Mayo Clinic Study Of Aging Research Articles

Mayo normative studies: regression-based normative data for ages 30-91 years with a focus on the Boston Naming Test, Trail Making Test and Category Fluency.

Normative neuropsychological data are essential for interpretation of test performance in the context of demographic factors. The Mayo Normative Studies (MNS) aim to provide updated normative data for neuropsychological measures administered in the Mayo Clinic Study of Aging (MCSA), a population-based study of aging that randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. We examined demographic effects on neuropsychological measures and validated the regression-based norms in comparison to existing normative data developed in a similar sample. The MNS includes cognitively unimpaired adults ≥30 years of age (n = 4,428) participating in the MCSA. Multivariable linear regressions were used to determine demographic effects on test performance. Regression-based normative formulas were developed by first converting raw scores to normalized scaled scores and then regressing on age, age2, sex, and education. Total and sex-stratified base rates of low scores (T < 40) were examined in an older adult validation sample and compared with Mayo's Older Americans Normative Studies (MOANS) norms. Independent linear regressions revealed variable patterns of linear and/or quadratic effects of age (r2 = 6-27% variance explained), sex (0-13%), and education (2-10%) across measures. MNS norms improved base rates of low performance in the older adult validation sample overall and in sex-specific patterns relative to MOANS. Our results demonstrate the need for updated norms that consider complex demographic associations on test performance and that specifically exclude participants with mild cognitive impairment from the normative sample.

Modeling the temporal evolution of plasma p-tau in relation to amyloid beta and tau PET.

The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints. Individual timing of plasma p-tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants. Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aβ PET was the strongest. Plasma p-tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p-tau was associated with Aβ PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aβ PET.

Vascular risk, gait, behavioral, and plasma indicators of VCID.

Cost-effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non-imaging indicators of VCID using magnetic resonance imaging (MRI)-measured white matter (WM) damage and hypothesized that these indicators differ based on age. In 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid-attenuated inversion recovery (FLAIR)-MRI, we examined associations between baseline non-imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles. VRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata. Non-imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID. Non-imaging indicators of VCID can aid in prediction of MRI-measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non-imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non-imaging VCID indicators proposed in the future.

Determination of the Trans-Lamina Cribrosa Pressure Difference in a Community-Based Population and its Association with Open-Angle Glaucoma

To determine the trans-lamina cribrosa pressure difference (TLCPD) in a cohort of normal community-based patients and the relationship to primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). Retrospective cohort study of the Mayo Clinic Study of Aging. The Mayo Clinic Study of Aging is a prospective study evaluating the normal aging population. Mayo Clinic Study of Aging patients who underwent routine lumbar puncture (LP) studies with eye examinations were reviewed. The trans-lamina cribrosa pressure difference was calculated in 2 contexts of intraocular pressure (IOP): (1) maximum IOP at eye visit closest in time to the LP (closest-in-time TLCPD); and (2) IOP before IOP-lowering treatment (pretreatment IOP and pretreatment TLCPD) in POAG and NTG patients. Glaucoma patients without POAG or NTG were excluded. Regression analyses were performed to determine the relationship with glaucoma. IOP, intracranial pressure, TLCPD, POAG, normal-tension glaucoma (NTG) diagnosis, glaucoma parameters. Five hundred forty-eight patients were analyzed. Of these, there were 38 treated glaucoma patients (14 POAG and 24 NTG) and 510 nonglaucomatous patients. Cerebral spinal fluid (CSF) opening pressure was 155.0 ± 42.2 mmH2O in nonglaucomatous patients, 144.0 ± 34.0 mmH2O in POAG (P= 0.15 vs. nonglaucomatous patients), and 136.6 ± 29.3 mmH2O in NTG (P= 0.017 vs. nonglaucomatous patients). Intraocular pressure was 15.47 ± 2.9 mmHg in nonglaucomatous patients, 26.6 ± 3.7 mmHg in POAG, and 17.4 ± 3.4 mmHg in NTG. The closest-in-time TLCPD in the nonglaucomatous cohort was 4.07 ± 4.22 mmHg, which was lower than both the POAG cohort (7.19 ± 3.6 mmHg) and the NTG cohort (5.79 ± 4.5 mmHg, P= 0.04). Pretreatment TLCPD for the overall glaucoma cohort was 10.57 ± 6.1 mmHg. The POAG cohort had a higher pretreatment TLCPD (16.05 ± 5.2 mmHg) than the NTG cohort (7.37 ± 4.1 mmHg; P < 0.0001). Closest-in-time TLCPD for the nonglaucoma cohort (4.07± 4.2 mmHg) was significantly lower than pretreatment TLCPDs for both POAG (16.05 ± 5.2 mmHg; P < 0.0001) and NTG (7.37 ± 4.1 mmHg; P < 0.0001) cohorts. This study establishes the baseline TLCPD in a large cohort of normal, community-based patients. The differences in regression analysis between TLCPD and IOP suggests NTG pathophysiology is partially driven by TLCPD, but is also likely multifactorial. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Characterizing Performance Gaps of a Code-Based Dementia Algorithm in a Population-Based Cohort of Cognitive Aging.

