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© 2014 Macmillan Publishers Limited Memory impairment is the cardinal early feature of Alzheimer’s disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics app

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD., Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted., Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model., Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Background: Microbial dysbiosis has been reported to contribute to development of neurodegenerative diseases, however, there is a need to identify causative/prognostic indicators., Objectives: To comparatively analyze gut microbiome composition in symptomatic LBD (dementia/mild cognitive impairment), iRBD, and cohabiting controls without LBD or iRBD., Methods: 16S rRNA amplicon sequencing was performed in 38 cases (27 LBD, 11 iRBD) and 39 cohabitant controls. 19 non-cohabitant healthy controls (HCs) were also included to contrast differences between cohabitant cases and controls., Results: Microbiome composition of cohabitant controls and LBD and iRBD cases were strikingly similar. No differences were observed between LBD, and iRBD only showed reduced Bacteroides, compared with cohabitant controls. There were several taxonomic differences in gut microbiome composition between non-cohabitant HCs and cases., Conclusions: Minimal microbiome differences were observed between iRBD or LBD cases and cohabitant controls. These findings underscore the importance of using cohabiting controls in future gut microbiome studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

There is increasing interest in Alzheimer's disease related plasma biomarkers due to their accessibility and scalability. We hypothesized that integrating plasma biomarkers with other commonly used and available participant data (MRI, cardiovascular factors, lifestyle, genetics) using machine learning (ML) models can improve individual prediction of cognitive outcomes. Further, our goal was to evaluate the heterogeneity of these predictors across different age strata. This longitudinal study included 1185 participants from the Mayo Clinic Study of Aging who had complete plasma analyte work-up at baseline. We used the Quanterix Simoa immunoassay to measure neurofilament light, Aβ 1-42 and Aβ 1-40 (used as Aβ 42 /Aβ 40 ratio), glial fibrillary acidic protein, and phosphorylated tau 181 (p-tau181). Participants' brain health was evaluated through gray and white matter structural MRIs. The study also considered cardiovascular factors (hyperlipidemia, hypertension, stroke, diabetes, chronic kidney disease), lifestyle factors (area deprivation index, body mass index, cognitive and physical activities), and genetic factors ( APOE , single nucleotide polymorphisms, and polygenic risk scores). An ML model was developed to predict cognitive outcomes at baseline and decline (slope). Three models were created: a base model with groups of risk factors as predictors, an enhanced model included socio-demographics, and a final enhanced model by incorporating plasma and socio-demographics into the base models. Models were explained for three age strata: younger than 65 years, 65-80 years, and older than 80 years, and further divided based on amyloid positivity status. Regardless of amyloid status the plasma biomarkers showed comparable performance ( R ² = 0.15) to MRI ( R ² = 0.18) and cardiovascular measures ( R ² = 0.10) when predicting cognitive decline. Inclusion of cardiovascular or MRI measures with plasma in the presence of socio-demographic improved cognitive decline prediction ( R ² = 0.26 and 0.27). For amyloid positive individuals Aβ 42 /Aβ 40 , glial fibrillary acidic protein and p-tau181 were the top predictors of cognitive decline while Aβ 42 /Aβ 40 was prominent for amyloid negative participants across all age groups. Socio-demographics explained a large portion of the variance in the amyloid negative individuals while the plasma biomarkers predominantly explained the variance in amyloid positive individuals (21% to 37% from the younger to the older age group). Plasma biomarkers performed similarly to MRI and cardiovascular measures when predicting cognitive outcomes and combining them with either measure resulted in better performance. Top predictors were heterogeneous between cross-sectional and longitudinal cognition models, across age groups, and amyloid status. Multimodal approaches will enhance the usefulness of plasma biomarkers through careful considerations of a study population's socio-demographics, brain and cardiovascular health., Competing Interests: There are no relevant disclosures relevant to this publication., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: We aimed to evaluate clinical interpretation cutpoints for two plasma phosphorylated tau (p-tau)217 assays (ALZpath and Lumipulse) as predictors of amyloid status for implementation in clinical practice., Methods: Clinical performance of plasma p-tau217 against amyloid positron emission tomography status was evaluated in participants with mild cognitive impairment or mild dementia (n = 427)., Results: Using a one-cutpoint approach (negative/positive), neither assay achieved ≥ 90% in both sensitivity and specificity. A two-cutpoint approach yielding 92% sensitivity and 96% specificity provided the desired balance of false positives and false negatives, while categorizing 20% and 39% of results as indeterminate for the Lumipulse and ALZpath assays, respectively., Discussion: This study provides a systematic framework for selection of assay-specific cutpoints for clinical use of plasma p-tau217 for determination of amyloid status. Our findings suggest that a two-cutpoint approach may have advantages in optimizing diagnostic accuracy while minimizing potential harm from false positive results., Highlights: Phosphorylated tau (p-tau)217 cutpoints for detection of amyloid pathology were established. A two-cutpoint approach exhibited the best performance for clinical laboratory use. p-tau217 assays differed in the percentage of results categorized as intermediate., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

