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Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

Despite recent advances in fluid biomarker research in Alzheimer's disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau275 and MTBR-tau282) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick's disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau275 and MTBR-tau282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

INTRODUCTION: This ongoing, prospective study examines the effectiveness of methods used to successfully recruit and retain 238 Black older adults in a longitudinal, observational Alzheimer's disease (AD) study. METHODS: Recruitment strategies included traditional media, established research registries, speaking engagements, community events, and snowball sampling. Participants were asked to complete an annual office testing session, blood‐based biomarker collection, optional one‐time magnetic resonance imaging (MRI) scan, and community workshop. RESULTS: Within the first 22 months of active recruitment, 629 individuals expressed interest in participating, and 238 enrolled in the ongoing study. Of the recruitment methods used, snowball sampling, community events, and speaking engagements were the most effective. DISCUSSION: The systemic underrepresentation of Black participants in AD research impacts the ability to generalize research findings and determine the effectiveness and safety of disease‐modifying treatments. Research to slow, stop, or prevent AD remains a top priority but requires diversity in sample representation. Highlights: Provide flexible appointments in the evening or weekends, offering transportation assistance, and allowing participants to complete study visits at alternative locations, such as senior centers or community centers.Continuously monitor and analyze recruitment data to identify trends, challenges, and opportunities for improvement.Implement targeted strategies to recruit participants who are underrepresented based on sex, gender, or education to increase representation.Diversify the research team to include members who reflect the racial and cultural backgrounds of the target population, to enhance trust and rapport with prospective participants. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate the frequency of modifiable dementia risk factors and their association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging. Methods: Modifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community‐dwelling African American (AA; n = 261) and non‐Hispanic White (nHW; n = 193) participants who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating [CDR] ≥ 0.5) and rates of decline (CDR Sum of Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index. Results: Hypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 2.13–8.67) and nHW participants (OR = 2.79, 95% CI = 1.21–6.44) but uniquely associated with faster decline in AA participants (β = 1.71, 95% CI = 0.69–2.73, p = 0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%, p < 0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA participants (β = 2.65, 95% CI = 0.38–4.91, p = 0.023). Interpretation: Modifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants. ANN NEUROL 2024;95:518–529 [ABSTRACT FROM AUTHOR]

Background: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. Methods: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education. Results: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. Conclusions: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI. [ABSTRACT FROM AUTHOR]

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐σ and FLAIR‐σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐μ decreased and T1‐σ and FLAIR‐σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Delay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed. METHODS: Recommendations were developed using results from a web‐based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA. RESULTS: Survey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria. DISCUSSION: These consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials. [ABSTRACT FROM AUTHOR]

The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5–6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18–45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45–50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50–55 years and an accelerated decrease for hippocampal volume at the baseline age of 55–60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65–70 years. Another acceleration in the rate of change occurred at the baseline age of 65–70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18–45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease. [ABSTRACT FROM AUTHOR]

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes.Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology.Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology.Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01).Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old. [ABSTRACT FROM AUTHOR]

1The relative safety and efficacy of putative amyloid- -lowering therapies in patients with sporadic early-symptomatic Alzheimer disease. Unknowns exist around treatment effects in patients with clinically atypical AD, autosomal dominant AD, and AD with coexistent neurodegenerative pathologies. Recent advances in Alzheimer disease (AD) therapeutics represent a step in the right direction for patients with AD. Donanemab treatment in TRAILBLAZER-ALZ2 used a different approach (treatment until amyloid PET negative), with 52% of treated individuals (71% of treated patients with intermediate burden of tau neuropathology confirmed on tau-PET) achieving amyloid clearance by 12 months [[2]]. [Extracted from the article]

Background and purpose: Autoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt–Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE. Methods: Patients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total‐tau, phosphorylated181 tau and amyloid‐β42 levels were compared. Results: Of 11 CJD cases, four were autopsy proven; the rest had positive real‐time quaking‐induced conversion testing. Disease‐associated autoantibodies were detected in 8/15 cases of AE: leucine‐rich glioma‐inactivated 1 and neuronal intermediate filaments (two cases each), and N‐methyl‐d‐aspartate receptor, contactin‐associated protein‐like 2, dipeptidyl‐peptidase‐like protein 6 and immunoglobulin‐like cell adhesion molecule IgLON family member 5. Total‐tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17–2.11, p < 0.05, c = 0.93). Total‐tau was elevated in 91% of CJD cases (median > 1300, range 236–>1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total‐tau was elevated in 20% of AE cases (median 158, range 80–>1300 pg/ml). Conclusion: Total‐tau was greater in CJD than AE. Given that amyloid‐β42 and phosphorylated181 tau were comparable, the ratio differences were probably driven by elevated total‐tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia. [ABSTRACT FROM AUTHOR]

