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Summary: 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. [ABSTRACT FROM AUTHOR]

Objective: To estimate the test-retest and inter-rater reliability of the new Spanish abbreviated version of the Luria Neuropsychological Diagnosis (DNA-2) battery for older adults. Method: A total of thirty cognitively healthy volunteers were examined in this study. The participants completed a comprehensive standardized assessment, encompassing cognitive and functional performance. Intraclass correlation coefficients (ICC) were used to examine test-retest and inter-rater reliability. One month was allowed between administrations. Furthermore, correlations between Luria DNA-2 (total and domain subscores) and other classical cognitive measures were explored. Results: The test-retest reliability on the overall Luria DNA-2 score was high (ICC=.834, 95% CI [.680,.917], p <.001). Furthermore, the inter-rater reliability for the total score demonstrated an excellent concordance between administrators (ICC=.990, 95% CI [.979,.995], p <.001). Positive and significant correlations were observed between Luria DNA-2 (both total and domain subscores) and the Addenbrooke's Cognitive Examination (ACE-III; ρ =.857, p <.001). Conclusions: This study supports the adequate reliability of the Luria DNA-2, as an abbreviated neuropsychological battery, for assessing cognitive performance in Spaniards aged 55 years and older. Future studies should continue to explore the psychometric properties of the Luria DNA-2, particularly those related to its diagnostic validity for early detection of cognitive impairment. [ABSTRACT FROM AUTHOR]

Dementia remains an underdiagnosed syndrome, and there is a need to improve the early detection of cognitive decline. This narrative review examines the role of neuropsychological assessment in the characterization of cognitive changes associated with dementia syndrome at different states. The first section describes the early indicators of cognitive decline and the major barriers to their identification. Further, the optimal cognitive screening conditions and the most widely accepted tests are described. The second section analyzes the main differences in cognitive performance between Alzheimer's disease and other subtypes of dementia. Finally, the current challenges of neuropsychological assessment in aging/dementia and future approaches are discussed. Essentially, we find that current research is beginning to uncover early cognitive changes that precede dementia, while continuing to improve and refine the differential diagnosis of neurodegenerative disorders that cause dementia. However, neuropsychology faces several barriers, including the cultural diversity of the populations, a limited implementation in public health systems, and the adaptation to technological advances. Nowadays, neuropsychological assessment plays a fundamental role in characterizing cognitive decline in the different stages of dementia, but more efforts are needed to develop harmonized procedures that facilitate its use in different clinical contexts and research protocols. [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]

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 populationThe ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOEAD genetic profiles in ALFA are similar to clinical groups along the continuumALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD riskALFA is well suited to study pathogenic events/early pathophysiological changes in AD [ABSTRACT FROM AUTHOR]

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 (Aβ)42/40 was associated with Aβ 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 Aβ42/40 and Aβ‐PET, and CSF YKL‐40 partly explained the association between Aβ‐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 Aβ, CSF YKL‐40 mediates the latter association between Aβ and downstream Aβ‐induced tau pathology and tau‐induced neuronal injury. Highlights: Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations.Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ.CSF YKL‐40 mediated Aβ‐induced tau phosphorylation and tau‐induced neuronal injury. [ABSTRACT FROM AUTHOR]

