Synaptic protein CSF levels relate to memory scores in individuals without dementia.

INTRODUCTION: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from EMIF-AD MBD and ADNI. For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these groups. DISCUSSION: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.

INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup.

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer's disease: a systematic review.

BACKGROUND: Clinical trials in Alzheimer's disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development. METHODS: We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01-01-2017 and 01-01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type. RESULTS: We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aß (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers. CONCLUSIONS: As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Social cognition differentiates phenocopy syndrome of behavioural variant frontotemporal dementia from behavioural variant frontotemporal dementia.

BACKGROUND: Patients displaying clinical features of behavioural variant of frontotemporal dementia (bvFTD) but lacking both neuroimaging abnormalities and clinical progression are considered to represent the phenocopy syndrome of bvFTD (phFTD). Extensive clinical overlap between early phase bvFTD and phFTD hampers diagnostic distinction. We aimed to assess the diagnostic value of clinician-rated, self-reported and caregiver-reported symptoms for clinical distinction between phFTD and bvFTD. METHODS: There were 33 phFTD and 95 probable bvFTD patients included in the study (total N = 128). Clinician-rated, self-reported tests and caregiver-reported symptoms were compared between phFTD and bvFTD on social cognition, behaviour, mood and activities of daily living (ADL). Scores were compared between groups, followed by multiple logistic regression analysis, adjusted for age and sex. Receiver operating characteristic curves were plotted to assess diagnostic value. RESULTS: Using clinician-rated and self-reported tests, phFTD patients performed better on facial emotion recognition and reported more depressive symptoms. Caregiver-reported behavioural symptoms indicated higher behavioural and ADL impairment in phFTD compared to bvFTD. Facial emotion recognition provided highest diagnostic accuracy for distinction of phFTD from bvFTD (area under the curve (AUC) 0.813 95% CI 0.735-0.892, P < 0.001, sensitivity 81%, specificity 74%) followed by depressive symptoms (AUC 0.769 95% 0.674-0.864, P < 0.001 sensitivity 81%, specificity of 63%). CONCLUSION: Social cognition tests are most suitable for distinction of phFTD from bvFTD. Caregiver-reported questionnaires and phFTD diagnosis seemed inversely correlated, showing more symptoms in phFTD. Further research is needed on phFTD aetiology and in caregivers taking into account disease burden to assess what explains this discrepancy between clinician-rated and caregiver-based tools.

Biomarker-based staging of Alzheimer disease: rationale and clinical applications.

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-ß and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications.

Plasma oligomer beta-amyloid is associated with disease severity and cerebral amyloid deposition in Alzheimer's disease spectrum.

BACKGROUND: Multimer detection system-oligomeric amyloid-ß (MDS-OAß) is a measure of plasma OAß, which is associated with Alzheimer's disease (AD) pathology. However, the relationship between MDS-OAß and disease severity of AD is not clear. We aimed to investigate MDS-OAß levels in different stages of AD and analyze the association between MDS-OAß and cerebral Aß deposition, cognitive function, and cortical thickness in subjects within the AD continuum. METHODS: In this cross-sectional study, we analyzed a total 126 participants who underwent plasma MDS-OAß, structural magnetic resonance image of brain, and neurocognitive measures using Korean version of the Consortium to Establish a Registry for Alzheimer's Disease, and cerebral Aß deposition or amyloid positron emission tomography (A-PET) assessed by [18F] flutemetamol PET. Subjects were divided into 4 groups: N = 39 for normal control (NC), N = 31 for A-PET-negative mild cognitive impairment (MCI) patients, N = 30 for A-PET-positive MCI patients, and N = 22 for AD dementia patients. The severity of cerebral Aß deposition was expressed as standard uptake value ratio (SUVR). RESULTS: Compared to the NC (0.803 ± 0.27), MDS-OAß level was higher in the A-PET-negative MCI group (0.946 ± 0.137) and highest in the A-PET-positive MCI group (1.07 ± 0.17). MDS-OAß level in the AD dementia group was higher than in the NC, but it fell to that of the A-PET-negative MCI group level (0.958 ± 0.103). There were negative associations between MDS-OAß and cognitive function and both global and regional cerebral Aß deposition (SUVR). Cortical thickness of the left fusiform gyrus showed a negative association with MDS-OAß when we excluded the AD dementia group. CONCLUSIONS: These findings suggest that MDS-OAß is not only associated with neurocognitive staging, but also with cerebral Aß burden in patients along the AD continuum.

Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease.