Multiple algorithms with variable performance have been developed to identify dementia using combinations of billing codes and medication data that are widely available from electronic health records (EHR). If the characteristics of misclassified patients are clearly identified, modifying existing algorithms to improve performance may be possible. To examine the performance of a code-based algorithm to identify dementia cases in the population-based Mayo Clinic Study of Aging (MCSA) where dementia diagnosis (i.e., reference standard) is actively assessed through routine follow-up and describe the characteristics of persons incorrectly categorized. There were 5,316 participants (age at baseline (mean (SD)): 73.3 (9.68) years; 50.7% male) without dementia at baseline and available EHR data. ICD-9/10 codes and prescription medications for dementia were extracted between baseline and one year after an MCSA dementia diagnosis or last follow-up. Fisher's exact or Kruskal-Wallis tests were used to compare characteristics between groups. Algorithm sensitivity and specificity were 0.70 (95% CI: 0.67, 0.74) and 0.95 (95% CI: 0.95, 0.96). False positives (i.e., participants falsely diagnosed with dementia by the algorithm) were older, with higher Charlson comorbidity index, more likely to have mild cognitive impairment (MCI), and longer follow-up (versus true negatives). False negatives (versus true positives) were older, more likely to have MCI, or have more functional limitations. We observed a moderate-high performance of the code-based diagnosis method against the population-based MCSA reference standard dementia diagnosis. Older participants and those with MCI at baseline were more likely to be misclassified.

Cognitive Performance, Sociodemographic Factors, Pure-Tone Audiometry, and their Association with Speech Discrimination: A Prospective Population-Based Study of 1,061 Older Adults.

Hearing loss is increasingly recognized as a chronic disease state with important health sequelae. Although considered a central component of routine audiometric testing, the degree to which various patient factors influence speech discrimination is poorly characterized to date. The primary objective of the current work was to describe associations of cognitive performance, sociodemographic factors, and pure-tone audiometry with speech discrimination in older adults. Prospective study. Olmsted County, Minnesota. There were 1,061 study participants 50 years or older at enrollment in the population-based Mayo Clinic Study of Aging between November 2004 and December 2019 who underwent formal audiometric and cognitive testing included in the current investigation. The primary outcome measure was word recognition scores (WRSs; measured as <100% vs 100% as well as continuous), with pure-tone averages (PTAs; 0.5, 1, 2, and 3 kHz), age, sex, years of education, state area deprivation index (ADI) quintiles, and global cognition z scores as explanatory features. The mean (SD) age among the 1,061 participants was 76 (9) years with 528 (50%) males. Participant age [OR (95% CI) for a 10-year increase of 1.8 (1.4-2.3), p < 0.001], male sex [OR = 2.6 (1.9-3.7), p < 0.001], and PTA [OR for a 10-dB hearing loss increase of 2.4 (2.1-2.8), p < 0.001] were all significantly associated with <100% WRSs, with the greatest explanatory ability attributable to the PTA. Years of education ( p = 0.9), state ADI quintile ( p = 0.6), and global cognitive performance ( p = 0.2) were not associated with WRS. The multivariable model demonstrated strong predictive ability for less than perfect WRSs, with a c index of 0.854. Similar results were seen for WRSs analyzed as continuous, with the multivariable model resulting in an R2 value of 0.433. Although PTA exhibited the greatest influence on speech discrimination, advancing age and male sex both independently increased the likelihood of having worse speech discrimination among older adults, even after accounting for years of education, neighborhood-level socioeconomic disadvantage, and cognitive function. These findings help identify patient factors that can be instrumental when designing screening programs for adult-onset hearing loss.

