Explore the vast range of titles available.

Many studies suggest that information about past experience, or episodic memory, is divided into discrete units called “events.” Yet we can often remember experiences that span multiple events. Events that occur in close succession might simply be linked because of their proximity to one another, but we can also build links between events that occur farther apart in time. Intuitively, some kind of organizing principle should enable temporally distant events to become bridged in memory. We tested the hypothesis that episodic memory exhibits a narrative-level organization, enabling temporally distant events to be better remembered if they form a coherent narrative. Furthermore, we tested whether post-encoding memory consolidation is necessary to integrate temporally distant events. In three experiments, participants learned and subsequently recalled events from fictional stories, in which pairs of temporally distant events involving side characters (“sideplots”) either formed one coherent narrative or two unrelated narratives. Across participants, we varied whether recall was assessed immediately after learning, or after a delay: 24 hours, 12 hours between morning and evening (“wake”), or 12 hours between evening and morning (“sleep”). Participants recalled more information about coherent than unrelated narrative events, in most delay conditions, including immediate recall and wake conditions, suggesting that post-encoding consolidation was not necessary to integrate temporally distant events into a larger narrative. Furthermore, post hoc modeling across experiments suggested that narrative coherence facilitated recall over and above any effects of sentence-level semantic similarity. This reliable memory benefit for coherent narrative events supports theoretical accounts which propose that narratives provide a high-level architecture for episodic memory.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross‐sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface‐based approach paired with an anatomically fine‐grained parcellation of the cortical surface (i.e., HCP‐MMP1.0 atlas). Second, we combined cross‐sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter‐seeded resting‐state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically‐intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis. In this cross‐sectional and longitudinal multimodal MR imaging study, we showed that logopenic variant of primary progressive aphasia (lvPPA) symptomatology and longitudinal atrophy progression relate to anatomical changes in two partly overlapping functional networks anchored to two left temporoparietal epicenters. These regions were defined as anatomical loci of early atrophy in a mild cohort of well‐characterized individuals with lvPPA using a surface‐based approach paired with a fine‐grained parcellation of the cortical surface. These findings support a model of neurodegenerative disease where neurodegeneration preferentially targets brain regions connected to specific disease epicenters, thereby driving the symptomatology that characterizes each clinical syndrome.

Background Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer’s disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables. Methods We retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET ( 11 C-PIB), tau-PET ( 18 F-flortaucipir, FTP), and blood draw assessments within 1 year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline ( n  = 85) and follow-up visits ( n  = 28; 1.5 ± 0.7 years). Results Plasma p-tau217 and cortical FTP-SUVR were correlated ( r  = 0.61, p  < .001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET Centiloids were weakly correlated with FTP-SUVR ( r  = 0.26, p  = 0.02), but not with p-tau217 ( r  = 0.10, p  = 0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model. Conclusion Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI or dementia due to AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration.

INTRODUCTION Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated. METHODS We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD. RESULTS We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini‐Mental Status Examination (MMSE) decline over time (p = 0.033). DISCUSSION Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort. Highlights Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation? Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09). Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008). Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022). Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).