OBJECTIVES: Higher-educated patients with Alzheimer disease (AD) can harbor greater neuropathologic burden than those with less education despite similar symptom severity. In this study, we assessed whether this observation is also present in potential preclinical AD stages, namely in individuals with subjective cognitive decline and clinical features increasing AD likelihood (SCD+). METHODS: Amyloid-PET information ([18F]Flutemetamol or [18F]Florbetaben) of individuals with SCD+, mild cognitive impairment (MCI), and AD were retrieved from the AMYPAD-DPMS cohort, a multicenter randomized controlled study. Group classification was based on the recommendations by the SCD-I and NIA-AA working groups. Amyloid PET images were acquired within 8 months after initial screening and processed with AMYPYPE. Amyloid load was based on global Centiloid (CL) values. Educational level was indexed by formal schooling and subsequent higher education in years. Using linear regression analysis, the main effect of education on CL values was tested across the entire cohort, followed by the assessment of an education-by-diagnostic-group interaction (covariates: age, sex, and recruiting memory clinic). To account for influences of non-AD pathology and comorbidities concerning the tested amyloid-education association, we compared white matter hyperintensity (WMH) severity, cardiovascular events, depression, and anxiety history between lower-educated and higher-educated groups within each diagnostic category using the Fisher exact test or χ2 test. Education groups were defined using a median split on education (Md = 13 years) in a subsample of the initial cohort, for whom this information was available. RESULTS: Across the cohort of 212 individuals with SCD+ (M(Age) = 69.17 years, F 42.45%), 258 individuals with MCI (M(Age) = 72.93, F 43.80%), and 195 individuals with dementia (M(Age) = 74.07, F 48.72%), no main effect of education (ß = 0.52, 95% CI -0.30 to 1.58), but a significant education-by-group interaction on CL values, was found (p = 0.024) using linear regression modeling. This interaction was driven by a negative association of education and CL values in the SCD+ group (ß = -0.11, 95% CI -4.85 to -0.21) and a positive association in the MCI group (ß = 0.15, 95% CI 0.79-5.22). No education-dependent differences in terms of WMH severity and comorbidities were found in the subsample (100 cases with SCD+, 97 cases with MCI, 72 cases with dementia). DISCUSSION: Education may represent a factor oppositely modulating subjective awareness in preclinical stages and objective severity of ongoing neuropathologic processes in clinical stages.

European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders.

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.

Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study.

BACKGROUND: Apolipoprotein-E (APOE) genetic testing for Alzheimer's disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one's genetic risk for Alzheimer's disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment. METHODS: An online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran's Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios. RESULTS: Most participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77-89%), would participate in medication trials (79-88%), and would make long-term arrangements, e.g. retirement, health care, will (69-82%), with larger proportions for scenarios with higher hypothetical genetic risk. CONCLUSIONS: Our findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.

Virtual neural network-guided optimization of non-invasive brain stimulation in Alzheimer's disease.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with potential for counteracting disrupted brain network activity in Alzheimer's disease (AD) to improve cognition. However, the results of tDCS studies in AD have been variable due to different methodological choices such as electrode placement. To address this, a virtual brain network model of AD was used to explore tDCS optimization. We compared a large, representative set of virtual tDCS intervention setups, to identify the theoretically optimized tDCS electrode positions for restoring functional network features disrupted in AD. We simulated 20 tDCS setups using a computational dynamic network model of 78 neural masses coupled according to human structural topology. AD network damage was simulated using an activity-dependent degeneration algorithm. Current flow modeling was used to estimate tDCS-targeted cortical regions for different electrode positions, and excitability of the pyramidal neurons of the corresponding neural masses was modulated to simulate tDCS. Outcome measures were relative power spectral density (alpha bands, 8-10 Hz and 10-13 Hz), total spectral power, posterior alpha peak frequency, and connectivity measures phase lag index (PLI) and amplitude envelope correlation (AEC). Virtual tDCS performance varied, with optimized strategies improving all outcome measures, while others caused further deterioration. The best performing setup involved right parietal anodal stimulation, with a contralateral supraorbital cathode. A clear correlation between the network role of stimulated regions and tDCS success was not observed. This modeling-informed approach can guide and perhaps accelerate tDCS therapy development and enhance our understanding of tDCS effects. Follow-up studies will compare the general predictions to personalized virtual models and validate them with tDCS-magnetoencephalography (MEG) in a clinical AD patient cohort.

What's in a score: A longitudinal investigation of scores based on item response theory and classical test theory for the Amsterdam Instrumental Activities of Daily Living Questionnaire in cognitively normal and impaired older adults.

OBJECTIVE: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. METHOD: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. RESULTS: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = -0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = -0.15, 95% confidence interval, 95% CI [-0.28, -0.03], effect size = -0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [-0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. CONCLUSIONS: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study.

