Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology.

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aß42/40, p-tau181, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [18F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, using False Discovery Rate to correct for multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau181 with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials.

CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease.

INTRODUCTION: We examined whether baseline glial markers soluble triggering receptor expressed on myeloid cell 2 (sTREM2), chitinase 3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF), and plasma GFAP are associated with cognitive change in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD). METHODS: A total of 353 CU (mean age 60.9 years) participants were included (mean follow-up time 3.28 years). Linear regression models with cognition as outcome were used. We also tested whether amyloid beta (Aß) status modified these associations. RESULTS: Higher baseline CSF sTREM2 was associated with a positive global cognition (Preclinical Alzheimer's Cognitive Composite) rate of change, and better memory and executive outcomes, independently of AD pathology. Higher baseline plasma GFAP was associated with a decline on attention rate of change. Stratified analyses by Aß status showed that CSF sTREM2 and YKL-40 were positively associated with executive functioning in amyloid negative (Aß-) individuals. DISCUSSION: Our results suggest that a TREM2-mediated microglial response may be associated with better longitudinal cognitive performance. HIGHLIGHTS: Higher cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cell 2 (sTREM2) relates to better longitudinal cognitive performance. The association between CSF sTREM2 and cognition is independent of Alzheimer's disease (AD) pathology. Targeting microglial reactivity may be a therapeutic strategy for AD prevention.

Omega-3 blood biomarkers relate to brain glucose uptake in individuals at risk of Alzheimer's disease dementia.

INTRODUCTION: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake. METHODS: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). RESULTS: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants. DISCUSSION: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia. Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega-3 from marine and plant sources.Foods rich in omega-3 might be useful in early features of AD.

Time-encoded ASL reveals lower cerebral blood flow in the early AD continuum.

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aß) negative (-), CU Aß positive (+), and CI Aß+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te-ASL was more sensitive at detecting CBF reduction in the CU Aß+ and CI Aß+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aß, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD. HIGHLIGHTS: Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration.

Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum.

Introduction: The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum. Methods: We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aß42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis. Results: CSF Aß42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aß-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aß42/40 and meta-memory persisted. In the SCD subset, higher Aß-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance. Discussion: These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.

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.

Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort.

OBJECTIVE: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. METHODS: This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and Aß1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. RESULTS: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aß1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. INTERPRETATION: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068.

The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study.

BACKGROUND: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. METHODS: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid ß-amyloid (Aß)42 and Aß40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaßeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aß-negative and Aß-positive individuals. FINDINGS: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aß-positive and 194 as Aß-negative. In Aß-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aß-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aß-positive group. INTERPRETATION: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aß-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. FUNDING: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

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.

Atypical cortical hierarchy in Aß-positive older adults and its reflection in spontaneous speech.

Abnormal deposition of Aß amyloid is an early neuropathological marker of Alzheimer's disease (AD), arising long ahead of clinical symptoms. Non-invasive measures of associated early neurofunctional changes, together with easily accessible behavioral readouts of these changes, could be of great clinical benefit. We pursued this aim by investigating large-scale cortical gradients of functional connectivity with functional MRI, which capture the hierarchical integration of cortical functions, together with acoustic-prosodic features from spontaneous speech, in cognitively unimpaired older adults with and without Aß positivity (total N = 188). We predicted distortions of the cortical hierarchy associated with prosodic changes in the Aß + group. Results confirmed substantially altered cortical hierarchies and less variability in these in the Aß + group, together with an increase in quantitative prosodic measures, which correlated with gradient variability as well as digit span test scores. Overall, these findings confirm that long before the clinical stage and objective cognitive impairment, increased risk of cognitive decline as indexed by Aß accumulation is marked by neurofunctional changes in the cortical hierarchy, which are related to automatically extractable speech patterns and alterations in working memory functions.

Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression.

INTRODUCTION: We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. METHODS: We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. RESULTS: Cerebrospinal fluid (CSF) amyloid beta (Aß)42/40 was associated with Aß aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aß42/40 and Aß-PET, and CSF YKL-40 partly explained the association between Aß-PET, p-tau181 , and NfL. DISCUSSION: Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aß, CSF YKL-40 mediates the latter association between Aß and downstream Aß-induced tau pathology and tau-induced neuronal injury. HIGHLIGHTS: Lower CSF Aß42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aß and insoluble Aß. CSF YKL-40 mediated Aß-induced tau phosphorylation and tau-induced neuronal injury.

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum.

INTRODUCTION: In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions. METHODS: We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD. DISCUSSION: It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Risk of cognitive decline progression is associated to increased blood-brain-barrier permeability: A longitudinal study in a memory unit clinical cohort.

INTRODUCTION: This study examined the relationship between blood-brain-barrier permeability (BBBp), measured by cerebrospinal fluid/serum albumin ratio (QAlb), and cognitive decline progression in a clinical cohort. METHODS: This prospective observational study included 334 participants from the BIODEGMAR cohort. Cognitive decline progression was defined as an increase in Global Deterioration Scale and/or Clinical Dementia Rating scores. Associations between BBBp, demographics, and clinical factors were explored. RESULTS: Male sex, diabetes mellitus, and cerebrovascular burden were associated with increased log-QAlb. Vascular cognitive impairment patients had the highest log-QAlb levels. Among the 273 participants with valid follow-up data, 154 (56.4%) showed cognitive decline progression. An 8% increase in the hazard of clinical worsening was observed for each 10% increase in log-QAlb. DISCUSSION: These results suggest that increased BBBp in individuals with cognitive decline may contribute to clinical worsening, pointing to potential targeted therapies. QAlb could be a useful biomarker for identifying patients with a worse prognosis.