Background Due to the lack of in vivo molecular biomarkers for Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which commonly co‐occurs with Alzheimer’s disease (AD), it is challenging to identify patients with mixed AD/LATE pathology. Autopsy studies have suggested that AD patients with greater hippocampal atrophy are disproportionately enriched in having concomitant LATE. Here we define the lower quartile of hippocampal volume as a biomarker of possible LATE with AD. Method We identified 164 cognitively impaired participants from ADNI who had structural MRI, amyloid‐PET, and tau‐PET within 365 days. Patients were grouped based on hippocampal volume quartiles (adjusted for age and intracranial volume) and amyloid‐PET‐status into suspected 1) AD‐only (volume>50th‐percentile, amyloid‐positive), n = 100, 2) LATE‐only (volume<25th‐percentile, amyloid‐negative), n = 14, 3) AD+LATE (volume<25th‐percentile, amyloid‐positive), n = 50. 250 cognitively normal, amyloid‐negative participants were also included. Patterns of atrophy were examined to assess whether the AD+LATE group had features suggestive of LATE beyond hippocampal atrophy. Result Suspected‐AD+LATE group had lower MMSE, CDR, and hippocampal volume and higher ITG‐tau‐SUVR compared to the suspected‐AD‐only group (Figure‐1A). Suspected‐AD‐only group showed predominant posterior hippocampal atrophy whereas LATE showed a more severe anterior hippocampal atrophy (Figure‐1B/2B). When compared to the AD‐only group, suspected LATE‐only and AD+LATE groups showed significantly lower thickness in ERC, PHC, BA35, BA36 (Figure‐2A); there were no differences between LATE‐only and AD+LATE groups. Suspected‐AD+LATE group showed features suggestive of LATE in prior work (Figure‐2B). Whole brain analysis demonstrated that in comparison to controls the suspected‐AD‐only group showed lower thickness in typical AD regions (posterior hippocampus and temporoparietal regions), suspected‐LATE‐only group showed lower thickness in more anterior MTL regions including temporal pole consistent with LATE pathology, whereas suspected‐AD+LATE group showed lower thickness in both AD‐ and LATE‐like regions (Figure‐3A). Assessing neurodegeneration driven due to non‐tau factors by controlling for ITG‐tau‐SUVR revealed similar atrophy patterns for both suspected LATE‐only and AD+LATE groups compared to the AD‐only group. Both groups showed decreased thickness isolated to anterior hippocampus extending into temporal pole (Figure‐3B). Conclusion Using a simple hippocampal volume percentile‐based metric may enrich in patients with concomitant LATE on the AD continuum and could potentially be examined in the context of clinical trials and anti‐amyloid therapies.

Overlap in clinical presentations, absence of well-validated in-vivo biomarkers for Limbic-predominant age-related TDP-43 encephalopathy (LATE), and frequent co-occurrence with AD, complicates identifying mixed AD/LATE cases. Autopsy studies suggest greater hippocampal atrophy in AD patients with concomitant LATE. We aimed to identify patients along the AD continuum enriched for LATE by defining the lower quartile of hippocampal volume (HV) as a biomarker for possible LATE and explore atrophy patterns and cognitive profiles. 164 cognitively impaired participants from ADNI with T1-MRI and amyloid- and tau-PET within 365 days were grouped based on HV quartiles (adjusted for age/intracranial volume) and amyloid status into suspected 1) AD-only (HV>50th-percentile, amyloid-positive), 2) LATE-only (HV<25th-percentile, amyloid-negative), 3) AD+LATE (HV<25th-percentile, amyloid-positive). We used a novel surface-based pointwise regional thickness analysis framework to examine cross-sectional and longitudinal atrophy patterns in the medial temporal lobe (MTL) and determine if AD+LATE showed LATE features beyond hippocampal atrophy. We assessed cross-sectional and longitudinal differences across 4 cognitive domains (memory, executive function, language, visuospatial). Suspected-AD+LATE showed imaging features suggestive of LATE (Figure-1B(II)), lower MMSE, CDR, and HV, but higher ITG-tau-SUVR compared to suspected-AD-only (Figure-1A). Suspected-AD-only showed predominant posterior hippocampal atrophy whereas AD+LATE showed more severe anterior hippocampal and amygdala atrophy (Figure-1B(I)) despite overlapping global tau loads between groups. Patterns of anterior-posterior atrophy and asymmetry were similar in LATE-only and AD+LATE (Figure-1B(II)). Cross-sectionally, AD+LATE showed significantly lower thickness in MTL-cortex (Figure-2A) compared to AD-only but primarily in anterior MTL-cortex when controlling for tau. Longitudinally, LATE-only showed slower atrophy than AD-only (stronger effects in Figure-2B(I)>Figure-2B(II)). AD+LATE showed faster atrophy than AD, however, the effect weakened when controlling for tau (Figure-2B(IV-V). Cross-sectionally, LATE-only and AD+LATE group showed lower memory and language scores than AD-only, even after controlling for tau (Figure-3A); however, longitudinally, AD+LATE declined faster across all domains, differing from AD-only when controlling for tau, suggesting a more aggressive disease (Figure 3B). Patients in lower quartile of HV on the AD continuum exhibit LATE-like patterns, suggesting underlying LATE pathology. A simple HV percentile-based metric may help identify patients with concomitant LATE and AD with potential relevance for clinical trials and anti-amyloid therapies.

