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The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Background and objectivesThe goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.MethodsThe FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)-positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.ResultsParticipants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.DiscussionPresence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.Trial registration informationClinicalTrials.gov identifier: NCT02008357.Classification of evidenceThis study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21-0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59-0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = -0.20, 95% CI [-0.38 - -0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = -0.38, 95% CI [-0.54 - -0.19], p < 0.001) and inferior-temporal lobe (r = -0.23, 95% CI [-0.41 - -0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84-0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aβ burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aβ-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aβ burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

INTRODUCTION: To assess the relationship between memory performance defined by the Stages of Objective Memory Impairment (SOMI) system and the Alzheimers disease (AD) ATN (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) biomarker system. METHODS: We used data from the Harvard Aging Brain Study cohort to estimate the level of ATN biomarkers: amyloid beta (C-Pittsburgh compound B-positron emission tomography [PET]), tau (F-18-flortaucipir [FTP] PET), and neurodegeneration (magnetic resonance imaging volumetrics). We assessed the cross-sectional relationship of SOMI classification with global amyloid levels, entorhinal and inferior temporal tau deposition, and hippocampal atrophy. RESULTS: Participants with both memory storage and retrieval deficits (SOMI-3, -4) had smaller hippocampal volumes and higher entorhinal and inferior temporal tau burden than participants with no memory impairment (SOMI-0) or mild retrieval difficulty (SOMI-1). Amyloid burden did not differ among SOMI stages. DISCUSSION: This pilot supports the close relationship between tau pathology and memory impairment across the AD continuum.  SOMI may be useful to determine eligibility for randomized controlled trials prior to the assessment of biomarker status.

BackgroundImpairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD.MethodsIn a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized.ResultsThe rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p

Cognitive reserve is inherently a dynamic construct; however, traditional methods of estimating reserve have focused on static proxy variables. A recently proposed psychometric approach entails modeling reserve as residual cognition not explained by demographic and brain variables. In this study, we extended this approach to longitudinal measurement and examined how change in reserve relates to clinical outcomes in late life and influences the effect of brain atrophy on cognitive decline. Results indicated that cognitive reserve changes were associated with progression of clinical diagnosis. More rapid depletion of cognitive reserve was associated with faster decline in nonmemory cognitive functions, even after accounting for longitudinal brain atrophy. The effect of longitudinal brain atrophy on cognitive decline differed based on the extent to which an individual's reserve changed. Whereas depletion of reserve appeared to unmask the effects of brain atrophy on cognitive decline, maintenance of reserve buffered against the negative effects of brain atrophy. Study results highlight that changes in reserve may have important implications for individual differences in cognitive aging trajectories.

Remote, digital cognitive testing on an individual's own device provides the opportunity to deploy previously understudied but promising cognitive paradigms in preclinical Alzheimer's disease (AD). The Boston Remote Assessment for NeuroCognitive Health (BRANCH) captures a personalized learning curve for the same information presented over seven consecutive days. Here, we examined BRANCH multi-day learning curves (MDLCs) in 167 cognitively unimpaired older adults (age = 74.3 ± 7.5, 63% female) with different amyloid-β (A) and tau (T) biomarker profiles on positron emission tomography. MDLC scores decreased across ascending biomarker groups, with the A + T- group performing numerically worse (β = –0.24, 95%CI[–0.55,0.07], p = 0.128) and the A + T+ group performing significantly worse (β = –0.58, 95%CI[–1.06,–0.10], p = 0.018) than the A-T- group. Further, lower MDLC scores were associated with greater cortical thinning (β = 0.18, 95%CI[0.04,0.34], p = 0.013). Our results suggest that diminished MDLCs track with advanced AD pathophysiology, and demonstrate how a digital multi-day learning paradigm can provide novel insights about cognitive decline during preclinical AD. [ABSTRACT FROM AUTHOR]