Memory performance mediates subjective sleep quality associations with cerebrospinal fluid Alzheimer's disease biomarker levels and hippocampal volume among individuals with mild cognitive symptoms.

Sleep disturbances are prevalent in Alzheimer's disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross-sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non-significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory-impaired populations, emphasising the importance of complementing subjective measures with objective assessments.

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.

Reference Data for Attentional, Executive, Linguistic, and Visual Processing Tests Obtained from Cognitively Healthy Individuals with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels.

BACKGROUND: Conventional neuropsychological norms likely include cognitively unimpaired (CU) individuals with preclinical Alzheimer's disease (AD) pathology (amyloid-ß, tau, and neurodegeneration) since they are based on cohorts without AD biomarkers data. Due to this limitation, population-based norms would lack sensitivity for detecting subtle cognitive decline due to AD, the transitional stage between healthy cognition and mild cognitive impairment. We have recently published norms for memory tests in individuals with normal cerebrospinal fluid (CSF) AD biomarker levels. OBJECTIVE: The aim of the present study was to provide further AD biomarker-based cognitive references covering attentional, executive function, linguistic, and visual processing tests. METHODS: We analyzed 248 CU individuals aged between 50-70 years old with normal CSF Aß, p-tau, and neurodegeneration (t-tau) biomarker levels. The tests included were the Trail Making Test (TMT), Semantic Fluency Test, Digit and Symbol Span, Coding, Matrix Reasoning, Judgement of Line Orientation and Visual Puzzles. Normative data were developed based on regression models adjusted for age, education, and sex when needed. We present equations to calculate z-scores, the corresponding normative percentile tables, and online calculators. RESULTS: Age, education, and sex were associated with performance in all tests, except education for the TMT-A, and sex for the TMT-B, Coding, and Semantic Fluency. Cut-offs derived from the current biomarker-based reference data were higher and more sensitive than standard norms. CONCLUSION: We developed reference data obtained from individuals with evidence of non-pathologic AD biomarker levels that may improve the objective characterization of subtle cognitive decline in preclinical AD.

Differential effects of sleep on brain structure and metabolism at the preclinical stages of AD.

INTRODUCTION: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self-reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals. METHODS: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel-wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status. RESULTS: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self-reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages. DISCUSSION: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD-related neurodegeneration in areas involved in sleep-wake regulation may induce or worsen sleep disturbances. Highlights Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology. Poor sleep exacerbates brain changes observed in preclinical AD. Sleep is an appealing therapeutic strategy for preventing AD.

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial.

Importance: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. Objective: To assess the clinical effect of amyloid PET in memory clinic patients. Design, Setting, and Participants: The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023. Intervention: Amyloid PET. Main Outcome and Measure: The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months. Results: A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001). Conclusion and Relevance: In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients. Trial Registration: EudraCT Number: 2017-002527-21.

NEURONORMA Cognitive Battery Associations with Cerebrospinal Fluid Amyloid-ß and Tau Levels in the Continuum of Alzheimer's Disease.

BACKGROUND: Neuropsychological assessments are essential to define the cognitive profile and contribute to the diagnosis of Alzheimer's disease (AD). The progress in knowledge about the pathophysiological process of the disease has allowed conceptualizing AD through biomarkers as a biological continuum that encompasses different clinical stages. OBJECTIVE: To explore the association between cerebrospinal fluid (CSF) biomarkers of AD and cognition using the NEURONORMA battery, in a sample of cognitively unimpaired (CU), mild cognitive impaired (MCI), and mild dementia of the Alzheimer type (DAT) subjects, and to characterize the cognitive profiles in MCI subjects classified by A/T/N system. METHODS: 42 CU, 35 MCI, and 35 mild DAT were assessed using the NEURONORMA battery. Core AD biomarkers [amyloid-ß42 (Aß42) peptide, total tau (t-tau), and phosphorylated tau 181 (p-tau181)] proteins were measured in CSF. Correlation coefficients, multivariate regression, and effect sizes were calculated. We explored the age- and education-adjusted cognitive profiles by A/T/N variants within the MCI group. RESULTS: Cognitive outcomes were directly associated with CSF Aß42 and inversely with CSF tau measures. We found differences in both biomarkers and cognitive outcomes comparing all pairs except for CSF measures between cognitively impaired groups. The highest effect size was in memory tasks and biomarkers ratios. Lower performances were in memory and executive domains in MCI subjects with AD pathology (A+T+N±) compared to those with normal levels of AD biomarkers (A- T- N). CONCLUSION: This study provides further evidence of the validity of Spanish NEURONORMA cognitive battery to characterize cognitive impairment in the AD pathological continuum.

Dementia prevention in memory clinics: recommendations from the European task force for brain health services.

Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence supports the efficacy of preventive interventions on persons with intact cognition and high dementia risk. We report recommendations for the deployment of second-generation memory clinics (Brain Health Services) whose mission is evidence-based and ethical dementia prevention in at-risk individuals. The cornerstone interventions consist of (i) assessment of genetic and potentially modifiable risk factors including brain pathology, and risk stratification, (ii) risk communication with ad-hoc protocols, (iii) risk reduction with multi-domain interventions, and (iv) cognitive enhancement with cognitive and physical training. A roadmap is proposed for concept validation and ensuing clinical deployment.