Background: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. Methods: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. Results: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36–54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. Conclusions: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD. [ABSTRACT FROM AUTHOR]

Creutzfeldt–Jakob disease (CJD) is a rare, uniformly fatal prion disease. Although CJD commonly presents with rapidly progressive dementia, ataxia, and myoclonus, substantial clinicopathological heterogeneity is observed in clinical practice. Unusual and predominantly cognitive clinical manifestations of CJD mimicking common dementia syndromes are known to pose as an obstacle to early diagnosis and prognosis. We report a series of three patients with probable or definite CJD (one male and two females, ages 52, 58 and 68) who presented to our tertiary behavioral neurology clinic at Mayo Clinic Rochester that met criteria for a newly defined progressive dysexecutive syndrome. Glucose hypometabolism patterns assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) strongly resembled those of dysexecutive variant of Alzheimer's disease (dAD). However, magnetic resonance imaging (MRI) demonstrated restricted diffusion in neocortical areas and deep nuclei, while cerebrospinal fluid biomarkers indicated abnormal levels of 14-3-3, total-tau, and prion seeding activity (RT-QuIC), establishing the diagnosis of CJD. Electroencephalogram (EEG) additionally revealed features previously documented in atypical cases of CJD. This series of clinical cases demonstrates that CJD can present with a predominantly dysexecutive syndrome and FDG-PET hypometabolism typically seen in dAD. This prompts for the need to integrate information on clinical course with multimodal imaging and fluid biomarkers to provide a precise etiology for dementia syndromes. This has important clinical implications for the diagnosis and prognosis of CJD in the context of emerging clinical characterization of progressive dysexecutive syndromes in neurodegenerative diseases like dAD. [ABSTRACT FROM AUTHOR]

Bivariate correlation coefficients (BCCs) are often calculated to gauge the relationship between two variables in medical research. In a family-type clustered design where multiple participants from same units/families are enrolled, BCCs can be defined and estimated at various hierarchical levels (subject level, family level and marginal BCC). Heterogeneity usually exists between subject groups and, as a result, subject level BCCs may differ between subject groups. In the framework of bivariate linear mixed effects modeling, we define and estimate BCCs at various hierarchical levels in a family-type clustered design, accommodating subject group heterogeneity. Simplified and modified asymptotic confidence intervals are constructed to the BCC differences and Wald type tests are conducted. A real-world family-type clustered study of Alzheimer disease (AD) is analyzed to estimate and compare BCCs among well-established AD biomarkers between mutation carriers and non-carriers in autosomal dominant AD asymptomatic individuals. Extensive simulation studies are conducted across a wide range of scenarios to evaluate the performance of the proposed estimators and the type-I error rate and power of the proposed statistical tests. Abbreviations: BCC: bivariate correlation coefficient; BLM: bivariate linear mixed effects model; CI: confidence interval; AD: Alzheimer's disease; DIAN: The Dominantly Inherited Alzheimer Network; SA: simple asymptotic; MA: modified asymptotic [ABSTRACT FROM AUTHOR]

Introduction: We examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB). Methods: In 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209). Results: REM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles. Discussion: An earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles. [ABSTRACT FROM AUTHOR]

Objective: Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer's disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. Methods: Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid‐beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. Results: Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. Interpretation: MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies. [ABSTRACT FROM AUTHOR]

Background: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable.Objective: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone.Methods: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31-513).Results: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p = 0.04), or lower CSF Aβ40 at presentation (rho = -0.83; p = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p = 0.03) or higher late ARIA-E scores (rho = 0.70; p = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p = 0.66).Conclusion: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness. [ABSTRACT FROM AUTHOR]

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine‐rich glioma‐inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [18F]flortaucipir PET neuroimaging associated with persistent cognitive impairment and hippocampal atrophy in four recovering LGI1 patients (3 men; median age, 67 [37–88] years). Imaging findings in cases were compared with those observed in age‐ and gender‐similar cognitively normal individuals (n = 124) and individuals with early‐symptomatic Alzheimer disease (n = 11). Elevated [18F]flortaucipir retention was observed in the two LGI1 patients with hippocampal atrophy and persistent cognitive impairment, including one with autopsy‐confirmed Alzheimer disease. Tau neuropathology may associate with cognitive complaints and hippocampal atrophy in recovering LGI1 patients. [ABSTRACT FROM AUTHOR]

