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We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A−) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A− individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A− groups. After classifying this matched sample for phospho-tau pathology (T−/T+), individuals with A+/T+ were significantly more memory-impaired than A−/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer’s disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer’s disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.

Most current models of recognition memory fail to separately model item and person heterogeneity which makes it difficult to assess ability at the latent construct level and prevents the administration of adaptive tests. Here we propose to employ a General Condorcet Model for Recognition (GCMR) in order to estimate ability, response bias and item difficulty in dichotomous recognition memory tasks. Using a Bayesian modeling framework and MCMC inference, we perform 3 separate validation studies comparing GCMR to the Rasch model from IRT and the 2-High-Threshold (2HT) recognition model. First, two simulations demonstrate that recovery of GCMR ability estimates with varying sparsity and test difficulty is more robust and that estimates improve from the two other models under common test scenarios. Then, using a real dataset, face validity is confirmed by replicating previous findings of general and domain-specific age effects (Güsten et al. in Cortex 137:138–148, https://doi.org/10.1016/j.cortex.2020.12.017, 2021). Using cross-validation we show better out-of-sample prediction for the GCMR as compared to Rasch and 2HT model. In addition, we present a hierarchical extension of the model that is able to estimate age- and domain-specific effects directly, without recurring to a two-stage procedure. Finally, an adaptive test using the GCMR is simulated, showing that the test length necessary to obtain reliable ability estimates can be significantly reduced compared to a non-adaptive procedure. The GCMR allows to model trial-by-trial performance and to increase the efficiency and reliability of recognition memory assessments.

Amyloid-beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age-related Aβ-independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low-Aβ subgroup.MethodsWe included 488 adults (40-91 years; low-Aβ: n=355, 65.2±11.5 years) from the BioFINDER-2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1- and T2-weighted magnetic resonance images. Thickness of early/late neocortical AD-regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [18F]RO948- and [18F]flutemetamol-PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ-PET or cerebrospinal fluid Aβ-42/40 ratio. Global cognition was measured using delayed word-list recall, trail making test B, and animal fluency.ResultsIncreasing age was associated with higher tau-PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau-PET remained even when including Aβ-PET as a mediator (Fig. 1).Age and local tau-PET, but not Aβ-PET, where negatively associated with structure in most examined regions (Figs. 2-3). Age-structure associations were serially mediated via tau-PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low-Aβ subgroup, tau-PET mediated the age-structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age-global cognition relationship was serially mediated via MTL tau-PET and subiculum volume, even when including global Aβ-PET as additional mediator (Fig. 4).ConclusionWe observe partially Aβ-independent associations between age and tau-PET signal across the neocortex. Interestingly, partially Aβ-independent tau-PET signal appears to mediate the age-structure associations in and outside the MTL (PPC), also in the low-Aβ group, and the age-MTL structure-cognition associations. This potentially provides in vivo support for Primary Age-related Tauopathy downstream effects on structure, beyond the MTL, and cognition.

Remote and unsupervised cognitive testing using smartphones may improve sensitivity to detect preclinical Alzheimer’s disease (AD). In particular, cognitive testing at-home enables the evaluation of the potentially more sensitive long-term delayed memory retrieval, which is commonly not feasible in a clinical setting.MethodHere, we investigated the association between remote and unsupervised smartphone-based cognitive assessments and in-clinic cognitive measurement in older participants (CDR = 0, MMSE = 29.2, age = 77). The sample (non-demented at age 70) was derived from the Swedish population-based Gothenburg H70 Birth Cohort Studies. In a subsample of participants, the retrospective correlation with cerebrospinal fluid (CSF) biomarkers analyzed at age 70 was further explored. To this point, 177 H70-participants have consented and were enrolled into the smartphone sub-study. They completed an “Object-in-Room Recall Test“ (ORR) remotely and unsupervised using own mobile devices, and the recall session was initiated 24 hours after the initial learning phase. Available previously assessed CSF measures included the Aβ42/Aβ40-ratio, t-tau, p-tau, neurofilament light (NFL), and neurogranin, available in-clinic cognitive tests included the Rey Auditory Verbal Learning Test (RAVLT), Semantic Fluency, Digit-Symbol-Coding, and Mini Mental State Examination. The above-mentioned cognitive tests were used to derive the Preclinical Alzheimer's Cognitive Composite (PACC5), a composite designed to be sensitive to cognitive change in preclinical AD. All associations were examined using Pearson correlation coefficient.ResultPreliminary analyses in a subset of participants yielded relatively strong positive correlations between PACC5 (R = .50, p

International audience; Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aβ-positive cognitively impaired compared to both Aβ-negative and Aβ-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aβ in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aβ pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aβ in preclinical phase of AD.