Background: PET quantifies tau and amyloid‐ß (Aß) pathology in preclinical AD. A 2‐min digital clock‐drawing test (DCTclockTM) captures clock‐drawing outcomes and processes, potentially more sensitive to cognitive deficits in preclinical AD than pencil‐and‐paper tests. The DCTclock summary score comprised subscores targeting multi‐domain cognitive performance (i.e., Drawing Efficiency, Information Processing, Spatial Reasoning, and Simple Motor). These subscores included unique features reflecting hesitation (pen‐stroke latencies) and speed during the drawing process (Table.1). Previous cross‐sectional study showed worse performance in the Spatial Reasoning domain was associated with high Aß and tau burden in older cognitive normal (CN) participants. This study evaluates whether longitudinal changes in DCTclock performance are associated with Aß and tau burden in preclinical AD, and explores DCTclock features that are most important for such associations. Methods: A total of 204 CN participants underwent baseline and follow‐up DCTclock assessments, Aß PET ([11C]PiB) and tau PET (Flortaucipir or [18F]MK‐6240, Table.2). Global Aß and regional tau burden were estimated as distribution volume ratios in neocortical aggregate regions and standardized uptake value ratios in entorhinal and inferior temporal using cerebellar gray reference, respectively. Separate linear mixed models examined associations between longitudinal DCTclock and 1) Aß, 2) tau, and 3) Aß and tau burden, adjusted for age, sex, and education. Separate models first examined DCTclock summary scores and domain‐specific subscores. Exploratory analyses then evaluated features within domains showing significant associations. Results: Elevated baseline Aß or tau is most strongly associated with accelerated decline in DCTclock performance in the Information Processing domain (Fig.1). Evaluating both Aß and tau in a single model, only tau showed significant associations with Information Processing subscores. The associations between DCTclock and Aß or tau were driven by latency features (Information Processing domain), including latency variability, longest latency, and average latency (Table.1). Notably, these features showed improved performance longitudinally in participants without Aß/tau burden, suggesting expected practice effects. Conclusion: Our results suggest that longitudinal decline in DCTclock performance, especially in information processing or executive function, is related to early Aß/tau burden in older CN adults. Diminished longitudinal DCTclock performance, especially in latency features uniquely captured by digital tools, may reflect greater cognitive efforts in preclinical AD. [ABSTRACT FROM AUTHOR]

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]

Background: Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are currently underdiagnosed in the community, and early detection of cognitive deficits is crucial for timely intervention. FACEmemory®, the first completely self-administered online memory test with voice recognition, has been launched as an accessible tool to detect such deficits. This study aims to investigate the neuropsychological associations between FACEmemory subscores and cognitive composites derived from traditional paper-and-pencil neuropsychological tests and to develop an optimal algorithm using FACEmemory data and demographics to discriminate cognitively healthy (CH) individuals from those with MCI. Methods: A total of 669 participants (266 CH, 206 non-amnestic MCI [naMCI], and 197 amnestic MCI [aMCI]) were included. Multiple linear regression analyses were conducted using a cognitive composite as the dependent variable and FACEmemory subscores and demographic data (age, sex, and schooling) as independent variables. Machine learning models were compared to identify an optimal algorithm for distinguishing between CH and MCI (whole MCI, aMCI, and naMCI). Results: Multiple regression analyses showed associations between FACEmemory scores and the domains of memory (ρ = 0.67), executive functions (ρ = 0.63), visuospatial/visuoperceptual abilities (ρ = 0.55), language (ρ = 0.43), praxis (ρ = 0.52), and attention (ρ = 0.31). An optimal algorithm distinguished between CH and aMCI, achieving a FACEmemory cutoff score of 44.5, with sensitivity and specificity values of 0.81 and 0.72, respectively. Conclusions: FACEmemory is a promising online tool for identifying early cognitive impairment, particularly aMCI. It may contribute to addressing the underdiagnosis of MCI and dementia in the community and in promoting preventive strategies. [ABSTRACT FROM AUTHOR]

The emergence of the United States Food and Drug Administration (FDA)‐approved amyloid‐targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease‐modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid‐related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families. As the landscape evolves with the approval of new Alzheimer's therapies, this resource stands poised for updates, ensuring its continued relevance in facilitating informed and meaningful patient‐provider dialogues. Highlights: Effective communication of risks, benefits, burdens, and costs of FDA‐approved amyloid‐targeting antibodies is essential to patients, families, and healthcare providers.The Alzheimer's Association's Clinical Meaningfulness Workgroup provides language for physicians and healthcare providers around treatment eligibility, benefits, ARIA, APOE genotyping, and treatment costs.This supplementary resource may be updated as new AD therapies become approved. [ABSTRACT FROM AUTHOR]

