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Background: In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b‐amyloid (Ab) is proposed as stage 2 of Alzheimer's disease (AD) by the NIA‐AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden. Methods: The present study includes cross‐sectional data from 9 independent cohorts with a total of 7217 CU older adults (57% female), aged 69.34 (1.20) years, recruited from general and memory‐clinic populations. Ab and tau biomarkers were measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Using established cut‐offs, 28% of participants were Aβ+, and 12% were Aβ+T+ (approximately one‐third of the sample had available tau data). We examined four SCD‐plus criteria as well as the mean number of SCD criteria met (i.e., mean SCD‐severity) in relation to both biomarker status and levels in logistic/linear regressions adjusted for age and sex for each cohort. Summary statistics were extracted for meta‐analyses. Results: The overall frequency of stage 2 AD varied from 7‐16% [4‐26%] according to each SCD‐plus criterion endorsement. Only 1‐5% [0‐8%] of participants meeting the SCD‐plus criteria also had both high Aβ and tau burden (Fig.1). The presence of self‐reported memory decline (SMD), an associated concern/worry, and a higher mean SCD‐severity were each associated with high Ab (status and continuous). Only the latter was associated with high tau status (Fig.2). Onset of SCD within the last 5 years, and feeling of worse performance than same‐age peers, were not associated with AD biomarkers at a Bonferroni‐corrected threshold. Conclusions: Our results suggest that widespread endorsement of multiple SCD features is more powerful than a single criterion alone in identifying both Aβ and tau in CU older adults. We found that the isolated SCD criterion was particularly sensitive to elevated Aβ, even after adjustment for tau, supporting the power of SCD as a very early behavioral marker of preclinical AD. [ABSTRACT FROM AUTHOR]

The Face Name Associative Memory Exam (FNAME) was introduced into the NIH Toolbox as part of the ARMADA study and establishes normative data for diverse participants, ages 64 to 85+, and proposes cutoff scores between biomarker positive versus negative (+/−) groups. The FNAME was administered to 257 participants across the clinical spectrum with 122 having amyloid biomarkers. Linear regression explored the association between demographics and FNAME and between amyloid (+/−) groups. Receiver operating characteristic curves (ROC) identified performance thresholds that best discriminated between biomarker (+/−) individuals. Lower FNAME scores occurred in males, older ages, Black/African Americans, Hispanics, and biomarker‐positive participants. ROC analyses demonstrated acceptable accuracy (0.73 to 0.77) but only when combined with clinical status. The diagnostic discrimination of amyloid positivity was acceptable but not excellent, suggesting the FNAME may be a better screening indicator of clinical status rather than amyloid deposition in cognitively normal individuals. Normative data are provided. [ABSTRACT FROM AUTHOR]

Background: Topographical staging of tauopathy in preclinical Alzheimer's disease (AD) posits early deposition in the entorhinal region (medial temporal lobe; MTL) followed by spread to adjacent neocortical (NEO) regions. Predictive models support a cascade of tau deposition as baseline MTL tau robustly predicts NEO tau accumulation. In clinically normal (CN) Ab+, elevated tau in MTL and NEO is associated with accelerated progression to dementia relative to those with only elevated MTL tau. The frequency and profile of neocortical tau resistance (defined as MTL+/NEO‐) remain unclear. Method: We defined tau resistance using two longitudinal datasets. To compare directly across MTL (entorhinal/amygdala/parahippocampal) and NEO (inferior‐temporal/fusiform/middle‐temporal/inferior‐parietal) composites, we averaged regional SUVrs within each composite then normed them to independent samples of younger CNAb‐ adults. We selected CN participants from ADNI and HABS with ≥2 time‐points of Flortaucipir‐PET (nHABS = 200; nADNI = 149; cerebellar‐greyreference). We extracted slopes from a linear mixed model covarying for age, APOEe4 and Abstatus. We compared baseline MTLnormed values with slopes in a NEOnormed. We defined tau resistance as those with elevated baseline MTLnormed tau‐PET but no change in NEOnormed tau‐PET over time. We used non‐parametric group comparisons to determine differences in a range of variables (Table1). Result: We found a poor to moderate correlation between baseline MTLnormed values and adjusted NEOnormed slopes (rHABS = 0.12; rADNI = 0.36; Fig.1), with a non‐linear association at higher levels of MTLnormed. In HABS, tau resistance was identified in 13% (n = 10) of those with elevated MTLnormed. There was a trend for Black/African American individuals to be less tau resistant (Table.1). In ADNI, 26% were identified (n = 11), there was a trend toward less APOEe4 carriers in the resistant group. Although the ranges of change were different across the two cohorts, adjusted MTLnormed and NEOnormed slopes were similarly strongly correlated (rHABS = 0.69; rADNI = 0.74; Fig.2). Conclusion: Our preliminary findings suggest that resistance to neocortical tau in CN exists in up to a quarter of those with elevated MTL. Given the complexities with determining cross‐sectional and longitudinal tau‐PET thresholds, our approach to identifying MTL+ or NEO+ may be too conservative. Future work will validate tau resistance via cognitive decline and clinical progression. [ABSTRACT FROM AUTHOR]