Subregions in the medial temporal lobe (MTL) are affected early by Alzheimer’s disease (AD) pathology and subject to grey matter atrophy. Measuring the earliest AD-related atrophy in the hippocampus is challenging as region-of-interest (ROI) analyses of hippocampal subregional volumes collapse across voxels within anatomical subregions. PET imaging studies, however, report accumulation of tau pathology between anatomical subregions in the earliest disease stages (Berron et al., 2021) fitting reports from the neuropathological literature (Lace et al., 2019; Ravikumar et al., 2021). Thus, sensitive in vivo methods of point-wise structural measures are needed in order to detect the earliest hippocampal thinning in AD along the anterior-posterior as well as the medial-lateral hippocampal axis.MethodHere we analyzed data from 76 amyloid-beta negative (Ab-) cognitively normal (CN), 46 Ab+ CN individuals and 25 Ab+ patients with mild cognitive impairment (MCI) from the BioFINDER-2 study, who underwent 7 Tesla T2-weighted structural magnetic resonance imaging, tau positron emission tomography imaging (using 18F-RO-948) and cognitive assessments. First, we segmented hippocampal subfields and extrahippocampal subregions. Second, we calculated point-wise hippocampal thickness estimates (Diers et al.) of hippocampal subfields subiculum, cornu ammonis (CA)1, CA2 and CA3 on the level of the hippocampal body. Thirdly, we extracted local tau-PET SUVR from Area 35 (A35), entorhinal cortex and amygdala. Finally, we assessed relationships between hippocampal local thickness and tau accumulation as well as cognitive performance.ResultOur analyses revealed earliest hippocampal thinning associated with tau accumulation in an area spanning the boundary of subiculum and CA1 at the level of the anterior hippocampal body. Ab+ MCI patients showed more posterior thinning in comparison to Ab- CU participants. Median thickness in an ROI comprising vertices with A35 tau-related thinning (A35-TauThinning-ROI) was significantly lower in MCI Ab+ and tended to be lower in CU Ab+ compared to CU Ab-. Higher median thickness in the hippocampal A35-TauThinning-ROI, but not whole CA1 nor subiculum thickness, was associated with better 10-Word-Delayed-Recall and higher PACC scores.ConclusionOur results suggest that tau-related thinning of hippocampal subregions can be observed already in early disease stages. Tau-related point-wise thickness measures were more sensitive compared to volumetric measures of anatomical subregions.

Cortical processing streams for item and contextual information come together in the entorhinal-hippocampal circuitry. Various evidence suggest that information-specific pathways organize the cortical – entorhinal interaction and the circuitry’s inner communication along the transversal axis. Here, we leveraged ultra-high field functional imaging and advance Maass, Berron et al. (2015) who report two functional routes segregating the entorhinal cortex (EC) and subiculum. Our data show specific scene processing in the functionally connected posterior-medial EC and distal subiculum. The regions of another route, that connects the anterior-lateral EC and a newly identified retrosplenial-based anterior-medial EC subregion with the CA1/subiculum border, process object and scene information similarly. Our results support topographical information flow in human entorhinal-hippocampal subregions with organized convergence of cortical processing streams and a unique route for contextual information. They characterize the functional organization of the circuitry and underpin its central role in memory function and pathological decline.