Eligibility for Anti-Amyloid Treatment in a Population-Based Study of Cognitive Aging.

Treatment options for Alzheimer disease (AD) are limited and have focused mainly on symptomatic therapy and improving quality of life. Recently, lecanemab, an anti-β-amyloid monoclonal antibody (mAb), received accelerated approval by the US Food and Drug Administration for treatment in the early stages of biomarker-confirmed symptomatic AD. An additional anti-β-amyloid mAb, aducanumab, was approved in 2021, and more will potentially become available in the near future. Research on the applicability and generalizability of the anti-β-amyloid mAb eligibility criteria on adults with biomarkers available in the general population has been lacking. The study's primary aim was to apply the clinical trial eligibility criteria for lecanemab treatment to participants with early AD of the population-based Mayo Clinic Study of Aging (MCSA) and assess the generalizability of anti-amyloid treatment. The secondary aim of this study was to apply the clinical trial eligibility criteria for aducanumab treatment in MCSA participants. This cross-sectional study aimed to apply the clinical trial eligibility criteria for lecanemab and aducanumab treatment to participants with early AD of the population-based MCSA and assess the generalizability of anti-amyloid treatment. Two hundred thirty-seven MCSA participants (mean age [SD] 80.9 [6.3] years, 54.9% male, and 97.5% White) with mild cognitive impairment (MCI) or mild dementia and increased brain amyloid burden by PiB PET comprised the study sample. Lecanemab trial's inclusion criteria reduced the study sample to 112 (47.3% of 237) participants. The trial's exclusion criteria further narrowed the number of potentially eligible participants to 19 (overall 8% of 237). Modifying the eligibility criteria to include all participants with MCI (instead of applying additional cognitive criteria) resulted in 17.4% of participants with MCI being eligible for lecanemab treatment. One hundred four participants (43.9% of 237) fulfilled the aducanumab clinical trial's inclusion criteria. The aducanumab trial's exclusion criteria further reduced the number of available participants, narrowing those eligible to 12 (5.1% of 237). Common exclusions were related to other chronic conditions and neuroimaging findings. Findings estimate the limited eligibility in typical older adults with cognitive impairment for anti-β-amyloid mAbs.

Comparison of Clinical, Genetic, and Pathologic Features of Limbic and Diffuse Transactive Response DNA-Binding Protein 43 Pathology in Alzheimer's Disease Neuropathologic Spectrum.

Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer's disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. 363 participants from the Mayo Clinic Study of Aging, Alzheimer's Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1-3 were classified as Limbic, those 4-6 as Diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. The cohort was 61% female and old at onset (median: 76 years [IQR:70-82]) and death (median: 88 years [IQR:82-92]). Fifty-four percent were Limbic and 46% Diffuse. Clinically, ∼10-20% increases in odds of being Diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores (p = 0.03), while 15-second longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by ~10-15%. There was evidence for association of APOEɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3-5) decreased the odds of diffuse TDP-43 pathology by 80-90%, while hippocampal sclerosis increased it sixfold (p < 0.001). Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP.