With the full FDA approval and centers for Medicare & Medicaid services (CMS) coverage of lecanemab and donanemab, a growing number of practices are offering anti-amyloid immunotherapy to appropriate patients with cognitive impairment (MCI) or mild dementia due to amyloid-positive Alzheimer's disease (AD). The goal of this paper is to provide updated practical considerations for radiologists, including implementation of MR imaging protocols, workflows and reporting and communication practices relevant to anti-amyloid immunotherapy and monitoring for amyloid-related imaging abnormalities (ARIA). Based on consensus discussion within an expanded ASNR Alzheimer's, ARIA, and Dementia study group, we will: (1) summarize the FDA guidelines for evaluation of radiographic ARIA; (2) review the three key MRI sequences for ARIA monitoring and standardized imaging protocols based on ASNR-industry collaborations; (3) provide imaging recommendations for three key patient scenarios; (4) highlight the role of the radiologist in the care team for this population; (5) discuss implementation of MRI protocols to detect ARIA in diverse practice settings; and (6) present results of the 2023 ASNR international neuroradiologist practice survey on dementia and ARIA imaging.ABBREVIATIONS: AD = Alzheimer's disease; ARIA = amyloid-related imaging abnormalities; APOE = apolipoprotein-E; CMS = centers for Medicare & Medicaid services; MCI = mild cognitive impairment., (© 2024 by American Journal of Neuroradiology.)

Background: Alzheimer disease (AD) and other dementias are associated with vascular changes and amyloid deposition, which may be reflected as density changes in the retinal capillaries. These changes may can be directly visualized and quantified with optical coherence tomography angiography (OCTA), making OCTA a potential noninvasive preclinical biomarker of small vessel disease and amyloid positivity. Our objective was to investigate the feasibility of retinal imaging metrics as noninvasive biomarkers of small vessel disease and amyloid positivity in the brain., Methods: We investigated associations between OCTA and neuroimaging and cognitive metrics in 41 participants without dementia from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center. OCTA metrics included superficial, deep, and full retina capillary density of the fovea, parafovea, and macula as well as the area of the foveal avascular zone (FAZ). Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds (CMB), lacunar infarcts, and amyloid positivity as evidenced on positron emission tomography (PET), whereas cognitive metrics included mini-mental status examination (MMSE) score. We performed generalized estimating equations to account for measurements in each eye while controlling for age and sex to estimate associations between OCTA metrics and neuroimaging and cognitive scores., Results: Associations between OCTA and neuroimaging metrics were restricted to the fovea. OCTA showed decreased capillary density with high burden of WMH in both the superficial (P = 0.003), deep (P = 0.004), and full retina (P = 0.01) in the fovea but not the parafovea or whole macula. Similarly, participants with amyloid PET positivity had significantly decreased capillary density in the superficial fovea (P = 0.027) and deep fovea (P = 0.03) but higher density in the superficial parafovea (P = 0.038). Participants with amyloid PET positivity also had a significantly larger FAZ (P = 0.031), whereas in those with high WMH burden the difference did not reach statistical significance (P = 0.075). There was also a positive association between MMSE and capillary density of the full retina within the fovea (P = 0.037) and in the superficial parafovea (P = 0.046). No associations were found between OCTA metrics and presence of CMB or presence of lacunar infarcts., Conclusion: The associations of lower foveal capillary density with cerebral WMH and amyloid positivity suggest that further research is warranted to evaluate for shared mechanisms of disease between small vessel disease and AD pathologies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by North American Neuro-Ophthalmology Society.)

