed between plasma NfL or CSF biomarkers concentrations and MMSE decline. Conclusion This longitudinal study highlights the potential prognostic value of baseline plasma p‐tau181 and GFAP concentrations for cognitive decline progression in AD.

Alzheimer's disease (AD) is the most common neurodegenerative dementia. Recent advancements in plasma biomarkers measuring phosphorylated tau (pTau), particularly pTau217, offer non-invasive, cost-effective alternatives to cerebrospinal fluid (CSF) and PET biomarkers for diagnosing AD. Plasma neurofilament light chain (NF-L) has also emerged as a potential marker of neurodegeneration. This multicenter study evaluated the utility of these biomarkers as diagnostic tools and explored their potential to facilitate implementation across multiple centers, ensuring diagnostic uniformity. Patients with mild cognitive impairment or mild dementia were recruited in a multicenter study (seven hospitals in Catalonia). Plasma levels of pTau217 and NF-L were measured using Lumipulse G (Fujirebio). Their diagnostic accuracy was compared to established CSF biomarkers. Additionally, the influence of demographic factors such as age, sex, BMI, and glomerular filtration rate (GFR) on pTau217 levels was analyzed. Of 212 enrolled patients, 27 were excluded due to pre-analytical complications. Therefore, 185 patients were analyzed [Table 1], including 50 non-neurodegenerative cases (SND), 119 AD cases, 5 Lewy body dementia cases (3 LBD Aβ-, 2 LBD Aβ+), and 12 frontotemporal dementia cases (9 FTD Aβ-, 3 FTD Aβ+). Plasma pTau217 detected amyloid pathology (Aβ+) with high accuracy using two cut-offs: a cut-off below 0.201 pg/mL yielded a sensitivity of 95%, with a negative predictive value of 87%. For values above 0.397 pg/mL, specificity reached 95%, with a positive predictive value of 97% [Figure 1]. These thresholds predicted β-amyloid status in 74% of cases. NF-L levels were elevated in neurodegenerative conditions with significant differences, but with low diagnostic precision (mean values: 26.434 vs 19.933 pg/mL, p = 0.01, AUC=0.634) [Figure 2]. Demographic factors, particularly BMI and GFR, had minimal effects on plasma biomarker levels, with limited impact on diagnostic performance. Plasma pTau217 showed high AD diagnostic accuracy, and may reduce the need for other procedures like CSF/PET. The use of two diagnostic thresholds appears optimal, with 26% of subjects in intermediate ranges, potentially indicating early AD changes. NF-L were elevated in neurodegeneration but showed limited clinical utility in our study. This study supports the use of pTau217 in clinical practice, promoting diagnostic uniformity across Catalonia.

Background Alzheimer's disease (AD) is the most common neurodegenerative dementia. Recent advancements in plasma biomarkers measuring phosphorylated tau (pTau), particularly pTau217, offer non‐invasive, cost‐effective alternatives to cerebrospinal fluid (CSF) and PET biomarkers for diagnosing AD. Plasma neurofilament light chain (NF‐L) has also emerged as a potential marker of neurodegeneration. This multicenter study evaluated the utility of these biomarkers as diagnostic tools and explored their potential to facilitate implementation across multiple centers, ensuring diagnostic uniformity. Method Patients with mild cognitive impairment or mild dementia were recruited in a multicenter study (seven hospitals in Catalonia). Plasma levels of pTau217 and NF‐L were measured using Lumipulse G (Fujirebio). Their diagnostic accuracy was compared to established CSF biomarkers. Additionally, the influence of demographic factors such as age, sex, BMI, and glomerular filtration rate (GFR) on pTau217 levels was analyzed. Result Of 212 enrolled patients, 27 were excluded due to pre‐analytical complications. Therefore, 185 patients were analyzed [Table 1], including 50 non‐neurodegenerative cases (SND), 119 AD cases, 5 Lewy body dementia cases (3 LBD Aβ‐, 2 LBD Aβ+), and 12 frontotemporal dementia cases (9 FTD Aβ‐, 3 FTD Aβ+). Plasma pTau217 detected amyloid pathology (Aβ+) with high accuracy using two cut‐offs: a cut‐off below 0.201 pg/mL yielded a sensitivity of 95%, with a negative predictive value of 87%. For values above 0.397 pg/mL, specificity reached 95%, with a positive predictive value of 97% [Figure 1]. These thresholds predicted β‐amyloid status in 74% of cases. NF‐L levels were elevated in neurodegenerative conditions with significant differences, but with low diagnostic precision (mean values: 26.434 vs 19.933 pg/mL, p = 0.01, AUC=0.634) [Figure 2]. Demographic factors, particularly BMI and GFR, had minimal effects on plasma biomarker levels, with limited impact on diagnostic performance. Conclusion Plasma pTau217 showed high AD diagnostic accuracy, and may reduce the need for other procedures like CSF/PET. The use of two diagnostic thresholds appears optimal, with 26% of subjects in intermediate ranges, potentially indicating early AD changes. NF‐L were elevated in neurodegeneration but showed limited clinical utility in our study. This study supports the use of pTau217 in clinical practice, promoting diagnostic uniformity across Catalonia.