Association of tamoxifen and raloxifene therapy with cognitive performance, odds of mild cognitive impairment, and neuroimaging markers of neurodegeneration

AbstractBackgroundTamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone receptor‐positive breast cancer. Raloxifene, another SERM, has been used for the treatment of osteoporosis in post‐menopausal women. The aim of this cross‐sectional study was to examine whether a history of tamoxifen or raloxifene use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or structural neurodegenerative MRI markers.MethodThe study included women with and without a personal history of breast cancer enrolled in the Mayo Clinic Study of Aging (MCSA). A history of breast cancer and use of SERMs before the MCSA enrollment visit was abstracted using the Rochester Epidemiology Project medical‐linkage system. Participants had a diagnosis of MCI (prevalent) at the time of enrollment into the MCSA. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive measures z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), hippocampal volume, and Alzheimer’s disease signature cortical thickness.ResultAmong the women aged ≥ 50 at enrollment in the MCSA, 151 had a history of breast cancer, and 2235 had no prior history of any cancer. Of the 151 women with a history of breast cancer, 42 (28%) had taken tamoxifen and 109 (72%) had not at enrollment in the MCSA; 54 had neuroimaging data (tamoxifen = 16; no tamoxifen = 38). Among the women without prior history of cancer at enrollment in the MCSA, 76 (3%) had taken raloxifene and 2159 (97%) had not; 755 had neuroimaging data (raloxifene = 25; no raloxifene = 730). No significant associations between tamoxifen with global or domain‐specific cognition or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders (Table 1). Likewise raloxifene was not significantly associated with global or domain‐specific cognition or odds of MCI in women without a history of cancer after adjusting for confounders (Table 2). We did not find significant associations between SERMs and any neuroimaging outcome (Table 3).ConclusionOur results suggest use of tamoxifen or raloxifene is not significantly associated with cognition in postmenopausal women.

Cross‐sectional and longitudinal associations of plasma makers of amyloid and tau pathology and neurodegeneration with gait speed

AbstractBackgroundHigher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.MethodThis study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.ResultAt baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.ConclusionBoth cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.

Testing the brain maintenance and cognitive reserve hypothesis of cognitive aging: Application to vascular and metabolic risk factors

AbstractBackgroundTwo pathways that help explain cognitive health are 1) brain maintenance – referring to the relative absence of brain changes over time; 2) cognitive reserve – a property of the brain that allows for sustained cognitive ability in the presence of brain pathology. Both pathways influence cognitive aging and are best understood using longitudinal data. Our goal was to assess the effect of modifiable vascular/metabolic and lifestyle enrichment factors on these pathways using longitudinal brain changes measured on structural magnetic resonance imaging (MRI) and longitudinal cognitive decline. Lastly, we combined these pathways and their relationships in the same model.MethodWe identified 1250 participants from a well‐characterized sample of older adults from the Mayo Clinic Study of Aging with both longitudinal MRI and cognitive data. Linear mixed models were performed to assess the impact of modifiable factors on brain maintenance and cognitive reserve. Latent growth curve models (SEM) were used to assess the impact of brain structure and cognitive reserve on longitudinal cognition.ResultThe mean age of our sample was 78.8 years, with 45.4% female, and 27.1% APOE4 carriers. Mean follow‐up time was 4.0 years with a mean of 3.2 MRI scans per participant. Linear mixed models showed that poorer vascular/metabolic health (presence of vascular/metabolic conditions) was associated with lower cross‐sectional temporal region cortical thickness (‐0.014 (0.003), p&lt;0.001) and lower global cognition (‐0.042 (0.018), p = 0.024). Higher estimated cognitive reserve at baseline as assessed by education/occupation composite (0.103 (0.01), p&lt;0.001) was associated with higher global cognition. Unexpectedly, late‐life physical activities were related to lower global cognition (‐0.05 (0.007), p = 0.004). Our final latent growth curve SEM fit the data well showing temporal associations between unmodifiable characteristics, cognitive reserve, and brain structural pathways, as well as the influence of modifiable vascular/metabolic factors.ConclusionWe found that brain maintenance and cognitive reserve pathways were related to better cognition over time. We further showed that vascular/metabolic health impacts long‐term cognitive outcomes (i.e. cognitive aging) primarily through the brain maintenance pathway. These data provide a modeling scheme for future studies and can aid in assessing the pathways by which individual factors may influence cognitive aging.