Objective: To evaluate the performance of Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers in a tertiary neurology clinic setting with high frequency of non-AD cases, including normal pressure hydrocephalus (NPH)., Methods: There were 534 patients who underwent AD CSF biomarkers (Roche Elecsys Aβ42, p-Tau181, total-Tau) from April 1, 2020, through April 23, 2021. A behavioral neurologist blinded to CSF results assigned a clinical diagnosis retrospectively on the basis of consensus criteria, and a neuroradiologist blinded to the diagnosis and CSF studies graded brain magnetic resonance images for indicators of CSF dynamics disorders. Associations between biomarkers, diagnoses, and imaging were assessed by χ 2 , analysis of covariance, and linear regression methods., Results: Median age at time of testing was 67 years (range, 19 to 96 years), median symptom duration was 2 years (range, 0.4 to 28 years), and median Short Test of Mental Status score was 30 (range, 0 to 38). Clinical diagnoses significantly correlated with different CSF biomarker values (χ 2 =208.3; P=10e-4). p-Tau181/Aβ42 ratios above 0.023 positively correlated with Alzheimer dementia (more than individual measures). This ratio also had the best performance for differentiating Alzheimer dementia from NPH (area under the curve, 0.869). Imaging markers supportive of CSF dynamics disorders correlated with low Aβ42, p-Tau181, and total-Tau., Conclusion: In a heterogeneous clinical population, abnormal p-Tau181/Aβ42 ratios (>0.023) have the strongest association with Alzheimer dementia and probably represent a comorbid AD pathologic component in persons clearly matching non-AD neurodegenerative syndromes. Altered CSF dynamics were associated with lower concentrations of AD CSF biomarkers regardless of clinical diagnosis, but the ratio compensates for these changes. In the appropriate clinical setting, an isolated abnormal Aβ42 should prompt consideration of NPH., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials., Competing Interests: V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., Avid Radiopharmaceuticals and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, Avid Radiopharmaceuticals and the NIH (NIA, NCI). D.S.K. serves on a Data Safety Monitoring Board for the DIAN study and for a tau therapeutic for Biogen but receives no personal compensation; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California; has served as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation; and receives funding from the NIH. B.F.B. receives honorarium for SAB activities for the Tau Consortium, is an investigator in clinical trials sponsored by Alector, Biogen, Cognition Therapeutics, EIP Pharma and Transposon and receives funding from the NIH. C.R.J. has no commercial conflicts and receives research support from the NIH, the GHR Foundation and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. R.C.P. consults for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Genentech, Inc.; Eisai, Inc.; and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement., Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy., Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses., Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET)., Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02)., Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

There is a longstanding ambiguity regarding the clinical diagnosis of dementia syndromes predominantly targeting executive functions versus behaviour and personality. This is due to an incomplete understanding of the macro-scale anatomy underlying these symptomatologies, a partial overlap in clinical features and the fact that both phenotypes can emerge from the same pathology and vice versa. We collected data from a patient cohort of which 52 had dysexecutive Alzheimer's disease, 30 had behavioural variant frontotemporal dementia (bvFTD), seven met clinical criteria for bvFTD but had Alzheimer's disease pathology (behavioural Alzheimer's disease) and 28 had amnestic Alzheimer's disease. We first assessed group-wise differences in clinical and cognitive features and patterns of fluorodeoxyglucose (FDG) PET hypometabolism. We then performed a spectral decomposition of covariance between FDG-PET images to yield latent patterns of relative hypometabolism unbiased by diagnostic classification, which are referred to as 'eigenbrains'. These eigenbrains were subsequently linked to clinical and cognitive data and meta-analytic topics from a large external database of neuroimaging studies reflecting a wide range of mental functions. Finally, we performed a data-driven exploratory linear discriminant analysis to perform eigenbrain-based multiclass diagnostic predictions. Dysexecutive Alzheimer's disease and bvFTD patients were the youngest at symptom onset, followed by behavioural Alzheimer's disease, then amnestic Alzheimer's disease. Dysexecutive Alzheimer's disease patients had worse cognitive performance on nearly all cognitive domains compared with other groups, except verbal fluency which was equally impaired in dysexecutive Alzheimer's disease and bvFTD. Hypometabolism was observed in heteromodal cortices in dysexecutive Alzheimer's disease, temporo-parietal areas in amnestic Alzheimer's disease and frontotemporal areas in bvFTD and behavioural Alzheimer's disease. The unbiased spectral decomposition analysis revealed that relative hypometabolism in heteromodal cortices was associated with worse dysexecutive symptomatology and a lower likelihood of presenting with behaviour/personality problems, whereas relative hypometabolism in frontotemporal areas was associated with a higher likelihood of presenting with behaviour/personality problems but did not correlate with most cognitive measures. The linear discriminant analysis yielded an accuracy of 82.1% in predicting diagnostic category and did not misclassify any dysexecutive Alzheimer's disease patient for behavioural Alzheimer's disease and vice versa. Our results strongly suggest a double dissociation in that distinct macro-scale underpinnings underlie predominant dysexecutive versus personality/behavioural symptomatology in dementia syndromes. This has important implications for the implementation of criteria to diagnose and distinguish these diseases and supports the use of data-driven techniques to inform the classification of neurodegenerative diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB., (© 2024. The Author(s).)

