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.

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.

Subjective cognitive decline across ethnoracial groups in the A4 study.

INTRODUCTION: The associations between subjective cognitive decline (SCD), cognition, and amyloid were explored across diverse participants in the A4 study. METHODS: Five thousand one hundred and fifty-one non-Hispanic White, 262 non-Hispanic Black, 179 Hispanic-White, and 225 Asian participants completed the Preclinical Alzheimer Cognitive Composite (PACC), self- and study partner-reported Cognitive Function Index (CFI). A subsample underwent amyloid positron emission tomography (18 F-florbetapir) (N = 4384). We examined self-reported CFI, PACC, amyloid, and study partner-reported CFI by ethnoracial group. RESULTS: The associations between PACC-CFI and amyloid-CFI were moderated by race. The relationships were weaker or non-significant in non-Hispanic Black and Hispanic White groups. Depression and anxiety scores were stronger predictors of CFI in these groups. Despite group differences in the types of study partners, self- and study partner-CFI were congruent across groups. DISCUSSION: SCD may not uniformly relate to cognition or AD biomarkers in different ethnoracial groups. Nonetheless, self- and study partner-SCD were congruent despite differences in study partner type. Highlights Association between SCD and objective cognition was moderated by ethnoracial group. Association between SCD and amyloid was moderated by ethnoracial group. Depression and anxiety were stronger predictors of SCD in Black and Hispanic groups. Study-partner and self-reported SCD are congruent across groups. Study-partner report was consistent despite difference in study partner types.

Association of cortical microstructure with amyloid-ß and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults.

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-ß and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-ß, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-ß, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-ß, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-ß and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-ß, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

Subjective Cognitive Decline and its Relation to Verbal Memory and Sex in Cognitively Unimpaired Individuals from a Colombian Cohort with Autosomal-Dominant Alzheimer's Disease.

OBJECTIVE: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance. METHODS: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education. RESULTS: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported (p = 0.02) and study partner-reported SCD (p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p = 0.03), but not study partner-reported SCD (p = 0.11) was associated with worse verbal memory. CONCLUSIONS: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline.

OBJECTIVE: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. METHODS: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aß-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. RESULTS: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). ß-amyloid (Aß)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aß + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04). INTERPRETATION: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aß were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.

Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease.

OBJECTIVE: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging - Alzheimer's Association (NIA-AA) research framework. METHOD: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models. RESULTS: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (ß = -.58, p < .001). Word List Delayed Recall (ß = -.22, p < .05) and Trail Making Test (ß = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (ß = -1.13, p < .001) and 4 (ß = -2.23, p < .001). CONCLUSIONS: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.

The impact of amyloid-beta and tau on prospective cognitive decline in older individuals.

OBJECTIVES: Amyloid-beta (Aß) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. METHODS: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aß (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aß PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. RESULTS: Higher levels of Aß and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aß was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aß. A significant interaction between tau and Aß was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. INTERPRETATION: Our results are consistent with the supposition that both Aß and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1-3 ANN NEUROL 2019;85:181-193.

Head-Mounted Display-Based Application for Cognitive Training.

Virtual Reality (VR) has had significant advances in rehabilitation, due to the gamification of cognitive activities that facilitate treatment. On the other hand, Immersive Virtual Reality (IVR) produces outstanding results due to the interactive features with the user. This work introduces a VR application for memory rehabilitation by walking through a maze and using the Oculus Go head-mounted display (HMD) technology. The mechanics of the game require memorizing geometric shapes while the player progresses in two modes, autonomous or manual, with two levels of difficulty depending on the number of elements to remember. The application is developed in the Unity 3D video game engine considering the optimization of computational resources to improve the performance in the processing and maintaining adequate benefits for the user, while the generated data is stored and sent to a remote server. The maze task was assessed with 29 subjects in a controlled environment. The obtained results show a significant correlation between participants' response accuracy in both the maze task and a face-pair test. Thus, the proposed task is able to perform memory assessments.

Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD.

INTRODUCTION: Demonstrating the "clinical meaningfulness" of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid-ß (Aß+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression. METHODS: Cox regression analyses were used to determine whether 3-year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aß+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative. RESULTS: Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta-analytic estimates were 5.47 (95% CI: 3.25-9.18) for MCI diagnosis and 4.49 (95% CI: 2.84-7.09) for Clinical Dementia Rating>0 in those with subtle decline (>-.14 to -.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing. DISCUSSION: Early "subtle cognitive decline" among Aß+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.