Risk and protective factors for dementia in cancer survivors vary by cancer type.

e24089 Background: Little is known about risk and protective factors for dementia in cancer survivors. With increasing longevity due to improved cancer therapy, it’s prudent to study factors contributing to cognitive impairment in this patient population. Methods: We performed multivariable cox regression analyses to assess established risk factors for all-cause dementia (age, education, APOE4-status, social and physical activity engagement) in breast and prostate cancer survivors. Patients 50+ years old with pathology-confirmed cancer diagnosis at Mayo Clinic were identified from a longitudinal, population-based cohort – Mayo Clinic Study of Aging. Analyses were controlled for age, APOE4-status, education, and cancer treatment. Results: We included a total of 209 patients with breast cancer (mean age 75.4 years, 24% APOE4-positive, median follow-up 6.8 years) and 352 with prostate cancer (mean age 77 years, 26% APOE4-positive, median follow-up 6.4 years). 31 patients with breast cancer (15%) and 66 patients with prostate cancer (20%) were diagnosed with dementia at last follow-up. Older age was associated with increased risk for dementia (5-year increase – breast: hazard ratio (HR) 1.9 [95%CI 1.3-2.7, p = 0.001]; prostate: HR 2.4 [95%CI 1.8-3.2, p &lt; 0.0001]). APOE4-positivity was associated with increased dementia risk in breast (HR 3.6 [95%CI 1.6-7.8, p &lt; 0.002]), but not prostate cancer (HR 1.2 [95%CI 0.7-2.0, p = 0.5]). More education was associated with lower dementia risk in prostate cancer (education year: HR 0.91 [95%CI 0.84-0.98, p &lt; 0.02]; education years &gt; 12: HR 0.26 [95%CI 0.1-0.6, p &lt; 0.001]). Physical activity engagement in mid-life was associated with lower dementia risk (prostate: HR 0.56 [95%CI 0.4-0.8, p &lt; 0.005]; breast: HR 0.48 [95%CI 0.3-0.9, p &lt; 0.02]). Conclusions: In this longitudinal, population-based study we found that some risk and protective factors for dementia in cancer survivors vary by cancer type. While advanced age is an expected dementia risk factor, there were mixed results for APOE4-positivity (increased risk only in breast cancer) and education (only protective in prostate cancer). Our results support further study into factors influencing dementia risk by cancer type in hopes of identifying preventative strategies.

Mayo‐PACC: Optimizing a parsimonious Preclinical Alzheimer’s disease cognitive composite comprised of public‐domain measures

AbstractBackgroundPreclinical Alzheimer’s cognitive composites (PACC) are designed to detect subtle cognitive changes in clinical trials. PACCs often include measures of memory, attention, and semantic fluency, with variations based on available measures. We created a Mayo Clinic PACC (Mayo‐PACC) to address limitations of existing PACCs by prioritizing parsimony, non‐proprietary measures, clinical applicability, and psychometric properties. We developed a Mayo‐PACC and examined sensitivity to detecting longitudinal cognitive change in amyloid positive (A+) older adults relative to the Preclinical Alzheimer’s Cognitive Composite‐Revised (PACC‐R). Exploratory analyses included comparison to other composites.MethodParticipants included 614 individuals in the Mayo Clinic Study of Aging (428 A‐ and 186 A+) age 65‐85 who were cognitively unimpaired at baseline with 7 years mean follow‐up. A+ was defined as PiB‐PET meta‐ROI SUVR ≥ 1.48 (centiloid 22). The Mayo‐PACC included the AVLT sum of trials (trials 1‐5, short delay, long delay), Trails B and Animal fluency. Measures included in the PACC‐R and other comparison composites are listed in Table 1. We calculated study‐specific z‐scores and examined psychometric properties of component measures including test‐retest reliability, practice effects, and distributional properties (ceiling/floor effects, skew, kurtosis). We examined sensitivity to preclinical cognitive change using slope estimates (difference in annualized change across A+ and A‐ groups) from linear mixed models (LMMs) for each composite. A jackknife procedure was used to calculate the standard error and subsequent confidence intervals of differences in rates of change (A+&gt;A‐ indicating more significant decline in A+). Significance was determined based on whether the 95% Confidence Interval (CI) contained 0 (alpha = .05).ResultAll composites showed sensitivity to amyloid‐related longitudinal cognitive decline (A+&gt;A‐ annualized change p&lt;.05; see Table 2). Jack‐knife comparisons revealed comparable utility of Mayo‐PACC and PACC‐R (CI contained 0, see Table 3). Exploratory analyses revealed Mayo‐PACC performed similarly to an adaptation of the ADCS‐PACC, Global‐z, Memory‐z and Attention‐z. The Mayo‐PACC performed better than a 2‐measure Mayo‐PACC‐remote and a single memory measure.ConclusionThe Mayo‐PACC provides a parsimonious composite score that has comparable utility for detecting A+&gt;A‐ cognitive decline compared to the PACC‐R and other composites and can be widely used in both research and clinical settings.