Background: Cognitively unimpaired (CU) adults with Alzheimer's disease (AD) pathologic change may be more vulnerable to developing neuropsychiatric symptoms. We reported an association of higher β‐amyloid (Aβ) and increased anxiety/depression during the COVID‐19 lockdown in CU adults (Akinci et al., 2022). Here, we investigated whether changes in Aβ1−42 predict post‐traumatic stress disorder (PTSD) symptomatology following COVID‐19 lockdown in CU adults at risk for AD. Method: We included 128 CU participants who underwent lumbar puncture 2.3±0.6 years before and 1.1±0.4 years after the lockdown. The outcome of interest was self‐reported PTSD symptomatology (Impact of Event Scale Revised) measured 1.7±0.1 years after the lockdown. The main predictor was annual rate of change in cerebrospinal fluid (CSF) Aβ1−42 measured with the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Other predictors included sex, age, years of education, stressors during COVID‐19, and anxiety/depression (Hospital Anxiety and Depression Scale, HADS) and perceived stress (Perceived Stress Scale, PSS) measured during lockdown. We performed regression analyses to explore the association between annual rate of change in Aβ1‐42 with PTSD scores adjusting for demographic and stressor variables, and further adjusting for HADS and PSS scores. We then explored the mediating effect of HADS and PSS on the association between change in Aβ1‐42 and PTSD scores. Result: Participant age ranged from 53−72 and 59% were women (Table 1). Independent of demographic variables and stressors experienced during COVID‐19, the rate of annual change in Aβ1‐42 predicted PTSD scores (p =.008; Table 2). This association attenuated after introducing HADS and PSS scores into the model (p =.066). We found full mediation effects of HADS and PSS scores, explaining 46% and 40% of the effect of annual change in Aβ1‐42 on PTSD scores, respectively (Figure 1). Conclusion: CU older adults with longitudinal CSF Aβ1−42 increases are more vulnerable to developing PTSD symptomatology after a stressful event, such as the pandemic. Anxiety/depression is one plausible mechanism through which increases in Aβ might exacerbate PTSD symptomatology. The results suggest a window for stress regulation during stressful events to prevent further mental health worsening in people at risk for AD. [ABSTRACT FROM AUTHOR]

Background: Air pollution is associated with cognitive performance, risk for AD and may accelerate biological aging. Biological aging due to telomere shortening has been associated with cognitive impairment. However, few studies have looked at the link between air pollution, telomere length, and cognitive performance among sexes. In this study, we investigated the joint effect of sex, air pollution, and leukocyte telomere length (LTL), on cognitive performance in cognitively unimpaired (CU) individuals at risk of AD. Method: The study included 1,472 middle‐aged CU adults with increased risk of AD from the ALFA study [Table 1]. Residential exposure to air pollutants including nitrogen dioxide (NO2) and particulate matter (PM2.5, PM10) was estimated by land use regression models. LTL was determined by qPCR from DNA extracted from peripheral blood leukocytes. LTL was residualized against chronological age and sex (rLTL). A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing and executive function. Further, episodic memory (EM), executive function and Preclinical Alzheimer Cognitive Composite (PACC) composites were calculated by averaging normalized raw scores of the subtests. Models were corrected by chronological age, years of education and APOE‐ε4 status. Sex‐specific effects were investigated by adjusting interaction models. Result: There was no overall effect of neither rLTL nor air pollution on cognitive performance, but crossover interactions with sex were found. Exposure to higher levels of NO2 and PM2.5 were associated with worse EM only in men [Figure 1]. Three‐way interaction models revealed longer rLTL and lower levels of air pollution were associated with better performance on PACC (for PM2.5, PM10 and NO2) and EM (for PM10 and NO2) among men. In women, these associations were only observed at higher exposure levels of air pollution [Figure 2]. Conclusion: The results show that lower levels of air pollution allow for the protective effect of rLTL on cognitive performance only in men for whom air pollution had a stronger negative impact. In women, the results show different mechanisms through which air pollution and rLTL affect cognitive performance. Further analyses will be conducted to gain insight into the observed effects. [ABSTRACT FROM AUTHOR]