BACKGROUND: The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. METHODS: Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. RESULTS: 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (ß = - 0.22, OR = 0.80, p < .05), more prior study visits (ß = - 0.93, OR = 0.40, p < .001), and positive family history of dementia (ß = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PCresearch = 27.4%, PCclinical = 9.0%, X2 = 10.56, p = .001), and loss of research interest (PCclinical = 46.3%, PCresearch = 16.5%, X2 = 32.34, p < .001). CONCLUSIONS: The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site.

Plasma Oligomer ß-Amyloid and White Matter Microstructural Integrity in Cognitively Normal Older Adults According to Cerebral Amyloid Deposition.

BACKGROUND: Multimer detection system-oligomeric amyloid-ß (MDS-OAß) measure plasma OAß level, which is associated with earlier Alzheimer's disease (AD) pathology. However, no study has investigated MDS-OAß differences in cognitive normal older adults (CN) with or without cerebral Aß burden and its correlation with Aß deposition and white matter (WM) integrity. OBJECTIVE: To investigate associations among cerebral Aß burden, MDS-OAß, and WM integrity in CN. DESIGN: This is a single center, cross-sectional study which used data from Catholic Aging Brain Imaging (CABI) database. SETTING: CABI database contains brain scans of patients who visited the outpatient clinic at Catholic Brain Health Center, Yeouido St. Mary's Hospital, The Catholic University of Korea, between 2017 and 2022. PARTICIPANTS: A total 34 amyloid-PET negative CN and 23 amyloid-PET positive CN were included. MEASUREMENTS: Plasma Aß level using MDS-OAß, cerebral Aß deposition level using global standardized uptake value ratio (SUVR) values, WM integrity using fractional anisotropy (FA) and mean diffusivity (MD), and cortical thickness from structural MRI were utilized. RESTULS: The amyloid-PET positive group showed higher MDS-OAß level than the amyloid-PET negative group (0.997 ± 0.19 vs. 0.79 ± 0.28, P <0.005), but they did not differ in WM integrity or cortical thickness. The MDS-OAß positive group showed higher global cerebral Aß deposition or mean global SUVR values (0.609 ± 0.135 vs. 0.533 ± 0.121 vs. P <0.05), lower regional FA of left forceps minor and the right superior longitudinal fasciculus (family-wise error rate, p <0.05), and lower cortical thickness of left fusiform (p <0.05, Monte Carlo simulation) than the MDS-OAß negative group. MDS-OAß was positively associated with global cerebral Aß deposition (r=0.278, P <0.05) and negatively associated (r = - 0.324, P < 0.05) with regional WM integrity. CONCLUSIONS: In this study, MDS-OAß value demonstrated earlier and different AD pathology than cerebral Aß retention according to amyloid-PET. Longitudinal studies are needed to elucidate the causal relationships of plasma OAß and cerebral Aß with WM integrity disturbance and cortical atrophy during the AD trajectory.

Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.

BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (ß-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. METHODS: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). RESULTS: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (ß = -0.52, CI -0.74 to -0.30, p < 0.001) and participants with AD (ß = -0.30, CI -0.58 to -0.02, p = 0.04). DISCUSSION: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline.

Neurophysiological alterations in mice and humans carrying mutations in APP and PSEN1 genes.

BACKGROUND: Studies in animal models of Alzheimer's disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction. Whether and how AD-related neurophysiological alterations translate between mice and humans remains however uncertain. METHODS: We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early pre-symptomatic changes. Longitudinal local field potential recordings were performed in APP/PS1 mice and cross-sectional magnetoencephalography recordings in human APP and/or PSEN1 mutation carriers. All recordings were acquired in the left frontal cortex, parietal cortex, and hippocampus. Spectral power and functional connectivity were analyzed and compared with wildtype control mice and healthy age-matched human subjects. RESULTS: APP/PS1 mice showed increased absolute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 moa. Relative power showed an overall shift from lower to higher frequencies over almost the entire recording period and across all three brain regions. Human mutation carriers, on the other hand, did not show changes in power except for an increase in relative theta power in the hippocampus. Mouse parietal cortex and hippocampal power spectra showed a characteristic peak at around 8 Hz which was not significantly altered in transgenic mice. Human power spectra showed a characteristic peak at around 9 Hz, the frequency of which was significantly reduced in mutation carriers. Significant alterations in functional connectivity were detected in theta, alpha, beta, and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers. CONCLUSIONS: Both mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one-to-one between species. Alterations in absolute and relative power in mice should be interpreted with care and may be due to overexpression of amyloid in combination with the absence of tau pathology and cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models, for instance, those also including tau pathology, provide better translation to the human AD continuum.