Smart Cupboard for Assessing Memory in Home Environment.

Sensor systems for the Internet of Things (IoT) make it possible to continuously monitor people, gathering information without any extra effort from them. Thus, the IoT can be very helpful in the context of early disease detection, which can improve peoples' quality of life by applying the right treatment and measures at an early stage. This paper presents a new use of IoT sensor systems-we present a novel three-door smart cupboard that can measure the memory of a user, aiming at detecting potential memory losses. The smart cupboard has three sensors connected to a Raspberry Pi, whose aim is to detect which doors are opened. Inside of the Raspberry Pi, a Python script detects the openings of the doors, and classifies the events between attempts of finding something without success and the events of actually finding it, in order to measure the user's memory concerning the objects' locations (among the three compartments of the smart cupboard). The smart cupboard was assessed with 23 different users in a controlled environment. This smart cupboard was powered by an external battery. The memory assessments of the smart cupboard were compared with a validated test of memory assessment about face-name associations and a self-reported test about self-perceived memory. We found a significant correlation between the smart cupboard results and both memory measurement methods. Thus, we conclude that the proposed novel smart cupboard successfully measured memory.

The Impact of Awareness of and Concern About Memory Performance on the Prediction of Progression From Mild Cognitive Impairment to Alzheimer Disease Dementia.

OBJECTIVE: To investigate the relationship of awareness of and concern about memory performance to progression from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. METHODS: Participants (n = 33) had a diagnosis of MCI at baseline and a diagnosis of MCI or AD dementia at follow-up. Participants were categorized as "Stable-MCI" if they retained an MCI diagnosis at follow-up (mean follow-up = 18.0 months) or "Progressor-MCI" if they were diagnosed with AD dementia at follow-up (mean follow-up = 21.6 months). Awareness was measured using the residual from regressing a participant's objective memory score onto their subjective complaint score (i.e., residual<0 indicates overestimation of performance). Concern was assessed using a questionnaire examining the degree of concern when forgetting. Logistic regression was used to determine whether the presence of these syndromes could predict future diagnosis of AD dementia, and repeated measures analysis of covariance tests were used to examine longitudinal patterns of these syndromes. RESULTS: Baseline anosognosia was apparent in the Progressor-MCI group, whereas participants in the Stable-MCI group demonstrated relative awareness of their memory performance. Baseline awareness scores successfully predicted whether an individual would progress to AD-dementia. Neither group showed change in awareness of performance over time. Neither group showed differences in concern about memory performance at baseline or change in concern about performance over time. CONCLUSION: These data suggest that anosognosia may appear prior to the onset of AD dementia, while anosodiaphoria likely does not appear until later in the AD continuum. Additionally, neither group showed significant changes in awareness or concern over time, suggesting that change in these variables may happen over longer periods.

PET staging of amyloidosis using striatum.

INTRODUCTION: Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures. METHODS: We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition. RESULTS: Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid. DISCUSSION: PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research.

Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts.

INTRODUCTION: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid ß (Aß) burden and apolipoprotein E genotype. METHODS: We analyzed sex-specific effects on Aß-positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed-effects models of cognitive change by sex, Aß-positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow-up. RESULTS: Apolipoprotein ε4 prevalence and Aß burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aß exhibited faster decline than males. Post hoc contrasts suggested that females who were Aß and apolipoprotein ε4 positive declined faster than their male counterparts. DISCUSSION: Although Aß did not differ by sex, cognitive decline was greater in females with higher Aß. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease-related cognitive decline.

Harvard Aging Brain Study: Dataset and accessibility.

The Harvard Aging Brain Study is sharing its data with the global research community. The longitudinal dataset consists of a 284-subject cohort with the following modalities acquired: demographics, clinical assessment, comprehensive neuropsychological testing, clinical biomarkers, and neuroimaging. To promote more extensive analyses, imaging data was designed to be compatible with other publicly available datasets. A cloud-based system enables access to interested researchers with blinded data available contingent upon completion of a data usage agreement and administrative approval. Data collection is ongoing and currently in its fifth year.