Background: In this study, we evaluated the association between tau PET and fluid biomarkers and explored biological mechanisms associated with elevated tau in cognitively unimpaired(CU) individuals. Method: Seventy‐nine CU individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted MRI, CSF and plasma biomarkers. Longitudinal changes in cognition were measured using cognition composites(Table1). Participants were categorized into AT stages using CSF biomarkers and pre‐established cut‐offs(Table 1). [18F]RO‐948 SUVR was measured in entorhinal(BraakI/II), limbic(BraakIII/IV), and neocortical(BraakV/VI) regions using the inferior cerebellum as reference. Regional positivity thresholds per Braak region were calculated as mean+2SD of the A‐T‐ group. [18F]flutemetamol PET scans were quantified in Centiloids(CL). Associations between [18F]RO‐948 SUVRs and AD biomarkers (Figure1) were assessed using Pearson correlations. Receiver Operating Curve(ROC) analyses were conducted to determine the capacity of biomarkers to predict BraakI/II positivity. In those with CL>cut‐off for tau‐PET positivity, differences in non‐core AD fluid biomarkers(Figure2) and longitudinal cognition were sought between tau BraakI/II positive and negative individuals. The mediating effect of non‐core AD biomarkers on the AD pathophysiological cascade were sought. FDR‐corrected p‐values<0.05 were considered significant. Result: Nine cases(11.4%) were positive in BraakI/II. Following a hierarchical pattern, four of them were also positive for BraakIII/IV and one for BraakV/VI. Fluid biomarkers presented correlations with tau PET SUVR in all Braak stages (Figure1) and predictive capacity for tau‐PET positivity in BraakI/II(Table2). In individuals with CL>32.53, BraakI/II positives had higher levels of CSF‐GFAP(p<0.01) and CSF‐NFL(p = 0.03), and presented declines in PACC and in visual, attention, and memory composites (Figure1). CSF‐GFAP partially mediated the association between CL and tau‐PET (16%) and between tau‐PET and CSF‐NfL (30%). Conclusion: Early in the AD continuum, [18F]RO‐948 PET conformed to the Braak hierarchical model. CSF and plasma biomarkers showed moderate associations with tau PET SUVR but good capacity to predict tau PET positivity in BraakI/II. Tau‐PET positivity in this region was associated with higher astrogliosis, neurodegeneration and cognitive decline as compared to tau‐PET negatives with similar levels of amyloid deposition. Astrogliosis partially explained the observed associations between amyloid deposition and the presence of tau tangles in medial temporal regions and, even strongly, between the latter and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies show that multiparity (≥3 children) is associated with a higher risk of clincal AD in cognitively unimpaired (CU) women. However, studies exploring the impact of parity on AD biomarkers are scarce. We explored the association between number of children and imaging and fluid AD biomarkers, and the related interaction with neurodegeneration and cognition. Method: We included 210 CU parous women from the ALFA+ cohort with 34 nulliparous women and 152 men with children as controls. The number of children was dichotomized as <3 children vs ≥3 children. All CSF biomarkers were measured using the Roche NeuroToolKit and Elecsys® immunoassays (both Roche Diagnostics International Ltd), except p‐tau231 and GAP‐43 (ELISA). All plasma biomarkers were measured using the Simoa HD‐X (Quanterix Corp) except sICAM1 (MSD). Jack's cortical thickness AD signature was used as a marker of neurodegeneration. Cognitive change (3‐year follow‐up) was measured with a PACC‐like composite as well as for individual cognitive domains. Biomarkers differences between parity groups were analyzed with ANCOVA adjusted by age. Independent linear models with biomarkers, AD signature and cognitive change as dependent variable were constructed. The number of children was set as predictor, and age, APOE‐ε4, and age at first birth as covariates in all models. Interaction terms between number of children and biomarkers were modeled. p‐values <0.05 were considered as significant. Result: Several biomarkers were significantly higher in grand multiparours women (Table 1). Linear regression results (Table 2, Fig. 1A) showed that multiparity was associated with higher CSF p‐tau181 levels. Moreover, multiparity interacted with CSF p‐tau181 to predict thinner cortical thickness in AD‐sensitive regions and a steeper decline in executive function (Table 2, Fig. 1B & 1C). No significant associations in men and nulliparous women were found. Conclusion: Having ≥3 children increases the risk of higher CSF p‐tau181 levels in CU middle‐aged women, with CSF p‐tau181 having a more deleterious effect on cortical thickness and change on executive function performance. These findings contribute to our understanding of the higher risk for AD observed in CU multiparous women, who show higher susceptibility and more adverse downstream consequences to tau pathology. [ABSTRACT FROM AUTHOR]