Albert, Marilyn

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E (APOE) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort’s median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aβ42/40, total tau, and Aβ42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.

Abstract Preclinical Alzheimer’s disease describes some individuals who harbour Alzheimer’s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer’s-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including APOE-ɛ4 and APOE-ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n = 808) where amyloid burden was assessed by Pittsburgh Compound B ([11C]-PiB) positron emission tomography. In this study, we found that APOE-ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P = 1.46 × 10−8; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P = 0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.

Introduction: Understanding the role of risk factors associated with accelerated cognitive decline has important public health relevance for the aging US population. To test hypotheses that mid-life cardiovascular (CV) risk factors increase risk of dementia in old age, the Atherosclerosis Risk in Communities (ARIC) cohort was evaluated for dementia in 2011-2013. Anticipating challenges of complete dementia ascertainment in an elderly population, supplementary data sources were collected to aid analysis accounting for potentially informative attrition. Methods: ARIC enrolled 15,792 participants 45-64 years old at baseline (1987-1989) from four US communities and collected baseline CV exposure data. A complete neurocognitive battery including informant interview was completed 2011-2013, yielding an algorithmic diagnosis of dementia, mild cognitive impairment (MCI) or normal cognition. Cognitively impaired and a random sample of cognitively normal were selected for further clinical evaluation. Syndromic diagnoses (dementia/MCI/normal) and etiologic diagnoses were made by a panel of experts using standardized criteria. Standardized protocols, timely reports of reviewer reliability, ongoing training of reviewers and a web-based data management system were developed to ensure reliability, consistency and efficiency of data collection and review. Living participants not attending the visit were asked to complete the Telephone Interview for Cognitive Status (TICS). Based on dementia discharge codes and death codes identified during cohort surveillance, interviewer impression of hearing loss or cognitive impairment or need for a proxy during semi-annual calls, or random sampling, participants refusing the TICS are eligible for proxy dementia interview. Medicare claims are being examined to identify missed dementia discharge codes. Results: Of 11,017 participants alive as of 2011, 6495 (59%) completed the neurocognitive battery; 2937 of these (45%) were selected for, and completed, additional clinical assessments and classification by committee (algorithmic or reviewer diagnosis: dementia 5%, MCI 21%). Of the 4522 participants who did not undergo the neurocognitive battery, 1463 (32%) completed the TICS (dementia 7%), while 1627 of the remaining participants were eligible for proxy calls (903 completed to date, dementia 58%). Conclusions: Participants who were not examined were more likely to be cognitively impaired, highlighting the importance of collecting supplementary data to support analyses of midlife CV risk factors accounting for informative attrition. Collection of exam data in an elderly cohort is difficult and requires a multi-pronged approach, especially for an outcome highly correlated with attrition. The strategy described here could be applied in other settings.

Introduction: The microvascular contribution to dementia may be under-recognized because of the inability to visualize the brain microvasculature in vivo. Although the easily-imaged retinal vasculature may be a surrogate measure for that in the brain, large prospective studies of the relationship between retinal vascular signs and dementia are scarce. Hypothesis: Retinal signs are associated with greater subsequent risk of all-cause dementia and etiologic subtype over 20 years in 12482 men and women (mean age of 60 years when retinal signs were measured, 22% African American). Methods: Retinal signs were measured using fundus photography (1993-1995). Presence and etiology of dementia and mild cognitive impairment (MCI) were adjudicated using data collected in 2011-13, including a complete neuropsychological battery and brain magnetic resonance imaging (subset of participants). For participants not attending the 2011-13 visit, dementia cases were identified using the Telephone Interview for Cognitive Status–Modified or informant interview, or by hospitalization or death certificate code. Multivariable-adjusted Cox proportional hazards models and logistic regression were used to quantify the relationship of retinal signs with dementia risk and with etiologic subtype, respectively. Results: During a mean 16 years of follow-up, 1259 (10%) participants developed dementia. Moderate or severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% CI: 1.36, 2.55) and generalized arteriolar narrowing, measured as the central retinal arteriolar equivalent (CRAE, narrowest quartile vs. widest three quartiles), (HR, 1.26; 95% CI: 1.09, 1.45) were associated with all-cause dementia. Results did not differ by diabetes, race or APOE ε4 genotype. Retinopathy was associated with cerebrovascular-related dementia and MCI (odds ratio, 2.66; 95% CI: 1.30, 5.42). Conclusions: Retinal photography captures small vascular signs in the eye that are related to increased dementia risk. Emerging techniques, such as optical coherence tomography angiography, may have the sensitivity to provide surrogate indices of microvascular lesions relevant to dementia in older adults.