Background Overlap in clinical presentations, absence of well‐validated in‐vivo biomarkers for Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), and frequent co‐occurrence with AD, complicates identifying mixed AD/LATE cases. Autopsy studies suggest greater hippocampal atrophy in AD patients with concomitant LATE. We aimed to identify patients along the AD continuum enriched for LATE by defining the lower quartile of hippocampal volume (HV) as a biomarker for possible LATE and explore atrophy patterns and cognitive profiles. Method 164 cognitively impaired participants from ADNI with T1‐MRI and amyloid‐ and tau‐PET within 365 days were grouped based on HV quartiles (adjusted for age/intracranial volume) and amyloid status into suspected 1) AD‐only (HV>50th‐percentile, amyloid‐positive), 2) LATE‐only (HV<25th‐percentile, amyloid‐negative), 3) AD+LATE (HV<25th‐percentile, amyloid‐positive). We used a novel surface‐based pointwise regional thickness analysis framework to examine cross‐sectional and longitudinal atrophy patterns in the medial temporal lobe (MTL) and determine if AD+LATE showed LATE features beyond hippocampal atrophy. We assessed cross‐sectional and longitudinal differences across 4 cognitive domains (memory, executive function, language, visuospatial). Result Suspected‐AD+LATE showed imaging features suggestive of LATE (Figure 1B(II)), lower MMSE, CDR, and HV, but higher ITG‐tau‐SUVR compared to suspected‐AD‐only (Figure 1A). Suspected‐AD‐only showed predominant posterior hippocampal atrophy whereas AD+LATE showed more severe anterior hippocampal and amygdala atrophy (Figure 1B(I)) despite overlapping global tau loads between groups. Patterns of anterior‐posterior atrophy and asymmetry were similar in LATE‐only and AD+LATE (Figure 1B(II)). Cross‐sectionally, AD+LATE showed significantly lower thickness in MTL‐cortex (Figure 2A) compared to AD‐only but primarily in anterior MTL‐cortex when controlling for tau. Longitudinally, LATE‐only showed slower atrophy than AD‐only (stronger effects in Figure 2B(I)>Figure 2B(II)). AD+LATE showed faster atrophy than AD, however, the effect weakened when controlling for tau (Figure 2B(IV‐V). Cross‐sectionally, LATE‐only and AD+LATE group showed lower memory and language scores than AD‐only, even after controlling for tau (Figure 3A); however, longitudinally, AD+LATE declined faster across all domains, differing from AD‐only when controlling for tau, suggesting a more aggressive disease (Figure 3B). Conclusion Patients in lower quartile of HV on the AD continuum exhibit LATE‐like patterns, suggesting underlying LATE pathology. A simple HV percentile‐based metric may help identify patients with concomitant LATE and AD with potential relevance for clinical trials and anti‐amyloid therapies.