Background: Optimizing longitudinal cognitive and biomarker trajectories can distill multiple observations from one individual into a single metric. Relative to other individuals, this metric can represent an individual's distance from an anchor‐point based on their rate and non‐linearity of change. We have recently developed a cognitive time (c‐time) based on the cognitive trajectories of clinically normal older adults. We examined the association between c‐time and a previously published 'time‐to‐Aβ+ threshold' and how these metrics align with demographics and other biomarkers. Method: We identified 135 clinically normal older adults from the Harvard Aging Brain Study (Agemean:73years(±5.9); Female:61%) with ≥3 neuropsychological assessments and PiB‐PET, ≥1 Flortaucipir‐PET, ≥2 volumetric MRI, and diagnostic follow up. We defined c‐time using iterative non‐linear least‐squares optimization to define a curvilinear function that described the group‐level Preclinical Alzheimer Cognitive Composite (PACC) trajectory (Fig1D). Each participant's PACC trajectory was subsequently located on the curve using the same optimization framework (Fig1E). We identified the anchor‐point of cognitive decline (c‐time) using piecewise linear mixed‐effects models. Time‐to‐Aβ+ was calculated using the published sampled iterative local approximation (SILA; Fig1A) algorithm with the anchor‐point indicating Aβ+ threshold (Fig1B). We examined associations between c‐time and time‐to‐Aβ+ using linear regression. Individuals were subsequently placed into groups depending on their position relative to the anchor‐point on each axis, as well as the line‐of‐best‐fit (Fig2). We compared the groups on demographics, and both cross‐sectional and longitudinal indices of medial temporal (MTL) Flortaucipir‐PET (entorhinal, parahippocampal, amygdala) and ICV‐adjusted hippocampal volume. Result: C‐time and time‐to‐Aβ+ were significantly associated (r = 0.42,p<0.001). Only one participant (who progressed to MCI/dementia) was post‐c‐time and remained pre‐time‐to‐Aβ+, supporting the notion that time‐to‐Aβ+ occurs prior to cognitive inflection. Individuals post‐c‐time and post‐time‐to‐Aβ+ (Group 1) were more likely to be APOEε4 carriers, progressors to MCI/dementia, have significantly higher baseline MTL tau and lower hippocampal volume, and faster hippocampal atrophy (Fig3). Group 2 (post‐time‐to‐Aβ+/pre‐c‐time) were more likely APOEε4 carriers. Notably, no age or other effects were apparent between groups. Conclusion: Optimizing longitudinal cognitive and biomarker data to estimate a preclinical disease continuum can provide unique, and potentially age‐independent, information about the distance an individual might be from disease‐relevant events. [ABSTRACT FROM AUTHOR]