Introduction: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease., Methods: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans., Results: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB., Discussion: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD., Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations., Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes., Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests., Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy., Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = -0.14 [95% CI, -0.42 to 0.14]; P = .32)., Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals., Methods: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure., Results: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide., Discussion: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor imaging (DTI) (fractional anisotropy; FA, mean diffusivity; MD) and neurite orientation dispersion and density imaging (NODDI) (neurite density index; NDI, orientation and dispersion index; ODI). Linear mixed-effects models accounting for age and family relatedness revealed alterations across DTI and NODDI metrics in all mutation carriers and in symptomatic carriers, with the most significant differences involving fronto-temporal WM tracts. Asymptomatic carriers showed higher entorhinal MD and lower cingulum FA and patterns of higher ODI mostly involving temporal areas and long association and projections fibers. Regression models between estimated time to or time from disease and DTI and NODDI metrics in key regions (amygdala, cingulum, entorhinal, inferior temporal, uncinate fasciculus) in all carriers showed increasing abnormalities with estimated time to or time from disease onset, with FA and NDI showing the strongest relationships. Neurite-based metrics, particularly ODI, appear to be particularly sensitive to early WM involvement in asymptomatic carriers., Competing Interests: Declaration of Competing Interest CRJ receives no personal compensation from any commercial entity. He receives research support from National Institute of Health (NIH), the GHR Foundation, and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. RCP consults for Roche, Inc., Merck, Inc., Biogen, Inc., Genentech, Inc., Eisai, Inc., and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role. BB receives honoraria for SAB activities for the Tau Consortium, and has received research grant support but no personal compensation for clinical trials from Alector, Biogen, Transposon, Cognition Therapeutics, GE Healthcare. VKR receives research funding from the NIH and the Mangurian Foundation for Lewy Body disease research, has provided educational content for Medscape, is co-PI for a clinical trial supported by the Alzheimer’s Association, and is a site clinician for clinical trials supported by Eisai, the Alzheimer's Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. EMR has no disclosure and receives funding from the NIH. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157–206) and Vigil Neuroscience, Inc. (VGL101–01.002, VGL101–01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. KK consults Biogen, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly and receives funding from NIH and Alzheimer’s Drug Discovery Foundation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Substantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes., Methods: A total of 799 PD patients were included and classified into tremor-dominant (TD) (N = 345), akinetic-rigid (AR) (N = 227), gait-difficulty (GD) (N = 82), and mixed (MX) (N = 145) phenotypic subtypes. After array genotyping and subsequent imputation, a total of 7,918,344 variants were assessed for association with each PD subtype using logistic regression models that were adjusted for age, sex, and the top five principal components of GWAS data., Results: We identified one genome-wide significant association (P < 5 × 10 -8 ), which was between the MIR3976HG rs7504760 variant and the AR subtype (Odds ratio [OR] = 6.12, P = 2.57 × 10 -8 ). Suggestive associations (P < 1 × 10 -6 ) were observed regarding TD for RP11-497G19.3/RP11-497G19.1 rs7304254 (OR = 3.33, P = 3.89 × 10 -7 ), regarding GD for HES2 rs111473931 (OR = 3.18, P = 6.85 × 10 -7 ), RP11-400D2.3/CTD-2012I17.1 rs149082205 (OR = 8.96, P = 9.08 × 10 -7 ), and RN7SL408P/SGK1 rs56161738 (OR = 2.97, P = 6.19 × 10 -7 ), and regarding MX for MMRN2 rs112991171 (OR = 4.98, P = 1.02 × 10 -7 )., Conclusion: Our findings indicate that genetic variation may account for part of the clinical heterogeneity of PD. In particular, we found a novel genome-wide significant association between MIR3976HG variation and the AR PD subtype. Replication of these findings will be important in order to better define the genetic architecture of clinical variability in PD disease presentation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objectives: Alzheimer disease (AD) has a polygenic architecture, for which genome-wide association studies (GWAS) have helped elucidate sequence variants (SVs) influencing susceptibility. Polygenic risk score (PRS) approaches show promise for generating summary measures of inherited risk for clinical AD based on the effects of APOE and other GWAS hits. However, existing PRS approaches, based on traditional regression models, explain only modest variation in AD dementia risk and AD-related endophenotypes. We hypothesized that machine learning (ML) models of polygenic risk (ML-PRS) could outperform standard regression-based PRS methods and therefore have the potential for greater clinical utility., Methods: We analyzed combined data from the Mayo Clinic Study of Aging (n = 1,791) and the Alzheimer's Disease Neuroimaging Initiative (n = 864). An AD PRS was computed for each participant using the top common SVs obtained from a large AD dementia GWAS. In parallel, ML models were trained using those SV genotypes, with amyloid PET burden as the primary outcome. Secondary outcomes included amyloid PET positivity and clinical diagnosis (cognitively unimpaired vs impaired). We compared performance between ML-PRS and standard PRS across 100 training sessions with different data splits. In each session, data were split into 80% training and 20% testing, and then five-fold cross-validation was used within the training set to ensure the best model was produced for testing. We also applied permutation importance techniques to assess which genetic factors contributed most to outcome prediction., Results: ML-PRS models outperformed the AD PRS ( r 2 = 0.28 vs r 2 = 0.24 in test set) in explaining variation in amyloid PET burden. Among ML approaches, methods accounting for nonlinear genetic influences were superior to linear methods. ML-PRS models were also more accurate when predicting amyloid PET positivity (area under the curve [AUC] = 0.80 vs AUC = 0.63) and the presence of cognitive impairment (AUC = 0.75 vs AUC = 0.54) compared with the standard PRS., Discussion: We found that ML-PRS approaches improved upon standard PRS for prediction of AD endophenotypes, partly related to improved accounting for nonlinear effects of genetic susceptibility alleles. Further adaptations of the ML-PRS framework could help to close the gap of remaining unexplained heritability for AD and therefore facilitate more accurate presymptomatic and early-stage risk stratification for clinical decision-making., Competing Interests: Dr. Graff-Radford receives research support from the NIH. Dr. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receives research support from GE Health care, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH. Dr. Knopman serves on a Data Safety Monitoring Board for the DIAN study, serves on a Data Safety Monitoring Board for Biogen but receives no personal compensation, is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, and serves as a consultant for Roche, Samus Therapeutics, Third Rock, and Alzeca Biosciences but receives no personal compensation. Dr. Jack receives no personal compensation from any commercial entity. Dr. Petersen serves as a consultant for Roche Inc., Merck Inc., and Biogen, Inc., serves on the Data Safety Monitoring Board for Genentech, Inc., and receives royalty from Oxford University Press and UpToDate. He receives research support from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Ross consulted for SciNeuro pharmaceuticals. Dr. Vemuri received speaker fees from Miller Medical Communications, Inc. and receives research support from the NIH. Dr. Ramanan receives research funding from the NIH and the Mangurian Foundation for Lewy Body disease research, has provided educational content for Medscape, is an Associate Editor for the Journal of Alzheimer's disease, and is an investigator in clinical trials sponsored by the Alzheimer's Association, Eisai, the Alzheimer's Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. The remaining authors report no relevant financial disclosures or competing interests. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Genetic mutations causative of frontotemporal lobar degeneration (FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter-individual variability in their patterns of network degeneration and clinical manifestations. We collected clinical and 18 Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

