Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844–852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures—approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomes.

Importance: The strongest genetic risk factor for AD, the apolipoprotein E (APOE) gene, has a stronger association among females compared to males. Yet, limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. Objective: Evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, Participants: This meta-analysis selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals, and included population based and clinic based samples. Inclusion in our analysis required APOE genotype data and either CSF data (n=1798, 48% female, 13% AD, 94% Caucasian, 70±9 years) or autopsy data (n=5,109, 56% female, 97% Caucasian, 84±9 years) available for analysis. Main Outcome and Measures: Biomarker analyses included levels of Aβ−42, total tau (t-tau), and phosphorylated tau (p-tau) measured in CSF. Autopsy analyses included CERAD staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results: After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF t-tau (β=0.41 [95% CI: 0.27, 0.55], p<0.001) and p-tau (β=0.24 [0.09, 0.38], p=0.001), whereby APOE showed a stronger association among females compared to males. Post hoc analyses suggested this sex difference was present in amyloid positive individuals (β=0.41 [0.20, 0.62], p<0.001), but not among amyloid negative individuals (β=0.06 [−0.18, 0.31], p=0.62). We did not observe sex differences in the association between APOE and Aβ−42, neuritic plaque burden, or neurofibrillary tangle burden. Conclusions and Relevance: We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among females compared to males across multiple independent datasets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau, and the lack of a sex difference in the association with neurofibrillary tangles at autopsy, suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

Objective The objective of this study was to compare whether different sources of cognitive complaint (i.e., subjective and informant) predict diagnostic conversion in nondemented older adults. Methods Participants from the National Alzheimer’s Coordinating Center had a baseline diagnosis of normal cognition (NC; n=4414, 73±8 years, 69% female) or mild cognitive impairment (MCI; n=1843, 74±8 years, 52% female). Multinomial logistic regression related baseline cognitive complaint (no-complaint, self only, informant only, or both self-and informant) to diagnostic outcome (reversion, stable or conversion). Results At follow-up, 14% of NC participants converted to MCI/dementia (3.5±1.8 years), and 41% of MCI participants converted to dementia (3.0±1.6 years). Among NC participants, self-complaint only (OR=2.1; 99%CI=1.5–2.9, p<0.001), informant-complaint only (OR=2.2; 99%CI=1.2–3.9, p<0.001), and both self-and informant-complaint (OR=4.2; 99%CI=2.9–6.0, p<0.001) were associated with diagnostic conversion, compared to no-complaint. Among participants with MCI—compared with no-complaint, informant-complaint only (OR, 2.2; 99% CI, 1.2–4.3, P = .002), and both self- and informant-complaint (OR, 2.9; 99% CI, 1.8–4.8; P < .001)—were associated with conversion. Conclusions Cognitive complaints are related to conversion among non-demented older adults. Complaint from both (i.e. mutual complaint) sources was most predictive of diagnostic outcome, followed by informant complaint, highlighting the need for obtaining informant corroboration to enhance prognosis and distinguish underlying pathological processes from normal cognitive aging. Self-complaint was inconsistently related to diagnostic outcome.

Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer’s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer’s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values &lt; 2.5 × 10−20), and we observed novel correlations with neuropsychiatric conditions (P-values &lt; 7.9 × 10−4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer’s disease (P-values &gt; 0.42) nor associated with APOE (P-values &gt; 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer’s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Objective: To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.Methods: Participants with normal cognition (n 5 297) and mild cognitive impairment (n 5 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.Results: Latent variables of resilience predicted a decreased risk of conversion (hazard ratio , 0.54, p , 0.0001), slower cognitive decline (b . 0.02, p , 0.001), and slower rates of ventricular dilation (b , 24.7, p , 2 3 10 215 ). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline. Limited empirical attention has focused on elucidating the factors that prevent individuals with asymptomatic Alzheimer disease (AD), those with autopsy-confirmed AD pathology (b-amyloid [Ab] plaques and aggregation of neurofibrillary tangles) but without cognitive impairment, from expressing clinical AD. Conclusions:1,2 Both cognitive reserve, frequently operationalized by educational attainment, 1,2 and brain reserve, frequently operationalized by cranial volume, 3 confer resilience to cognitive deficits associated with AD pathology. However, it is quite likely that additional factors beyond traditional metrics of cognitive and brain reserve contribute to resilience observed in asymptomatic AD.The well-established CSF biomarkers of AD (levels of Ab-42 and total tau) may provide additional information that is useful for defining resilience. We therefore sought to leverage

Background Subjective cognitive decline (SCD) may indicate unhealthy cognitive changes, but no standardized SCD measurement exists. This pilot study aims to identify reliable SCD questions. Methods 112 cognitively normal (NC, 76±8 years, 63% female), 43 mild cognitive impairment (MCI; 77±7 years, 51% female), and 33 diagnostically ambiguous participants (79±9 years, 58% female) were recruited from a research registry and completed 57 self-report SCD questions. Psychometric methods were used for item-reduction. Results Factor analytic models assessed unidimensionality of the latent trait (SCD); 19 items were removed with extreme response distribution or trait-fit. Item response theory (IRT) provided information about question utility; 17 items with low information were dropped. Post-hoc simulation using computerized adaptive test (CAT) modeling selected the most commonly used items (n=9 of 21 items) that represented the latent trait well (r=0.94) and differentiated NC from MCI participants (F(1,146)=8.9, p=0.003). Conclusion Item response theory and computerized adaptive test modeling identified nine reliable SCD items. This pilot study is a first step toward refining SCD assessment in older adults. Replication of these findings and validation with Alzheimer’s disease biomarkers will be an important next step for the creation of a SCD screener.

Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10−8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10−8) but not females (P = 0.85, sex-interaction P = 2.9 × 10−4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.