Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment-data from the Dementia Competence Network.

ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.

Negative affective burden is associated with higher resting-state functional connectivity in subjective cognitive decline.

Subjective cognitive decline (SCD), as expressed by older adults, is associated with negative affect, which, in turn, is a likely risk factor for Alzheimer's Disease (AD). This study assessed the associations between negative affective burden, cognitive functioning, and functional connectivity in networks vulnerable to AD in the context of SCD. Older participants (60-90 years) with SCD (n = 51) and healthy controls (n = 50) were investigated in a cross-sectional study. Subclinical negative affective burden, quantified through a composite of self-reported negative affective factors, was related to cognitive functioning (self-perceived and objective) and functional connectivity. Seed-to-voxel analyses were carried out in default mode network (DMN) and salience network (SAL) nodes using resting-state functional magnetic resonance imaging. Greater negative affective burden was associated with lower self-perceived cognitive functioning and lower between-network functional connectivity of DMN and SAL nodes in the total sample. In addition, there was a significant moderation of SCD status. Greater negative affective burden related to higher functional connectivity within DMN (posterior cingulate-to-precuneus) and within SAL (anterior cingulate-to-insula) nodes in the SCD group, whereas in controls the inverse association was found. We show that negative affective burden is associated with functional brain alterations in older adults, regardless of SCD status. Specifically in the SCD phenotype, greater negative affective burden relates to higher functional connectivity within brain networks vulnerable to AD. Our findings imply that negative affective burden should be considered a potentially modifiable target for early intervention.

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial.

Importance: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. Objective: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. Design, Setting, and Participants: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. Interventions: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. Main Outcomes and Measures: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. Results: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. Conclusions and Relevance: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage. Trial Registration: ClinicalTrials.gov Identifier: NCT03094546.

Severity of Subjective Cognitive Complaints and Worries in Older Adults Are Associated With Cerebral Amyloid-ß Load.

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-ß) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-ß load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-ß, as well as regional amyloid-ß load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-ß load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-ß load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-ß load in the parietal cortex. Higher levels of worry were associated with higher amyloid-ß load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-ß burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.