With recent data demonstrating that lecanemab treatment can slow cognitive and functional decline in early symptomatic Alzheimer disease (AD), it is widely anticipated that this drug and potentially other monoclonal antibody infusions targeting β-amyloid protein will imminently be realistic options for some patients with AD. Given that these new antiamyloid monoclonal antibodies (mAbs) are associated with nontrivial risks and burdens of treatment that are radically different from current mainstays of AD management, effectively and equitably translating their use to real-world clinical care will require systematic and practice-specific modifications to existing workflows and infrastructure. In this Emerging Issues in Neurology article, we provide practical guidance for a wide audience of neurology clinicians on logistic adaptations and decision making around emerging antiamyloid mAbs. Specifically, we briefly summarize the rationale and available evidence supporting antiamyloid mAb use in AD to facilitate appropriate communication with patients and care partners on potential benefits. We also discuss pragmatic approaches to optimizing patient selection and treatment monitoring, with a particular focus on the value of incorporating shared decision making and multidisciplinary collaboration. In addition, we review some of the recognized limitations of current knowledge and highlight areas of future evolution to guide the development of sustainable and flexible models for treatment and follow-up. As the field enters a new era with disease-modifying treatment options for AD, it will be critical for neurology practices to prepare and continually innovate to ensure optimal outcomes for patients., (© 2023 American Academy of Neurology.)

Background and Objectives: Treatment options for Alzheimer disease (AD) are limited and have focused mainly on symptomatic therapy and improving quality of life. Recently, lecanemab, an anti-β-amyloid monoclonal antibody (mAb), received accelerated approval by the US Food and Drug Administration for treatment in the early stages of biomarker-confirmed symptomatic AD. An additional anti-β-amyloid mAb, aducanumab, was approved in 2021, and more will potentially become available in the near future. Research on the applicability and generalizability of the anti-β-amyloid mAb eligibility criteria on adults with biomarkers available in the general population has been lacking. The study's primary aim was to apply the clinical trial eligibility criteria for lecanemab treatment to participants with early AD of the population-based Mayo Clinic Study of Aging (MCSA) and assess the generalizability of anti-amyloid treatment. The secondary aim of this study was to apply the clinical trial eligibility criteria for aducanumab treatment in MCSA participants., Methods: This cross-sectional study aimed to apply the clinical trial eligibility criteria for lecanemab and aducanumab treatment to participants with early AD of the population-based MCSA and assess the generalizability of anti-amyloid treatment., Results: Two hundred thirty-seven MCSA participants (mean age [SD] 80.9 [6.3] years, 54.9% male, and 97.5% White) with mild cognitive impairment (MCI) or mild dementia and increased brain amyloid burden by PiB PET comprised the study sample. Lecanemab trial's inclusion criteria reduced the study sample to 112 (47.3% of 237) participants. The trial's exclusion criteria further narrowed the number of potentially eligible participants to 19 (overall 8% of 237). Modifying the eligibility criteria to include all participants with MCI (instead of applying additional cognitive criteria) resulted in 17.4% of participants with MCI being eligible for lecanemab treatment. One hundred four participants (43.9% of 237) fulfilled the aducanumab clinical trial's inclusion criteria. The aducanumab trial's exclusion criteria further reduced the number of available participants, narrowing those eligible to 12 (5.1% of 237). Common exclusions were related to other chronic conditions and neuroimaging findings., Discussion: Findings estimate the limited eligibility in typical older adults with cognitive impairment for anti-β-amyloid mAbs., (© 2023 American Academy of Neurology.)

Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrolment and treatment monitoring in Alzheimer's disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer's disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analysing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, amyloid-β42/40, glial fibrillary acidic protein or neurofilament light chain. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% versus 68%; P = 0.001). A machine learning approach incorporating plasma biomarkers, demographics and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set) and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity, which could non-invasively enhance the interpretation of blood-based AD biomarker profiles in the population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Recent advances in blood-based biomarkers offer the potential to revolutionize the diagnosis and management of Alzheimer disease (AD), but additional research in diverse populations is critical. We assessed the profiles of blood-based AD biomarkers and their relationships to cognition and common medical comorbidities in a biracial cohort., Methods: Participants were evaluated through the Mayo Clinic Jacksonville Alzheimer Disease Research Center and matched on age, sex, and cognitive status. Plasma AD biomarkers (β-amyloid peptide 1-42 [Aβ 42/40 ], plasma tau phosphorylated at position 181 [p-tau 181 ], glial fibrillary acidic protein [GFAP], and neurofilament light) were measured using the Quanterix SiMoA HD-X analyzer. Cognition was assessed with the Mini-Mental State Examination. Wilcoxon rank sum tests were used to assess for differences in plasma biomarker levels by sex. Linear models tested for associations of self-reported race, chronic kidney disease (CKD), and vascular risk factors with plasma AD biomarker levels. Additional models assessed for interactions between race and plasma biomarkers in predicting cognition., Results: The sample comprised African American (AA; N = 267) and non-Hispanic White (NHW; N = 268) participants, including 69% female participants and age range 43-100 (median 80.2) years. Education was higher in NHW participants (median 16 vs 12 years, p < 0.001) while APOE ε4 positivity was higher in AA participants (43% vs 34%; p = 0.04). We observed no differences in plasma AD biomarker levels between AA and NHW participants. These results were unchanged after stratifying by cognitive status (unimpaired vs impaired). Although the p-tau 181 -cognition association seemed stronger in NHW participants while the Aβ 42/40 -cognition association seemed stronger in AA participants, these findings did not survive after excluding individuals with CKD. Female participants displayed higher GFAP (177.5 pg/mL vs 157.73 pg/mL; p = 0.002) and lower p-tau 181 (2.62 pg/mL vs 3.28 pg/mL; p = 0.001) levels than male participants. Diabetes was inversely associated with GFAP levels (β = -0.01; p < 0.001)., Discussion: In a biracial community-based sample of adults, we observed that sex differences, CKD, and vascular risk factors, but not self-reported race, contributed to variation in plasma AD biomarkers. Although some prior studies have reported primary effects of race/ethnicity, our results reinforce the need to account for broad-based medical and social determinants of health (including sex, systemic comorbidities, and other factors) in effectively and equitably deploying plasma AD biomarkers in the general population., (© 2023 American Academy of Neurology.)

Background and Objectives: Variants in the CWH43 gene have been associated with normal pressure hydrocephalus (NPH). We aimed to replicate these findings, identify additional CWH43 variants, and further define the clinical phenotype associated with CWH43 variants., Methods: We determined the prevalence of CWH43 variants by whole-genome sequencing (WGS) in 94 patients with NPH. The odds of having CWH43 variant carriers develop NPH were determined through comparison with 532 Mayo Clinic Biobank volunteers without a history of NPH. For patients with NPH, we documented the head circumference, prevalence of disproportionate enlargement of subarachnoid hydrocephalus (DESH), microvascular changes on MRI quantified by the Fazekas scale, and ambulatory response to ventriculoperitoneal shunting., Results: We identified rare (MAF <0.05) coding CWH43 variants in 15 patients with NPH. Ten patients (Leu533Terfs, n = 8; Lys696Asnfs, n = 2) harbored previously reported predicted loss-of-function variants, and combined burden analysis confirmed risk association with NPH (OR 2.60, 95% CI 1.12-6.03, p = 0.027). Additional missense variations observed included Ile292Thr (n = 2), Ala469Ser (n = 2), and Ala626Val (n = 1). Though not quite statistically significant, in single variable analysis, the odds of having a head circumference above the 75th percentile of normal controls was more than 5 times higher for CWH43 variant carriers compared with that for noncarriers (unadjusted OR 5.67, 95% CI 0.96-108.55, p = 0.0 57 ), and this was consistent after adjusting for sex and height (OR 5.42, 95% CI 0.87-106.37, p = 0.073 ). DESH was present in 56.7% of noncarriers and only 21.4% of carriers ( p = 0.016), while sulcal trapping was also more prevalent among noncarriers (67.2% vs 35.7%, p = 0.030). All 8 of the 15 variant carriers who underwent ventriculoperitoneal shunting at our institution experienced ambulatory improvements., Discussion: CWH43 variants are frequent in patients with NPH. Predicted loss-of-function mutations were the most common; we identified missense mutations that require further study. Our findings suggest that congenital factors, rather than malabsorption or vascular dysfunction, are primary contributors to the CWH43 -related NPH clinical syndrome., Competing Interests: B.D. Elder: Consulting for Depuy Synthes and SI Bone, medical advisory board and stock in Injectsense, and institutional funding as site PI for clinical trials for Stryker and SI Bone. The other authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB., Methods: We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum., Results: Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB ( p < 0.001) and MCI-LB ( p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB ( p < 0.001) and DLB groups ( p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02)., Discussion: In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies., (© 2023 American Academy of Neurology.)