Background: Vascular risk factors have been associated with risk of cognitive decline, with increasing evidence that midlife exposure to these risk factors may be most important in conferring late-life risk of cognitive impairment. We explored associations between vascular risk factors measured in midlife and the development of dementia over 25 years in the biracial Atherosclerosis Risk in Communities (ARIC) cohort. Methods: Participants in the ARIC study were recruited from four U.S. communities in 1987-1989, at ages 45-64, with four additional in-person visits, surveillance for hospitalizations, annual phone calls, and repeated cognitive evaluations over a 25-year period. In 2011-2013, ARIC participants were seen for the ARIC Neurocognitive Study (ARIC-NCS), and underwent a detailed neurocognitive battery and informant interviews. Through adjudicated review, dementia cases were defined. Additional dementia cases were identified through the telephone interview for cognitive status (TICS) or informant interview for those participants not attending ARIC-NCS; or by a prior dementia ICD-9 code during a hospitalization. Results: Of 15,744 participants in the cohort, 1516 cases of dementia were identified, of whom over one third were among black participants. Risk of dementia was highest in individuals of black race, with less than a high school education, older age, APOE ε4 carriage, and who, at ARIC baseline, had hypertension, diabetes, or were current smokers (table). APOE ε4 and smoking were each stronger risk factors for dementia in whites than in blacks. Discussion: Vascular risk factors measured in midlife are associated with increased risk of dementia in this biracial cohort, in black and white participants. The risk associated with diabetes nears the increased risk associated with having an APOE ε4 allele. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Introduction: Cerebral microbleed (CMB) location may predict underlying pathology. Deep CMBs are more associated with hypertensive vascular disease, while lobar CMBs are more associated with cerebral amyloid angiopathy (CAA). The objective of this study was to determine the neuroimaging pathology associated with CMBs. Methods: We analyzed 1,831 nondemented ARIC participants (mean age=76.3 ±5.3 years, 40% male, 27% black) with 3T MRI scans at the fifth exam (2011-13). We fit multinomial logistic regression models to assess the effect of brain volumes (AD signature region atrophy, total gray matter, frontal, and log 2 -transformed white matter hyperintensities (WMH) volume), infarct frequencies (lacunar, non-lacunar, and total), and APOE (number of ε4 alleles) on CMB location (no, any deep, or lobar only CMBs). Models were weighted for the sample selection scheme and adjusted for age, male, education, hypertension, ever smoking status, diabetes, race-site membership, and estimated intracranial volume (brain volume models only). Results: The frequency of CMBs was 24.1%. A larger WMH volume, greater total infarct frequency, and smaller total grey volume increased the relative risks (RR) of both deep and lobar CMBs compared to no CMBs; increasing the WMH volume also increased the RR of deep to lobar CMBs. Additional lacunar infarcts increased the RR of deep compared to no CMBs, whereas AD signature region atrophy and APOE ε4 homozygosity increased the RR of lobar CMBs. Conclusion: CMBs are a common vascular pathology in the elderly. Deep CMB presence is associated with MRI features of hypertensive small vessel disease, while lobar CMB presence is associated with MRI features of CAA and Alzheimer’s disease.