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Study objectivesFast frequency sleep spindles are reduced in aging and Alzheimer's disease (AD), but the mechanisms and functional relevance of these deficits remain unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD.MethodsFifty-eight cognitively unimpaired, β-amyloid-negative, older adults (mean ± SD; 61.4 ± 6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high-density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13 to

Background and objectivesTo determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsWe studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2-7.5 years). CSF was analyzed for Aβ40, Aβ42, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ42 and Aβ42/Aβ40 ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death.ResultsCSF biomarkers were associated with neuropathologic measures of Aβ (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/Aβ42 and Aβ42/Aβ40 ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95-0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD-TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants.DiscussionCSF biomarkers, including P-tau, T-tau, Aβ42, Aβ40, and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology.Classification of evidenceThis study provides Class II evidence that distinct CSF biomarker patterns, including for P-tau, T-tau, Aβ42, Aβ40, and NFL, are associated with AD and FTLD neuropathology.

Background: Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VSHET) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau). Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk. Methods: The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; MeanAge(SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; MeanAge(SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status. Results: A+ prevalence was lower in KL-VSHET (p = 0.05), with no differences in T + prevalence (p = 0.52). KL-VSHET also had marginally lower odds of being A + T- (p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40). Conclusions: KL-VSHET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Growing evidence suggests a role for neuroinflammation in Alzheimer's disease (AD). We investigated complement pathway activity in AD patient cerebrospinal fluid (CSF) and evaluated its modulation by the anti‐tau antibody semorinemab. METHODS: Immunoassays were applied to measure CSF complement proteins C4, factor B (FB), C3 and their cleavage fragments C4a, C3a, and factor Bb (Bb) in AD patients and a separate cognitively unimpaired (CU) cohort. RESULTS: All measured CSF complement proteins were increased in AD versus CU subjects, with C4a displaying the most robust increase. Finally, semorinemab did not have a significant pharmacodynamic effect on CSF complement proteins. DISCUSSION: Elevated levels of CSF C4a, C4, C3a, C3, Bb, and FB are consistent with complement activation in AD brains. Despite showing a reduction in CSF soluble tau species, semorinemab did not impact complement protein levels or activity. Further studies are needed to determine the value of complement proteins as neuroinflammation biomarkers in AD. Highlights: Cerebrospinal fluid (CSF) complement proteins C4a, C3a, Bb, C4, C3, and factor B levels were increased in Alzheimer's disease (AD) patients compared to a separate cognitively unimpaired (CU) cohort.Baseline CSF complement protein levels were correlated with neuro‐axonal degeneration and glial activation biomarkers in AD patients.The investigational anti‐tau antibody semorinemab did not impact CSF complement protein levels or activity relative to the placebo arm. [ABSTRACT FROM AUTHOR]

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 (Aβ) negative (−), CU Aβ positive (+), and CI Aβ+. 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 Aβ+ and CI Aβ+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aβ, 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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL‐VS variant (KL‐VS heterozygosity [KL‐VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin‐6 [IL‐6], S100 calcium‐binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase‐3‐like protein 1 [YKL‐40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α‐synuclein [α‐Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS: This Alzheimer disease risk‐enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate‐adjusted multivariate regression examined relationships between age (mean‐split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL‐VSHET (N = 122) and non‐carriers (KL‐VSNC; N = 332). RESULTS: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age‐stratified analyses, KL‐VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL‐6, S100B, Ng, and α‐Syn (Ps ≥ 0.13) in KL‐VSHET. Although age‐related differences in GFAP, sTREM2, and YKL‐40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL‐VSNC. DISCUSSION: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL‐VSHET. Highlights: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction.KLOTHO KL‐VS non‐carriers exhibit this same pattern, which is does not significantly differ between younger and older KL‐VS heterozygotes for interleukin‐6, S100 calcium‐binding protein B, neurogranin, and total α‐synuclein.Although age‐related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase‐3‐like protein 1 are evident for both KL‐VS groups, the magnitude of the effect is markedly stronger for KL‐VS non‐carriers.Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL‐VS heterozygotes. [ABSTRACT FROM AUTHOR]

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 Ab42/40 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 Ab42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Ab-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Ab42/40 and meta-memory persisted. In the SCD subset, higher Ab-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. [ABSTRACT FROM AUTHOR]

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 Aβ1–42/1–40 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 Aβ1–42/1–40 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 [ABSTRACT FROM AUTHOR]