Background: Digital cognitive tools may provide unique opportunities to detect subtle changes in preclinical Alzheimer's disease (AD). Here, a maze test using a digital pen was evaluated in relation to AD pathological changes measured by amyloid‐β and tau burden. Method: 172 participants (CN = 161, MCI = 6, dementia = 5) completed the digital maze test, which included multiple "no‐choice" (NC; i.e., no decisions required to complete maze) or "choice" (CH) conditions (i.e., problem‐solving required to complete maze). Maze composite scores were calculated using the total test duration, total number of strokes, and total pen‐off‐page time for the NC and CH conditions separately. Global amyloid‐β PET was quantified with [11C]Pittsburgh‐Compound‐B (PiB) in available participants (n = 171). Entorhinal and inferior temporal tau were quantified with [18F]Flortaucipir (FTP) in available participants (n = 135). Participants completed a battery of traditional neuropsychological tests, with domain factor scores calculated for Executive Functioning (EF), Processing Speed (PS), and Memory (Mem). The associations between maze composite scores, global amyloid‐β, entorhinal tau, and inferior temporal tau were evaluated in separate linear regression models for both the total sample and CN only, correcting for age and education. Result: In the total sample, CH‐ and NC‐composites were moderately correlated with PS and EF factor scores (r's =.41‐.46) and less so with Mem factor scores (r's = 0.2‐0.35). In the total sample, higher PiB was significantly associated with worse performance in NC‐composite (β = 0.543, SE = 0.249, p <.05), but not for CH‐composite (β = 0.467, SE = 0.259, p =.07). Similar results were observed in the CN only sample (NC‐composite: β = 0.468, SE = 0.237, p <.05; CH‐composite: β = 0.469, SE = 0.278, p =.09). PiB was not associated with EF or PS factor scores in the total sample or CN only. Entorhinal and inferior temporal tau were not significantly associated with any maze composites. Conclusion: In a largely cognitively normal sample, performance on the digital maze test was associated with global amyloid‐β burden, particularly in the no‐choice condition, but not with tau. Digitally captured, nuanced performance in EF and PS may be related to early amyloid‐β pathology, but less so with downstream effects of tau. [ABSTRACT FROM AUTHOR]

Background: Self‐report of cognitive decline is an early behavioral manifestation of Alzheimer's disease at the preclinical stage, often thought to precede study partner‐report. Prior work has shown associations between subjective cognitive decline and amyloid, but less is known about tau deposition, particularly once tau has spread to neocortex. Using a multi‐cohort study of cognitively unimpaired individuals, we examined associations between self‐ and study partner‐report, amyloid and regional tau. Specifically, we hypothesized that greater self‐ and study partner‐report of cognitive decline would be observed with tau in the medial temporal lobe (MTL), whereas study partner‐report would be more strongly associated with neocortical (NEO) tau compared to self‐report. Method: 698 cognitively unimpaired individuals (55% elevated‐amyloid, mean age = 72.5, 58% female) came from the A4, LEARN, HABS, and SCD/IADL Studies. All participants underwent Flortaucipir‐PET quantified by SUVr. A MTL tau composite and a NEO tau composite were derived. An internally derived amyloid cut‐off was used for each study. Participants and their study partners completed the Cognitive Function Index (CFI), a 15‐item questionnaire asking about cognitive functioning over the last year. A series of linear regression models using tau (MTL vs. NEO) to predict CFI (self vs. study partner) were conducted, adjusting for age, sex, education, amyloid status and cohort. Result: We first examined amyloid status and CFI and found elevated‐amyloid was associated with higher self‐report (t = 2.8, p = 0.017), but not study partner‐report (t = 1.5, p = 0.12). Building on this model, greater MTL tau was associated with greater self‐report (t = 3.30, p<0.001) and study partner‐report (t = 3.4, p<0.001), but not amyloid status. Greater NEO tau was associated with greater self‐report (t = 3.2, p = 0.002) and study partner‐report (t = 4.1, p<0.00001), but not amyloid status. Conclusion: In this multi‐cohort study of cognitively unimpaired individuals, elevated‐amyloid was associated with greater self‐report CFI, but not study partner‐report. When accounting for amyloid status, both MTL and NEO tau were significantly associated with both self and study‐partner report, but effects were numerically stronger for study partner for NEO tau. These findings suggest that CFI report both from the participants and their study partners is valuable at the preclinical stage, but may evolve with increasing tau spread. [ABSTRACT FROM AUTHOR]