Background: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education., Methods: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers., Results: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results., Conclusion: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities., (© 2023. The Author(s).)

Staging the severity of Alzheimer's disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (n = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center; had a concurrent amyloid PET, tau PET and blood draw; and met clinical criteria for cognitively unimpaired (n = 864), mild cognitive impairment (n = 148) or Alzheimer's clinical syndrome with dementia (n = 124). The latter two groups were combined into a cognitively impaired group (n = 272). We used multinomial regression models to estimate discrimination [concordance (C) statistics] among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6) and a combined amyloid and tau PET stage (none/low versus intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ1-42 and Aβ1-40 (analysed as the Aβ42/Aβ40 ratio), glial fibrillary acidic protein and neurofilament light chain were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (n = 355) of cognitively unimpaired participants using the Lilly Meso Scale Discovery assay. Models with all Quanterix plasma analytes along with risk factors (age, sex and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78-0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72-0.85 versus C = 0.73-0.86). Discriminating a PET proxy of intermediate/high from none/low Alzheimer's disease neuropathological change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 versus 0.87 for unimpaired and C = 0.91 versus 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high versus intermediate amyloid (C = 0.85 versus 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 versus 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high versus none/low neuropathological change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10 -311 , MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10 -09 , MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10 -10 , MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10 -09 , MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10 -08 , MAF = 0.006, sex-interaction P = 9.8 × 10 -07 ) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10 -08 , MAF = 0.004, sex-interaction P = 1.3 × 10 -03 ). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies., (© 2023. The Author(s).)

Objective: Growing evidence suggests that patients with rheumatoid arthritis (RA) have increased risk for dementia. We assessed risk factors for incident dementia in an inception cohort of patients with RA., Methods: This retrospective population-based cohort study included residents of 8 counties in Minnesota who were ≥ 50 years of age when they met 1987 American College of Rheumatology criteria for incident RA between 1980 and 2014 and were followed until death/migration or December 31, 2019. Patients with dementia before RA incidence were excluded. Incident dementia was defined as 2 relevant International Classification of Diseases, 9th or 10th revision codes at least 30 days apart. Data on sociodemographics, disease characteristics, cardiovascular/cerebrovascular disease (CVD) risk factors, and comorbidities were abstracted from medical records., Results: The study included 886 patients with RA (mean age 65.1 yrs, 65.2% female). During the follow-up period (median 8.5 yrs), 103 patients developed dementia. After adjusting for age, sex, and calendar year of RA incidence, older age at RA incidence (HR 1.14 per 1 year increase, 95% CI 1.12-1.17), rheumatoid nodules (HR 1.76, 95% CI 1.05-2.95), hypertension (HR 1.84, 95% CI 1.19-2.85), presence of large joint swelling (HR 2.03, 95% CI 1.14-3.60), any CVD (HR 2.25, 95% CI 1.38-3.66), particularly ischemic stroke (HR 3.16, 95% CI 1.84-5.43) and heart failure (HR 1.82, 95% CI 1.10-3.00), anxiety (HR 1.86, 95% CI 1.16-2.97), and depression (HR 2.63, 95% CI 1.76-3.93) were associated with increased risk of dementia. After adjusting for CVD risk factors and any CVD, all covariates listed above were still significantly associated with risk of dementia., Conclusion: Apart from age, hypertension, depression, and anxiety, all of which are universally recognized risk factors for dementia, clinically active RA and presence of CVD were associated with an elevated risk of dementia incidence among patients with RA., (Copyright © 2023 by the Journal of Rheumatology.)