Objective: Elevated entorhinal cortex (EC) tau in low beta‐amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)‐derived locus coeruleus integrity, neocortical beta‐amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta‐amyloid PET‐negative. Methods: We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T‐MRI of the locus coeruleus, Pittsburgh compound‐B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB− sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR‐sum‐of‐boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. Results: We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB− sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden‐index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut‐off, lower locus coeruleus integrity was associated with a two‐fold increase in clinical progression, including mild cognitive impairment. Interpretation: Locus coeruleus integrity has promise as a low‐cost, non‐invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta‐amyloid individuals. ANN NEUROL 2024;96:650–661 [ABSTRACT FROM AUTHOR]

Validation of the Mobile Toolbox Faces and Names associative memory test is presented. Ninety‐two participants self‐administered Faces and Names in‐person; 956 self‐administered Faces and Names remotely but took convergent measures in person; and 123 self‐administered Faces and Names remotely twice, 14 days apart. Internal consistency (.76–.79) and test–retest reliability (ICC = .73) were acceptable. Convergent validity with WMS‐IV Verbal Paired Associates was satisfactory (immediate .54; delayed .58). The findings suggest the remotely administered Faces and Names is a reliable instrument. [ABSTRACT FROM AUTHOR]

Background: The National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) was developed to address the need for a brief yet comprehensive instrument to facilitate more uniform assessment in large‐scale research studies. Here, we investigated whether the cognitive measures of the NIHTB detect cognitive decline in biomarker‐confirmed Alzheimer's disease (AD). Method: We used data from N = 178 participants (age 76.5±8; 53% female) from the Assessing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA) study, who were recruited across nine research centers in the United States and had amyloid PET or amyloid‐beta42/tau CSF data available within two years of their baseline NIHTB assessment. Participants' cognitive status (normal (CN) or impaired (CI), based on standardized protocols) and amyloid status (Aβ‐/Aβ+, based on site‐specific cut‐offs) were combined to create three groups: healthy controls (CN Aβ‐, n = 113), asymptomatic AD (CN Aβ+, n = 24), and prodromal‐to‐mild AD (CI Aβ+, n = 34) (Table 1). The NIHTB was assessed at baseline, 12 and 24 months and includes five tasks measuring fluid cognition (attention, executive functions, processing speed, working memory, and episodic memory) and two tasks reflecting crystallized cognition (oral word reading and auditory word comprehension). Linear mixed‐effect models correcting for age, sex, and education were used to examine cross‐sectional and longitudinal NIHTB scores in the three study groups. Result: Compared to healthy controls, the prodromal‐to‐mild AD group had lower baseline scores on most NIHTB fluid tasks (Flanker Inhibitory Control and Attention, Dimensional Change Card Sort, Picture Sequence Memory, List Sort Working Memory) and showed accelerated decline over 12‐24 months on Pattern Comparison Processing Speed, List Sorting Working Memory and Picture Vocabulary (Figure 1). None of the NIHTB tasks detected cross‐sectional or longitudinal differences in the asymptomatic Aβ+ group compared to healthy controls over the course of this study. Conclusion: The NIHTB detects cross‐sectional impairment in episodic memory, attention, executive functions and working memory and longitudinal change in processing speed, working memory and auditory word comprehension in prodromal‐to‐mild AD. These findings further support the use of the NIHTB in AD research, but also imply that the optimal NIHTB composite to detect cognitive decline may differ across AD clinical stages. [ABSTRACT FROM AUTHOR]

ImportanceAs Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.ObjectiveTo demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study).Design, setting, and participantsWith the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.Main outcomes and measuresFor the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD "Aβ-positive" placebo group and compare them with an "Aβ-negative" group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ε4 and by clinical progression.ResultsIn ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P = .01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P = .002). In the ADCS-PI study, APOE-ε4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P = .01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P

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. [ABSTRACT FROM AUTHOR]