Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration.

BACKGROUND: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. METHODS: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aß, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). RESULTS: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. CONCLUSION: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer's disease.

BACKGROUND: Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aß)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology. METHODS: 142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aß)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates. RESULTS: At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity. CONCLUSIONS: Our findings demonstrate that the LC can provide resilience against Aß-related attention decline. However, when Aß accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aß-related cognitive decline.

Parental History of Memory Impairment and ß-Amyloid in Cognitively Unimpaired Older Adults.

Importance: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain ß-amyloid (Aß) burden, reduced brain metabolism, and lower gray matter volumes. Objective: To characterize maternal vs paternal history of memory impairment in terms of brain Aß-positron emission tomography (Aß-PET) and baseline cognition among a large sample of cognitively unimpaired older adults. Design, Setting, and Participants: This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aß levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded. Main Outcomes and Measures: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aß-PET and the Preclinical Alzheimer Cognitive Composite. Results: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aß-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aß-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aß in both early-onset and late-onset groups. There was no association with cognition. Conclusions and Relevance: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aß burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aß burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.

Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Results: Amyloid [unstandardized partial regression coefficient estimate (ß) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [ß = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition.

Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

Atrophy links lower novelty-related locus coeruleus connectivity to cognitive decline in preclinical AD.

INTRODUCTION: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FCLC-MTL) on cortical atrophy across Braak stage regions and its impact on cognition. METHODS: We analyzed functional magnetic resonance imaging and amyloid beta (Aß) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FCLC-MTL with longitudinal atrophy and cognition with and without Aß moderation. RESULTS: Cross-sectionally, lower FCLC-MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FCLC-MTL at elevated levels of Aß, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FCLC-MTL and subsequent cognitive decline. DISCUSSION: FCLC-MTL is implicated in Aß-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD. HIGHLIGHTS: Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aß-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aß burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.

Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study.

OBJECTIVES: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults. DESIGN: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. SETTING: Community-dwelling participants assessed at research visits in an academic medical center. PARTICIPANTS: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). MEASUREMENTS: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. RESULTS: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aß, we observed an association between AES-I and inferior temporal tau. CONCLUSIONS: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy.

Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER).

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.

Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing.

OBJECTIVE: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. METHODS: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60-91 years) were classified with elevated ß-amyloid (Aß+) and 128 (78%) were Aß- using positron emission tomography with 11C Pittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. RESULTS: At the cross-section, there were no statistically significant differences in performance between Aß+/- participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aß+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aß- participants (Cohen d = 0.49, 95% confidence interval = 0.10-0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). INTERPRETATION: Very early Aß-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507-517.

Increased intraindividual variability in reaction time performance is associated with emerging cognitive decline in cognitively unimpaired adults.

OBJECTIVE: To investigate whether intraindividual variability (IIV) in reaction time (RT) over monthly administered cognitive tasks is increased in cognitively unimpaired older adults who are at risk for cognitive decline, and whether this is independent of mean RT performance. METHOD: N = 109 cognitively unimpaired individuals (age 77.4 ± 5.0, 61.5% female, Mini-Mental State Examination 29.1 ± 1.3) from the Harvard Aging Brain Study completed the self-administered Computerized Cognitive Composite (C3) monthly at home for up to 1 year (12.7 ± 3.2 C3 assessments). Baseline C3 assessment coincided with routine in-clinic visits, including amyloid and tau positron emission tomography imaging and standardized cognitive testing, with cognitive testing repeated annually (1.6 ± 1.2 years follow-up). The C3 includes two simple RT tasks and two complex RT tasks. IIV estimates were derived by computing intraindividual standard deviations on residual RT scores after regressing out age and session order effects. Cross-sectional associations of IIV with cognition (global cognition, memory, executive functions [EF], processing speed) and amyloid and tau burden were examined using linear regression analyses correcting for demographics and mean RT. The association between IIV and cognitive decline was assessed using linear mixed models correcting for demographic factors, mean RT, and amyloid burden. RESULTS: After adjusting for mean RT, increased IIV on complex RT tasks was independently associated with worse EF performance (ß = -0.10, 95% CI [-.16, -0.03], p = .004), greater inferior-temporal tau deposition (ß = 0.18, 95% CI [0.02, 0.34], p = .024), and faster cognitive decline in those with elevated amyloid (ß = -0.62, 95% CI [-1.18, -0.06], p = .033). CONCLUSIONS: Increased variability in monthly RT may reflect subtle EF deficits and provide unique information about short-term cognitive decline in preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Capturing learning curves with the multiday Boston Remote Assessment of Neurocognitive Health (BRANCH): Feasibility, reliability, and validity.

OBJECTIVE: Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning over repeated evaluations on participants' own devices. This provides the opportunity to derive individual multiday learning curve scores over short intervals. Here, we report feasibility, reliability, and validity, of a 7-day cognitive battery from the Boston Remote Assessment for Neurocognitive Health (Multiday BRANCH), an unsupervised web-based assessment. METHOD: Multiday BRANCH was administered remotely to 181 cognitively unimpaired older adults using their own electronic devices. For 7 consecutive days, participants completed three tests with associative memory components (Face-Name, Groceries-Prices, Digit Signs), using the same stimuli, to capture multiday learning curves for each test. We assessed the feasibility of capturing learning curves across the 7 days. Additionally, we examined the reliability and associations of learning curves with demographics, and traditional cognitive and subjective report measures. RESULTS: Multiday BRANCH was feasible with 96% of participants completing all study assessments; there were no differences dependent on type of device used (t = 0.71, p = .48) or time of day completed (t = -0.08, p = .94). Psychometric properties of the learning curves were sound including good test-retest reliability of individuals' curves (intraclass correlation = 0.94). Learning curves were positively correlated with in-person cognitive tests and subjective report of cognitive complaints. CONCLUSIONS: Multiday BRANCH is a feasible, reliable, and valid cognitive measure that may be useful for identifying subtle changes in learning and memory processes in older adults. In the future, we will determine whether Multiday BRANCH is predictive of the presence of preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Using a digital tool to detect early changes in everyday functioning in older adults: A pilot study of the Assessment of Smartphone Everyday Tasks (ASSET).