Objective: This study was undertaken to assess cross-sectional and longitudinal [ 18 F]-flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC)., Methods: One hundred forty-three participants who had completed at least one flortaucipir PET and had autopsy-confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0-IV versus V-VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta-ROI, midbrain, globus pallidum, an AD meta-ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated., Results: Baseline uptake in the FTLD meta-ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD-related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%)., Interpretation: There are cross-sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016-1029., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Monoclonal antibodies are emerging disease-modifying therapies for Alzheimer disease that require brain MR imaging for eligibility assessment as well as for monitoring for amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities result from treatment-related loss of vascular integrity and may occur in 2 forms. Amyloid-related imaging abnormalities with edema or effusion are transient, treatment-induced edema or sulcal effusion, identified on T2-FLAIR. Amyloid-related imaging abnormalities with hemorrhage are treatment-induced microhemorrhages or superficial siderosis identified on T2* gradient recalled-echo. As monoclonal antibodies become more widely available, treatment screening and monitoring brain MR imaging examinations may greatly increase neuroradiology practice volumes. Radiologists must become familiar with the imaging appearance of amyloid-related imaging abnormalities, how to select an appropriate imaging protocol, and report findings in clinical practice. On the basis of clinical trial literature and expert experience from clinical trial imaging, we summarize imaging findings of amyloid-related imaging abnormalities, describe potential interpretation pitfalls, and provide recommendations for a standardized imaging protocol and an amyloid-related imaging abnormalities reporting template. Standardized imaging and reporting of these findings are important because an amyloid-related imaging abnormalities severity score, derived from the imaging findings, is used along with clinical status to determine patient management and eligibility for continued monoclonal antibody dosing., (© 2022 by American Journal of Neuroradiology.)

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 18 F-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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Importance: Detection of prion proteins in cerebrospinal fluid (CSF) using real-time quaking-induced conversion (RT-QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt-Jakob disease (CJD), facilitating earlier and more complete recognition of affected patients. It is unclear how expanded recognition of affected patients may affect the diagnostic and prognostic relevance of clinical features and diagnostic tests historically associated with CJD., Objective: To evaluate clinical features and diagnostic testing in patients presenting with CJD and determine the associations of these features with prognosis., Design, Setting, and Participants: This cohort study incorporated data from electronic medical records of patients with CJD treated at Mayo Clinic Enterprise tertiary care centers in Rochester, Minnesota; Jacksonville, Florida; and Scottsdale, Arizona. Participants included patients with definite or probable CJD assessed from 2014 to 2021. Data were analyzed October 2021 to January 2022., Exposures: Dominant presentation, clinical features, and diagnostic tests associated with CJD., Main Outcomes and Measures: The outcomes of interest were the sensitivity and prognostic value of clinical features and accessible diagnostic tests at presentation with possible CJD., Results: A total of 115 patients were identified, including 40 patients (35%) with definite CJD. Mean (SD) age at symptom onset was 64.8 (9.4) years, and 68 patients were women (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD was poor (eg, stereotyped electroencephalography anomalies: 17 of 105 patients [16%]; elevated CSF protein 14-3-3 levels: 54 of 90 patients [60%]). By comparison, biomarkers with good diagnostic sensitivity at presentation included RT-QuIC (66 of 71 patients [93%]), CSF total tau (T-tau) level greater than 1149 pg/mL (81 of 92 patients [88%]), and characteristic signal anomalies on magnetic resonance imaging (88 of 115 patients [77%]). Multivariable linear regression confirmed shorter survival in patients with myoclonus (difference, -125.9 [95% CI, -236.3 to -15.5] days; P = .03), visual or cerebellar signs (difference, -180.2 [95% CI, -282.2 to -78.2] days; P < .001), elevated CSF protein 14-3-3 levels (difference, -193 [95% CI, -304.9 to -82.9] days; P < .001), and elevated T-tau level (difference for every 1000 pg/mL elevation, -9.1 [95% CI, -17.7 to -1.0] days; P = .04)., Conclusions and Relevance: These findings suggest that CSF RT-QuIC, elevated CSF T-tau level, and stereotyped magnetic resonance imaging anomalies were associated with the diagnosis of CJD, while other clinical findings (eg, myoclonus), stereotyped electroencephalography anomalies, and CSF protein 14-3-3 levels offered less diagnostic value. Visual or cerebellar features, myoclonus, and CSF 14-3-3 and T-tau levels may be associated with disease duration, justifying continued inclusion in the evaluation of patients suspected to have CJD.

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted., (© 2022. The Author(s).)

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Preclinical Alzheimer's disease describes some individuals who harbour Alzheimer's pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer's-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies ( n  = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including APOE -ɛ4 and APOE -ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset ( n  = 808) where amyloid burden was assessed by Pittsburgh Compound B ([ 11 C]-PiB) positron emission tomography. In this study, we found that APOE -ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE -ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene ( P  = 1.46 × 10 -8 ; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset ( P  = 0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B , a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)