Evidence against a temporal association between cerebrovascular disease and Alzheimer’s disease imaging biomarkers

Whether a relationship exists between cerebrovascular disease and Alzheimer’s disease has been a source of controversy. Evaluation of the temporal progression of imaging biomarkers of these disease processes may inform mechanistic associations. We investigate the relationship of disease trajectories of cerebrovascular disease (white matter hyperintensity, WMH, and fractional anisotropy, FA) and Alzheimer’s disease (amyloid and tau PET) biomarkers in 2406 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants using accelerated failure time models. The model assumes a common pattern of progression for each biomarker that is shifted earlier or later in time for each individual and represented by a per participant age adjustment. An individual’s amyloid and tau PET adjustments show very weak temporal association with WMH and FA adjustments (R = −0.07 to 0.07); early/late amyloid or tau timing explains <1% of the variation in WMH and FA adjustment. Earlier onset of amyloid is associated with earlier onset of tau (R = 0.57, R2 = 32%). These findings support a strong mechanistic relationship between amyloid and tau aggregation, but not between WMH or FA and amyloid or tau PET.

Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea.

Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter (WM) integrity in older adults with obstructive sleep apnea (OSA). From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least 1 brain MRI and PSG. We quantified 2 CVD biomarkers: WM hyperintensities (WMHs) from fluid-attenuated inversion recovery (FLAIR)-MRI, and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (NREM stage 1 percentage, NREM stage 3 percentage [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOE ε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG. We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± SD age was 72.7 ± 9.6 years at MRI with nearly 60% being men. The absolute median (interquartile range [IQR]) interval between MRI and PSG was 1.74 (0.9-3.2) years. 90.7% were cognitively unimpaired (CU) during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006-0.111, p = 0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p = 0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005-0.015] vs 0.006 [0.003-0.009], p = 0.042) and lower genu FA (median [IQR] 0.57 [0.55-0.63] vs 0.63 [0.58-0.65], p = 0.007), when compared with those with mild/moderate OSA. We found that reduced slow-wave sleep and severe OSA were associated with higher burden of WM abnormalities in predominantly CU older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation.

Eligibility for Anti-Amyloid Treatment in a Population-Based Cohort Study of Aging (P5-6.006)

Eligibility for Anti-Amyloid Treatment in a Population-Based Cohort Study of Aging (P5-6.006)

Optical Coherence Tomography Angiography (OCTA) Retinal Imaging Can Detect Burden of Small Vessel Disease and Amyloid Deposition in the Brain (P11-5.001)