Background: PET and post‐mortem studies show that women consistently exhibit higher medial‐temporal and neocortical tau compared to men, independent of age or diagnostic status. What remains unclear is whether such sex differences are also observed in the plasma biomarkers and related to future tau‐PET deposition. We examined baseline and longitudinal phosphorylated‐tau (plasma p‐tau181‐UGOT), which was derived prior to a tau‐PET scan, in order to determine whether changes in p‐tau181 are associated with higher regional tau‐PET in women relative to men. Method: We selected 313 participants (clinically normal, n = 169; MCI/dementia, n = 144) from ADNI (Female% = 146(46%); AgeMean = 71(±7)years; APOEe4 = 105(34%); Ab+ = 162(52%)) with at least two timepoints of plasma p‐tau181‐UGOT measured in ADNI1/2/GO (time‐pointsMean = 3.7(±1)). Cross‐sectional Ab‐PET and tau‐PET (Flortaucipir) scan were collected in ADNI3 ((time‐difference from baseline plasmaMean = 7.1y(±1.9)). Two a priori tau‐PET partial volume corrected (PVC) regions were selected: entorhinal (EC) and inferior temporal (IT). We used linear regression to examine the influence of baseline p‐tau181 and sex on subsequent tau‐PET, adjusting for time gap between plasma‐PET and tau‐PET. Linear mixed‐effects models probed how retrospective change in plasma tau were associated with regional tau‐PET and sex, covarying for neocortical Ab‐PET, diagnosis, APOEe4 and age. We also examined interactions between sex and variables of interest. Result: Baseline p‐tau181 was strongly associated (b = 0.86 and b = 0.53) with subsequent tau‐PET, although sex did not display main effects in the model, nor did sex moderate the plasma‐PET association. Longitudinal p‐tau181 was not associated with subsequent tau‐PET. Women with accumulating p‐tau181 exhibited higher subsequent tau‐PET burden in EC and IT regions than men (p = 0.04 and p = 0.03, respectively; Figure 1). Higher‐order interactions between sex and tau‐PET with APOEe4, diagnosis or Ab‐PET were not significant, although, women diagnosed with MCI/dementia and elevated Ab seemed to drive the interaction (Figure 2). Conclusion: Elevated tau‐PET burden in women may be more strongly associated with prior increases in plasma p‐tau181 relative to men. Given the pre‐established association between p‐tau181 and Ab, this could be initial evidence that early events related to the deposition of Ab predict later cortical tau deposition in a sex‐specific manner. Given the novelty of examining longitudinal plasma measures, further investigation is necessitated beyond this preliminary evidence. [ABSTRACT FROM AUTHOR]