INTRODUCTIONMobile app-based unsupervised monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer’s disease, this is particularly relevant for patients who seek medical advice due to memory complaints.OBJECTIVEWe developed a Remote Digital Memory Composite score from an unsupervised remote and mobile cognitive assessment battery focused on episodic memory and long-term recall and assessed its construct validity using a neuropsychological composite score for early cognitive impairment in Alzheimer’s disease, the Preclinical Alzheimer’s Cognitive Composite (PACC5). We also assessed the test-retest reliability of the Remote Digital Memory Composite score across two independent test sessions. Finally, we assessed the diagnostic accuracy of the remote and unsupervised cognitive assessment battery when predicting PACC5-based cognitive impairment in a memory clinic sample and healthy controls.SETTINGThis was an add-on study of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) which was also performed in a separate memory clinic-based sample.PARTICIPANTSA total of 102 study participants were included as healthy controls (HC; n=25), cognitively unimpaired first-degree relatives of AD patients (REL; n=7), individuals with subjective cognitive decline (SCD; n= 48) or patients with mild cognitive impairment (MCI; n=22).MEASUREMENTSWe analyzed results from the objects-in-rooms recall (ORR) test, the mnemonic discrimination for objects and scenes (MDT-OS) test and the complex scene recognition (CSR) test implemented on the neotiv digital platform to derive a Remote Digital Memory Composite. Participants used the neotiv mobile app to complete one unsupervised test session every two weeks on their own mobile device in an environment of their choice. We assessed the relationships of the Remote Digital Memory Composite acquired through the mobile app and in-clinic measures of the PACC5 conducted by trained neuropsychologists in the memory clinics participating in the DELCODE study.RESULTS102 participants provided technically complete data for at least one single session of each of the three test paradigms, of which 87 participants provided data from at least two test sessions of each task. The derived Remote Digital Memory Composite score was highly correlated with the PACC5 score across all participants (r=.75, pCONCLUSIONOur results indicate that unsupervised mobile cognitive assessments in a memory clinic setting using the implementation in the neotiv digital platform has high construct validity and results in a good discrimination between cognitively impaired and unimpaired individuals based on the PACC5 score. Thus, it is feasible to complement neuropsychological assessment of episodic memory with unsupervised, remote assessments on mobile devices. This contributes to recent efforts for implementing remotely performed episodic memory assessment for case-finding and monitoring in large research trials and clinical care.

INTRODUCTIONImpaired long-term memory is a defining feature of Mild Cognitive Impairment (MCI). We tested whether this impairment is item-specific, limited to some memoranda whereas some remain consistently memorable.METHODSWe conducted item-based analyses of long-term visual recognition memory. 394 participants (healthy controls (HC), Subjective Cognitive Decline (SCD), and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs.RESULTSWe observed consistent memorability for images in HCs, SCDs, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set.DISCUSSIONIndividuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.

Progrediente kognitive Einbusen sind das klinische Leitsymptom der Alzheimer-Erkrankung. Die genaue Erfassung kognitiver Defizite und die Beurteilung ihrer Progredienz bereiten jedoch in der Versorgung und Fruhintervention grose Probleme. Welche Probleme ergeben sich aus der aktuellen Praxis des kognitiven Assessments von Patienten mit dem Leitsymptom Gedachtnisprobleme fur die Versorgung und Fruhintervention und welche Moglichkeiten ergeben sich aus dem Einsatz mobiler Apps? Auswertung aktueller Versorgungsstrukturen, Diskussion von Grundlagenarbeiten und Expertenempfehlungen und aktueller Entwicklungen. Die aktuelle Praxis der „Paper-pencil“-basierten und zeitlich sowie ortlich an die Praxis- und Klinikumgebung gebundenen Diagnostik kognitiver Defizite beeintrachtigt die Durchfuhrbarkeit, Validitat und Reliabilitat des kognitiven Assessments und die Einschatzung der Progredienz kognitiver Defizite und limitiert so einen sinnvollen Einsatz fur weiterfuhrende diagnostische Masnahmen und therapeutische Entscheidungen. Aktuelle Entwicklungen mobiler Apps, hier am Beispiel der neotiv-App exemplarisch dargestellt, konnen helfen, diese Probleme zu uberwinden. Mobile App-basierte Technologien konnen helfen, die kognitive Diagnostik von Patienten mit dem Leitsymptom Gedachtnisprobleme zu verbessern. Sie konnen Uber- und Unterversorgung reduzieren und einen gezielten und sinnvollen Einsatz weiterfuhrender Diagnostik ermoglichen. Daruber hinaus konnen sie risikomodifizierende praventive Masnahmen strukturieren, helfen iatrogene Ursachen kognitiver Probleme zu erkennen und in dieser Hinsicht auch die Patientenkompetenz starken.

Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimers disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-{beta} (A{beta}) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the A{beta}-positive cognitively impaired compared to both the A{beta}-positive and A{beta}-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with A{beta} pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not A{beta}, in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of A{beta}, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than A{beta} pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of A{beta} during the preclinical phase of AD.

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using18F-Flortaucipir for tau and11C-Pittsburgh compound B (PiB) for amyloid-β (Aβ). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau– OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau– OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau+ vs Tau– OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Aβ. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression.SIGNIFICANCE STATEMENTAbnormal neural activity occurs in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD). Because tau pathology first deposits in the MTL in aging, this altered activity may be due to local tau pathology, and distinct MTL subregions may be differentially vulnerable. We demonstrate that in older adults (OAs) with low tau pathology, there are focal alterations in activity in MTL subregions that first develop tau pathology, while OAs with high tau pathology have aberrant activity throughout MTL. Tau was associated with hyperactivity to repeated stimulus presentations, leading to reduced repetition suppression, the discrimination between novel and repeated stimuli. Our data suggest that tau deposition is related to abnormal activity in MTL before the onset of cognitive decline.