Background Overlap in clinical presentations, absence of well‐validated in‐vivo biomarkers for Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), and frequent co‐occurrence with AD, complicates identifying mixed AD/LATE cases. Autopsy studies suggest greater hippocampal atrophy in AD patients with concomitant LATE. We aimed to identify patients along the AD continuum enriched for LATE by defining the lower quartile of hippocampal volume (HV) as a biomarker for possible LATE and explore atrophy patterns and cognitive profiles. Method 164 cognitively impaired participants from ADNI with T1‐MRI and amyloid‐ and tau‐PET within 365 days were grouped based on HV quartiles (adjusted for age/intracranial volume) and amyloid status into suspected 1) AD‐only (HV>50th‐percentile, amyloid‐positive), 2) LATE‐only (HV<25th‐percentile, amyloid‐negative), 3) AD+LATE (HV<25th‐percentile, amyloid‐positive). We used a novel surface‐based pointwise regional thickness analysis framework to examine cross‐sectional and longitudinal atrophy patterns in the medial temporal lobe (MTL) and determine if AD+LATE showed LATE features beyond hippocampal atrophy. We assessed cross‐sectional and longitudinal differences across 4 cognitive domains (memory, executive function, language, visuospatial). Result Suspected‐AD+LATE showed imaging features suggestive of LATE (Figure‐1B(II)), lower MMSE, CDR, and HV, but higher ITG‐tau‐SUVR compared to suspected‐AD‐only (Figure‐1A). Suspected‐AD‐only showed predominant posterior hippocampal atrophy whereas AD+LATE showed more severe anterior hippocampal and amygdala atrophy (Figure‐1B(I)) despite overlapping global tau loads between groups. Patterns of anterior‐posterior atrophy and asymmetry were similar in LATE‐only and AD+LATE (Figure‐1B(II)). Cross‐sectionally, AD+LATE showed significantly lower thickness in MTL‐cortex (Figure‐2A) compared to AD‐only but primarily in anterior MTL‐cortex when controlling for tau. Longitudinally, LATE‐only showed slower atrophy than AD‐only (stronger effects in Figure‐2B(I)>Figure‐2B(II)). AD+LATE showed faster atrophy than AD, however, the effect weakened when controlling for tau (Figure‐2B(IV‐V). Cross‐sectionally, LATE‐only and AD+LATE group showed lower memory and language scores than AD‐only, even after controlling for tau (Figure‐3A); however, longitudinally, AD+LATE declined faster across all domains, differing from AD‐only when controlling for tau, suggesting a more aggressive disease (Figure 3B). Conclusion Patients in lower quartile of HV on the AD continuum exhibit LATE‐like patterns, suggesting underlying LATE pathology. A simple HV percentile‐based metric may help identify patients with concomitant LATE and AD with potential relevance for clinical trials and anti‐amyloid therapies.

INTRODUCTION We examined sex effects on amyloid positron emission tomography (PET) in a large cohort of patients evaluated for cognitive complaints in a “real‐world” specialty setting. METHODS We analyzed 10,361 amyloid PET scans (51% females) from the Imaging Dementia–Evidence for Amyloid Scanning Study. Amyloid positivity was defined by either local visual read or central PET processing and quantification (≥ 24.4 Centiloids). Sex differences were examined using multilinear regression and logistic regression adjusted for age, comorbidities, and other demographic and clinical covariates. RESULTS Females had higher rates of positive amyloid PET visual reads (63% vs. 59%, P < 0.001) and higher Centiloids (CLs; median 48.7 vs. 36.8, p < 0.001). On logistic regression, females had higher odds ratios (ORs) for positive amyloid PET (visual read OR 1.20, 95% confidence interval [CI]: 1.11–1.31; CL threshold–based OR 1.37, 95% CI: 1.26–1.49; both p < 0.001). DISCUSSION Females with cognitive impairment showed higher amyloid PET positivity and greater amyloid burden. Further research is needed to explore mechanisms and treatment implications. Highlights Females exhibited higher rates of amyloid positron emission tomography (PET) positivity and higher amyloid burden than males. These sex effects were found in patients with both mild cognitive impairment (MCI) and dementia. Females also had higher rates of dementia and amnestic MCI, while males had higher rates of non‐amnestic MCI and more cholinesterase inhibitor use.