Objective: 1) Evaluate the association of self- and study-partner report of subjective cognitive decline (SCD) to objective cognitive performance across ethnoracial groups. 2) Evaluate the concordance of self- and study partner report of SCD across ethnoracial groups. Participants and Methods: Participants were 5241 non-Hispanic White (NHW), 267 non-Hispanic Black (NHB), 225 Hispanic, and 228 Asian participants screened for the A4 study (N=5961). Participants completed the Preclinical Alzheimer Cognitive Composite (PACC), and self- and study partner-report of SCD using the Cognitive Function Index (CFI). Analysis of variance was used to assess difference in key variables by ethnoracial group. Regression analyses were conducted to evaluate the association of SCD and objective performance by ethnoracial group, and the association between self-and study partner report of SCD by ethnoracial group. Results: Asian participants reported the highest mean CFI relative to all other groups, while NHW reported the lowest (F(3,5957)=41.93, p <.001). Asian and NHW participants had higher PACC scores relative to NHB and Hispanic participants (F(3,5957)=41.93, p <.001). Regression analyses revealed higher CFI was associated with lower PACC score across groups, and this association was strongest in the Asian sample relative to other groups (F(10, 5897)=40.49, p<.001,R2=.06). Evaluation of study partner characteristics suggested NBH participants had the highest proportion on non-spousal study partners relative to other groups. Regression analyses revealed no differences in the association of self- and study partner report of SCD across ethnoracial groups (F(10, 5859)=132.9, p<.001, R2=0.18). Conclusions: Results suggest that that SCD is associated with objective cognitive performance across racial groups, although the strength of this association appears to vary in this sample. There is also consistent concordance between self- and study partner report of SCD across groups, despite differences in study partner relationships. SCD may be considered a valid predictor of subtle cognitive change across groups in the A4 sample. Limitations include small group sizes relative to the large NHW sample. Future work with larger, more representative samples are needed to further validate these findings. [ABSTRACT FROM AUTHOR]

Introduction: While the influence of cross-sectional β-amyloid (Aβ) on longitudinal changes in cognition is well established, longitudinal change-on-change between Aβ and cognition is less explored., Methods: A series of bivariate latent change score models (LCSM) examined the relationship between changes in 11 C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) and the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) while adjusting for covariates, including cross-sectional medial temporal lobe (MTL) tau-PET burden. We selected 352 clinically normal older participants with up to 9 years of PiB-PET and PACC-5 data from the Harvard Aging Brain Study (HABS)., Results: Aβ accumulation was associated with subsequent cognitive decline beyond the effects of cross-sectional Aβ burden. Within this model including covariates such as age, sex, and apolipoprotein ε4 (APOEε4) status, we found no evidence supporting previously published associations between cross-sectional tau-PET and cognitive intercept/slope., Discussion: Short-term Aβ changes are significantly associated with cognitive decline in clinically normal older adults and may eclipse the effect of cross-sectional Aβ and MTL tau., Highlights: Aβ accumulation is associated with subsequent cognitive decline. High Aβ burden is not the sole metric signaling impending cognitive decline. Contrary to prior work, MTL tau-PET and cognition were not associated in our models. Models of bivariate latent Aβ and cognitive change may eclipse the effects of MTL tau., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data., Competing Interests: Conflict of interest Paul Maruff is a full-time employee of Cogstate Ltd. Samuel N. Lockhart is a full time employee of Invicro LLC. SCJ has served in the past three years as a consultant to ALZPath and Enigma Biomedical.

The Face Name Associative Memory Exam (FNAME) was introduced into the NIH Toolbox as part of the ARMADA study and establishes normative data for diverse participants, ages 64 to 85+, and proposes cutoff scores between biomarker positive versus negative (+/-) groups. The FNAME was administered to 257 participants across the clinical spectrum with 122 having amyloid biomarkers. Linear regression explored the association between demographics and FNAME and between amyloid (+/-) groups. Receiver operating characteristic curves (ROC) identified performance thresholds that best discriminated between biomarker (+/-) individuals. Lower FNAME scores occurred in males, older ages, Black/African Americans, Hispanics, and biomarker-positive participants. ROC analyses demonstrated acceptable accuracy (0.73 to 0.77) but only when combined with clinical status. The diagnostic discrimination of amyloid positivity was acceptable but not excellent, suggesting the FNAME may be a better screening indicator of clinical status rather than amyloid deposition in cognitively normal individuals. Normative data are provided., Competing Interests: AS., C.F., O.R.S., H.M.K., and S.A. report no disclosures relevant to this manuscript. D.R. received salary support as a co‐PI on the ARMADA grant No. 1U2CAG057441. D.P. has been a paid consultant to FACIT, Debiopharm Beta6. D.R. has also served as a paid consultant for Biogen Idec, Digital Cognition Technologies, and Neurotrack. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)