Endel Tulving's episodic memory framework emphasizes the multifaceted re-experiencing of personal events. Indeed, decades of research focused on the experiential nature of episodic memories, usually treating recent episodic memory as a coherent experiential quality. However, recent insights into the functional architecture of the medial temporal lobe show that different types of mnemonic information are segregated into distinct neural pathways in brain circuits empirically associated with episodic memory. Moreover, recent memories do not fade as a whole under conditions of progressive neurodegeneration in these brain circuits, notably in Alzheimer's disease. Instead, certain memory content seem particularly vulnerable from the moment of their encoding while other content can remain memorable consistently across individuals and contexts. We propose that these observations are related to the content-specific functional architecture of the medial temporal lobe and consequently to a content-specific impairment of memory at different stages of the neurodegeneration. To develop Endel Tulving's inspirational legacy further and to advance our understanding of how memory function is affected by neurodegenerative conditions such as Alzheimer's disease, we postulate that it is compelling to focus on the representational content of recent episodic memories., Highlights • The functional anatomy of episodic memory segregates different memory content. • Alzheimer's disease may cause content-specific loss of recent memories • Content-specific memorability across individuals changes with Alzheimer's disease. • Content-specific assessment could provide new insights into episodic memory in health and disease

There is a pressing need to capture and track subtle cognitive change at the preclinical stage of Alzheimer's disease (AD) rapidly, cost‐effectively, and with high sensitivity. Concurrently, the landscape of digital cognitive assessment is rapidly evolving as technology advances, older adult tech‐adoption increases, and external events (i.e., COVID‐19) necessitate remote digital assessment. Here, we provide a snapshot review of the current state of digital cognitive assessment for preclinical AD including different device platforms/assessment approaches, levels of validation, and implementation challenges. We focus on articles, grants, and recent conference proceedings specifically querying the relationship between digital cognitive assessments and established biomarkers for preclinical AD (e.g., amyloid beta and tau) in clinically normal (CN) individuals. Several digital assessments were identified across platforms (e.g., digital pens, smartphones). Digital assessments varied by intended setting (e.g., remote vs. in‐clinic), level of supervision (e.g., self vs. supervised), and device origin (personal vs. study‐provided). At least 11 publications characterize digital cognitive assessment against AD biomarkers among CN. First available data demonstrate promising validity of this approach against both conventional assessment methods (moderate to large effect sizes) and relevant biomarkers (predominantly weak to moderate effect sizes). We discuss levels of validation and issues relating to usability, data quality, data protection, and attrition. While still in its infancy, digital cognitive assessment, especially when administered remotely, will undoubtedly play a major future role in screening for and tracking preclinical AD.

There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes.To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology.This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans.Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures.Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02).In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.

Recent findings suggest that the effect of aging on recognition memory is modality-dependent, affecting memory for objects and scenes differently. However, the lifespan trajectory of memory decline in these domains remains unclear. A major challenge for assessing domain-specific trajectories is the need to utilize different types of stimuli for each domain (objects and scenes). We tested the large sample required to cover much of the adult lifespan using a large stimulus range via web-based assessments. 1554 participants (18–77 years) performed an online mnemonic discrimination task, tested on a pool of 2708 stimuli (Berron et al., 2018). Using corrected hit-rate (Pr) as a measure of performance, we show age-related decline in mnemonic discrimination in both domains, notably with a stronger decline in object memory, driven by a linear increase in the false recognition rate with advancing age. These data are the first to identify a linear age-related decline in mnemonic discrimination and a stronger, linear trajectory of decline in the object domain. Our data can inform basic and clinical memory research on the effects of aging on memory and help advancing the implementation of digital cognitive research tools.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images., In this commentary, we outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies. This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images.

ObjectiveEstimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer’s disease.MethodsIn a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aβ, tau, and decreases in cognition with respect to the time of Aβ-positivity.ResultsSmall effect sizes of change in CSF Aβ42 and regional Aβ PET were estimated to occur several decades before Aβ-positivity. Increases in CSF tau occurred 11-12 years before Aβ-positivity. Temporoparietal tau PET showed increases 4-5 years before Aβ-positivity. Subtle cognitive dysfunction was observed 7-9 years before Aβ-positivity.ConclusionsIncreases in tau and cognitive dysfunction occur years before the presence of significant Aβ. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments.

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course “Biomarkers in neurodegenerative diseases”. In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.