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.

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.

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.

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.

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.

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.

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.

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.