Tau positron emission tomographic imaging in aging and early Alzheimer disease.

OBJECTIVE: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies. METHODS: We acquired tau positron emission tomography (PET) using (18)F T807 (AV1451), and amyloid-ß PET using (11)C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. RESULTS: We found abnormally high cortical (18)F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18)F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18)F T807 than with mean cortical (11)C PIB. Regional (18)F T807 was correlated with mean cortical (11)C PiB among both impaired and control subjects. INTERPRETATION: These findings suggest that (18)F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment.

Subjective cognitive concerns are associated with objective memory performance in Caucasian but not African-American persons.

Objective: subjective cognitive concerns (SCC) have been proposed as a means of identifying individuals at risk for Alzheimer's disease (AD). However, the utility of SCCs has not been well-explored for African-Americans, who are twice as likely to develop AD dementia as Caucasians. We investigated whether race affects the association between SCCs and objective memory performance. Methods: we used a composite of three SCC questionnaires, and three challenging episodic memory tests. We studied 289 (61% female; African-American n = 47) clinically normal older individuals. Two hierarchical linear regressions assessed the modifying role of race on the association between SCC and objective memory performance. The first regression was conducted on the full sample, while the second matched the racial groups on age, estimated verbal IQ and socioeconomic status. Results: in the full sample, both groups reported similar levels of SCCs, P = 0.10, although African-Americans performed worse on the memory tasks, P < 0.001. No group differences were observed in the matched sample. The SCC × race interaction term was nonsignificant in the full sample, ß = 0.109, P = 0.09, but was significant in the matched sample, ß = 0.422, P = 0.037. While a significant correlation was observed between SCCs and memory among Caucasians, r = -0.401, the correlation was not found among African-Americans, r = -0.052. Conclusions: results suggest that the dissociation between SCCs and memory performance in African-Americans may indicate qualitative differences in how diverse groups endorse cognitive concerns, even after considering socioeconomic and educational factors.

Subjective Cognitive Decline in Preclinical Alzheimer's Disease.

Older adults with subjective cognitive decline (SCD) in the absence of objective neuropsychological dysfunction are increasingly viewed as at risk for non-normative cognitive decline and eventual progression to Alzheimer's disease (AD) dementia. The past decade has witnessed tremendous growth in research on SCD, which may reflect the recognition of SCD as the earliest symptomatic manifestation of AD. Yet methodological challenges associated with establishing common assessment and classification procedures hamper the construct. This article reviews essential features of SCD associated with preclinical AD and current measurement approaches, highlighting challenges in harmonizing study findings across settings. We consider the relation of SCD to important variables and outcomes (e.g., AD biomarkers, clinical progression). We also examine the role of self- and informant-reports in SCD and various psychological, medical, and demographic factors that influence the self-report of cognition. We conclude with a discussion of intervention strategies for SCD, ethical considerations, and future research priorities.

The influence of demographic factors on subjective cognitive concerns and beta-amyloid.

BACKGROUND: Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aß) burden. METHODS: In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63-90 years (mean 73.7±6) with 6-20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aß burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aß burden and SCC. A post-hoc mediation model was implemented to further understand the relationship between Aß burden and SCC via their relationship with education. RESULTS: Age (ß = -0.84, p = 0.36) and sex (ß = -0.55, p = 0.22) did not modify the relationship between SCC and Aß burden. Fewer years of education was correlated with greater SCC (r = -0.12, p = 0.05), but the relationship between Aß burden and SCC was stronger in those with more education (ß = 1.16, p < 0.05). A partial mediation effect was found of Aß burden on SCC via education (b = -0.12, 95% CI [-0.31, -0.02]). CONCLUSIONS: These findings suggest that the association between SCC and Aß burden becomes stronger with greater educational attainment. Thus, SCC may be of particular importance in highly educated CN individuals harboring amyloid pathology.

Early and late change on the preclinical Alzheimer's cognitive composite in clinically normal older individuals with elevated amyloid ß.

INTRODUCTION: Sensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials. METHODS: We examined amyloid ß (Aß)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort. RESULTS: Aß+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aß group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression. DISCUSSION: This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the prevention trial design.