<h3>Objective:</h3> To investigate the utility of retinal imaging with optical coherence tomography angiography (OCTA) metrics as noninvasive biomarkers of small vessel disease and amyloid burden in the brain. <h3>Background:</h3> OCTA allows visualization and density measurements of the capillaries at various levels of the retina. Vascular changes and amyloid deposition associated with Alzheimer’s Disease (AD) and other dementias may be reflected as density changes in the retinal capillaries, making OCTA a noninvasive preclinical biomarker of small vessel disease and dementia. <h3>Design/Methods:</h3> We investigated associations between OCTA and neuroimaging metrics in 47 cognitively unimpaired participants from the Mayo Clinic Study of Aging. OCTA metrics were used as predictors and included superficial and deep capillary density of the fovea, parafovea, and macula as well as the foveal avascular zone (FAZ) area from both eyes. Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds, presence of lacunar infarcts, and the presence of amyloid deposition as evidenced on positron emission tomography (PET). We used linear models to test associations between OCT predictors and neuroimaging outcomes while controlling for age and sex. <h3>Results:</h3> Associations between neuroimaging metrics were restricted to the fovea, showing decreased capillary density with increased burden of WMH in both the superficial (p = 0.014) and deep (p = 0.013) fovea but not the parafovea or whole macula. Similarly, participants with amyloid deposition had decreased capillary density in the superficial (p=0.012) and deep (p = 0.015) fovea but not the parafovea or macula. Participants with amyloid deposition also had a significantly larger FAZ (p = 0.029). No associations were found between OCT metrics and presence of cerebral microbleeds or presence of lacunar infarcts. <h3>Conclusions:</h3> The foveal capillary density associations observed suggest a possible common mechanism of disease between small vessel disease and Alzheimer’s disease pathologies. <b>Disclosure:</b> Dr. Bermudez has nothing to disclose. Timothy Lesnick has received personal compensation for serving as an employee of Mayo Clinic. Dr. More has received intellectual property interests from a discovery or technology relating to health care. Dr. Ramanan has nothing to disclose. Dr. Knopman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for DIAN TU study. The institution of Dr. Knopman has received research support from NIH. Dr. Vemuri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Miller Medical Communications Inc.. The institution of Dr. Vemuri has received research support from NIH. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nestle. Dr. Petersen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech, Inc.. Dr. Petersen has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche, Inc.. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Graff-Radford has received personal compensation for serving as an employee of Mayo Clinic. Dr. Graff-Radford has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NINDS/NIH. Dr. Graff-Radford has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Graff-Radford has received research support from NIH. John J. Chen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. John J. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. John J. Chen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon.

The Experience of The COVID-19 Pandemic in a Population-Based Study of Cognitive Aging (P5-10.001)

<h3>Objective:</h3> To describe the COVID-19 pandemic experience (i.e., testing, infections, hospitalizations, patient characteristics) in participants of the population-based Mayo Clinic Study of Aging. <h3>Background:</h3> Older adults are at higher risk of worse outcomes following COVID-19 infection, especially those with comorbidities, including cognitive impairment <h3>Design/Methods:</h3> In a cohort of 4429 MCSA participants, we retrieved COVID-19 testing from March 2020 to September 2022 using the Rochester Epidemiology Project resources. In addition, we assessed “severe infection,” defined as hospitalization within 7 days before to 3 months after a positive test. All participants undergo a comprehensive cognitive evaluation in MCSA at every visit. Chi-squared tests and t-tests for two samples with equal variances were used to compare groups <h3>Results:</h3> 3399 (76.7%) participants were ever tested for COVID-19 infection, and 956 (mean age (SD) at first positive test: 71.3 (15.5) years; 51.3% male) tested positive. Participants who underwent testing (ever vs. never tested) were on average older, with higher body mass index (BMI), higher Charlson comorbidity index (CCI), and were more likely to be retired. Participants who tested positive (vs. negative) were on average younger, less likely to have cognitive impairment or be retired and had lower CCI. Participants with “severe infection” (N=212 (22.2%); vs. not “severe”) were on average significantly older, more likely to have cognitive impairment, higher CCI, higher national Area Deprivation Index ranking, fewer years of education and were more likely to be retired <h3>Conclusions:</h3> MCSA participants who tested positive were more likely to be younger and not cognitively impaired while those with severe infections were likely to be older and cognitively impaired. Our findings from a population-based study add to accumulating knowledge that suggests the importance of age and cognitive impairment for COVID-19 severe infection, eliminating reporting bias. Findings underscore valuable information to consider in future pandemic prevention interventions <b>Disclosure:</b> Dr. Ghoniem has nothing to disclose. Jeremiah Aakre has nothing to disclose. Anna Castillo has nothing to disclose. Dr. Elminawy has nothing to disclose. The institution of Dr. Machulda has received research support from NIH. The institution of Dr. Geda has received research support from NIH. Dr. Vemuri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Miller Medical Communications Inc.. The institution of Dr. Vemuri has received research support from NIH. The institution of Dr. Jack has received research support from NIH. The institution of Dr. Jack has received research support from Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr. Graff-Radford has received personal compensation for serving as an employee of Mayo Clinic. Dr. Graff-Radford has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NINDS/NIH. Dr. Graff-Radford has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. The institution of Dr. Graff-Radford has received research support from NIH. Dr. Knopman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for DIAN TU study. The institution of Dr. Knopman has received research support from NIH. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nestle. Dr. Petersen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech, Inc.. Dr. Petersen has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche, Inc.. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. The institution of Dr. Vassilaki has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for F. Hoffmann-La Roche Ltd . Dr. Vassilaki has stock in Abbott Laboratories. Dr. Vassilaki has stock in Johnson and Johnson. Dr. Vassilaki has stock in Medtronic. Dr. Vassilaki has stock in Amgen. Dr. Vassilaki has stock in AbbVie. Dr. Vassilaki has stock in Merck. The institution of Dr. Vassilaki has received research support from NIH. The institution of Dr. Vassilaki has received research support from European Union/ St. Anne’s University Hospital Brno, Czech Republic. The institution of an immediate family member of Dr. Vassilaki has received research support from Avobis Bio, LLC.

Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer's Disease and Vascular Pathology.

The National Institute on Aging-Alzheimer's Association Research Framework proposes defining Alzheimer's disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer's disease pathology measured by Aβ42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aβ42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aβ42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Default mode network failure and neurodegeneration across aging and amnestic and dysexecutive Alzheimer's disease.

From a complex systems perspective, clinical syndromes emerging from neurodegenerative diseases are thought to result from multiscale interactions between aggregates of misfolded proteins and the disequilibrium of large-scale networks coordinating functional operations underpinning cognitive phenomena. Across all syndromic presentations of Alzheimer's disease, age-related disruption of the default mode network is accelerated by amyloid deposition. Conversely, syndromic variability may reflect selective neurodegeneration of modular networks supporting specific cognitive abilities. In this study, we leveraged the breadth of the Human Connectome Project-Aging cohort of non-demented individuals (N = 724) as a normative cohort to assess the robustness of a biomarker of default mode network dysfunction in Alzheimer's disease, the network failure quotient, across the aging spectrum. We then examined the capacity of the network failure quotient and focal markers of neurodegeneration to discriminate patients with amnestic (N = 8) or dysexecutive (N = 10) Alzheimer's disease from the normative cohort at the patient level, as well as between Alzheimer's disease phenotypes. Importantly, all participants and patients were scanned using the Human Connectome Project-Aging protocol, allowing for the acquisition of high-resolution structural imaging and longer resting-state connectivity acquisition time. Using a regression framework, we found that the network failure quotient related to age, global and focal cortical thickness, hippocampal volume, and cognition in the normative Human Connectome Project-Aging cohort, replicating previous results from the Mayo Clinic Study of Aging that used a different scanning protocol. Then, we used quantile curves and group-wise comparisons to show that the network failure quotient commonly distinguished both dysexecutive and amnestic Alzheimer's disease patients from the normative cohort. In contrast, focal neurodegeneration markers were more phenotype-specific, where the neurodegeneration of parieto-frontal areas associated with dysexecutive Alzheimer's disease, while the neurodegeneration of hippocampal and temporal areas associated with amnestic Alzheimer's disease. Capitalizing on a large normative cohort and optimized imaging acquisition protocols, we highlight a biomarker of default mode network failure reflecting shared system-level pathophysiological mechanisms across aging and dysexecutive and amnestic Alzheimer's disease and biomarkers of focal neurodegeneration reflecting distinct pathognomonic processes across the amnestic and dysexecutive Alzheimer's disease phenotypes. These findings provide evidence that variability in inter-individual cognitive impairment in Alzheimer's disease may relate to both modular network degeneration and default mode network disruption. These results provide important information to advance complex systems approaches to cognitive aging and degeneration, expand the armamentarium of biomarkers available to aid diagnosis, monitor progression and inform clinical trials.