Background: Age-associated increases in medical complexity, frailty, and cognitive impairment may compromise reliable reporting of medical history.Objective: To evaluate the influence of increasing age and cognitive impairment on concordance between reported history of stroke and cerebral infarction, and reported history of diabetes and elevated hemoglobinA1c in community-dwelling older adults.Methods: The association between participant-specific factors and accurate reporting of stroke or diabetes was evaluated using multivariable logistic regression in 1,401 participants enrolled in longitudinal studies of memory and aging, including 425 participants with dementia (30.3%). Stroke and diabetes were selected as index variables as gold standard measures of both were obtained in all participants: magnetic resonance neuroimaging for cerebral infarcts and hemoglobinA1c (≥6.5%) for diabetes.Results: Concordance between reported history of stroke and imaging-confirmed cerebral infarction was low (sensitivity: 17.4%, 8/46; specificity: 97.9%, 799/816). Small infarcts were strongly associated with inaccurate reporting (OR = 265.8; 95% CI: 86.2, 819.4), suggesting that occult/silent infarcts contributed to discordant reporting. Reporting accuracy was higher concerning diabetes (sensitivity: 83.5%, 147/176; specificity: 96.2%, 1100/1143). A history of hypertension (OR = 2.3; 95% CI: 1.3, 4.2), higher hemoglobinA1c (OR = 1.9; 95% CI: 1.5, 2.4), and hemoglobinA1c compatible with impaired glucose tolerance (OR = 3.1; 95% CI 1.8, 5.3) associated with increased odds of discordant reporting. Cognitive impairment and increased age were not independently associated with reliable reporting.Conclusion: Factors beyond advancing age and cognitive impairment appear to drive discordance in reported medical history in older participants. Objective testing for cerebral infarcts or diabetes should be performed when relevant to diagnostic or therapeutic decisions in clinical and research settings. [ABSTRACT FROM AUTHOR]

Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)–PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)–PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log 10 (phosphorylated tau 181), CSF log 10 (phosphorylated tau 217), and MRI-based hippocampal volume. Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r =0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (–0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB–PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III. [ABSTRACT FROM AUTHOR]

The factors that predispose to relapse in patients recovering with autoimmune encephalitis (AE) are largely unknown, complicating efforts to distinguish patients with resurgent symptoms who may benefit from additional immune-modulating therapies from those with other causes of impairment. We report a patient with AE with leucine-rich glioma-inactivated 1 autoantibodies with a typical presentation, but atypical course complicated by treatment-refractory psychoses and progressive cognitive decline. We leveraged emergent molecular biomarkers, including [18F]florbetapir (amyloid) and [18F]flortaucipir AV45 (tau) PET neuroimaging, to evaluate for common neurodegenerative causes of impairment. The patient was followed until death and a brain autopsy performed. No evidence of active inflammation was observed on neuroimaging or cerebrospinal fluid analyses in our patient with resurgent, treatment-refractory cognitive decline. [18F]Florbetapir and [18F]flortaucipir retention were increased in cerebral cortices in a pattern consistent with symptomatic Alzheimer's disease. Immunomodulatory therapies were stopped, and appropriate counseling provided to the patient and family. The patient died 2.4 months following [18F]flortaucipir PET neuroimaging. Brain autopsy confirmed changes typical of Alzheimer's disease without evidence of active inflammation or sequelae of AE, establishing Alzheimer's disease as the likely cause of resurgent symptoms in this patient. Symptoms of age-related neurodegenerative illnesses may emerge following AE, particularly in older patients in whom neurodegenerative dementing illnesses are more common. Molecular biomarkers may aid in the evaluation of treatment-refractory patients with resurgent symptoms and signs, influencing management. Unlabelled Image • Cognitive impairment after autoimmune encephalitis may arise due to immune-mediated or other causes. • Common neurodegenerative diseases may present following autoimmune encephalitis. • The cause of cognitive impairment dictates the optimal management. • Emergent molecular biomarkers may inform the causes of cognitive impairment after autoimmune encephalitis. [ABSTRACT FROM AUTHOR]

Background: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A-) participants (18-89 years old). In independent samples of 144 CN/A-, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A-. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic. response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. [ABSTRACT FROM AUTHOR]

• Regional age-related atrophy varies in strength and pattern. • Non-linear pattern of age-related atrophy correlates with T1/T2 myelin content. • Additional atrophy not seen in preclinical Alzheimer disease. Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched. [ABSTRACT FROM AUTHOR]

Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connectivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer disease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance. [ABSTRACT FROM AUTHOR]