INTRODUCTION: To investigate the utility of a new digital tool for measuring everyday functioning in preclinical Alzheimer's disease, we piloted the Assessment of Smartphone Everyday Tasks (ASSET) application. METHODS: Forty-six participants (50.3 ± 27.1 years; 67% female; 20 young unimpaired, 17 old unimpaired, 9 mildly cognitively impaired) completed ASSET 7 times. ASSET comprises two main tasks, simulating a Patient Portal and a Calendar. We assessed ASSET's internal consistency, test-retest reliability, and user experience. RESULTS: ASSET main tasks correlated with each other (r = 0.75, 95% confidence interval [CI] = [0.58, 0.86]). Performance on ASSET's Patient Portal related to cognition (r = 0.64, 95% CI = [0.42, 0.79]) and observer ratings of everyday functioning (r = 0.57, 95% CI = [0.24, 0.79]). Test-retest reliability was good (intraclass correlation coefficient = 0.87, 95% CI = [0.77, 0.93]). Most participants rated their experience with ASSET neutrally or positively. DISCUSSION: ASSET is a promising smartphone-based digital assessment of everyday functioning. Future studies may investigate its utility for early diagnosis and evaluation of treatment of Alzheimer's disease.

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults.

BACKGROUND AND OBJECTIVES: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with ß-amyloid (Aß) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aß, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aß and tau. METHODS: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aß imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aß, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. RESULTS: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aß burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aß and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. DISCUSSION: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aß or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid.

INTRODUCTION: Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology. METHODS: 122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models. RESULTS: We find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants. CONCLUSIONS: The combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer's Disease-related episodic memory decline, suggesting utility in clinical trials.

People with Alzheimer's disease have problems with their memory and ability to acquire and process knowledge. Understanding the earliest brain changes leading to these problems helps identify those likely to develop Alzheimer's disease early in the disease process. This study used a marker that measures the mobility of water in the brain to investigate how these changes can predict development of a protein named tau and changes in people's memory. The participants showed no signs of memory impairment at the beginning of the study, but some developed memory decline during follow-up. Greater mobility of water in certain brain areas predicted future increase in tau and decline in memory, indicating this measure could be used to identify people at risk of developing Alzheimer's disease.

Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease.

BACKGROUND AND OBJECTIVES: The predictable Braak staging scheme suggests that cortical tau progression may be related to synaptically connected neurons. Animal and human neuroimaging studies demonstrated that changes in neuronal activity contribute to tau spreading. Whether similar mechanisms explain tau progression from the locus coeruleus (LC), a tiny noradrenergic brainstem nucleus involved in novelty, learning, and memory and among the earliest regions to accumulate tau, has not yet been established. We aimed to investigate whether novelty-related LC activity was associated with the accumulation of cortical tau and its implications for cognitive decline. METHODS: We combined functional MRI data of a novel vs repeated face-name learning paradigm, [18F]-FTP-PET, [11C]-PiB-PET, and longitudinal cognitive data from 92 well-characterized older individuals in the Harvard Aging Brain Study. We related novelty vs repetition LC activity to cortical tau deposition and to longitudinal decline in memory, executive function, and the Preclinical Alzheimer Disease Cognitive Composite (version 5; PACC5). Structural equation modeling was used to examine whether entorhinal cortical (EC) tau mediated the relationship between LC activity and cognitive decline and whether this depended on beta-amyloid deposition. RESULTS: The participants' average age at baseline was 69.67 ± 10.14 years. Fifty-one participants were female. Ninety-one participants were cognitively normal (CDR global = 0), and one participant had mild cognitive impairment (CDR global = 0.5) at baseline. Lower novelty-related LC activity was specifically related to greater tau deposition in the medial-lateral temporal cortex and steeper memory decline. LC activity during novelty vs repetition was not related to executive dysfunction or decline on the PACC5. The relationship between LC activity and memory decline was partially mediated by EC tau, particularly in individuals with elevated beta-amyloid deposition. DISCUSSION: Our results suggested that lower novelty-related LC activity is associated with the emergence of EC tau and that the downstream effects of this LC-EC pathway on memory decline also require the presence of elevated beta-amyloid. Longitudinal studies are required to investigate whether optimal LC activity has the potential to delay tau spread and memory decline, which may have implications for designing targeted interventions promoting resilience.

Relation of modifiable lifestyle and mood factors to cognitive concerns among participants and their study partners in the A4 screen data.

Introduction: Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory. Methods: We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi-site secondary prevention trial (A4 screen data; mean ±SD: age = 71.3 ±4.7, education = 16.6 ±2.8, 59% women, 96% non-Hispanic or Latino, 92% White]. Results: On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant-reported mood/anxiety. Discussion: Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant- and SP-reported concerns, which may inform trial recruitment and clinical interventions.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi-site cohort.

Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n = 3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short-term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow-up period provides additional insights into early Alzheimer's disease processes.

Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease.

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much-needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. HIGHLIGHTS: We discuss lessons learned on capturing cognitive changes in predementia stages of AD. We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials. We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials.