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Objective: To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations., Methods: Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models., Results: The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001-0.01] and DBP: β = 0.01 [95% CI, 0.003-0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes., Conclusion: Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life., Competing Interests: Financial disclosure/conflicts of interest: K.K. served on the data safety monitoring board of Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid Radiopharmaceuticals and Eli Lilly. She consults for Biogen. L.P. is a member of the advisory board for Flo Health, and receives ongoing funding from Win Fertility and Wolters Kluwer. C.G.S. reports receiving research funds from the NIH. M.L.S. reports receiving research funds from the DoD. J.A.F. receives ongoing institutional funding from the NIH. V.J.L. receives ongoing institutional funding from Siemens Healthcare, current institutional funding from Avid Pharmaceuticals, and past funding from PEERview, Inc. M.M.-A. receives ongoing funding from Biomedical Research Alliance of New York. M.I.C. receives institutional funding from the NIH and funding from UptoDate and American Society of Reproductive Medicine—Presidential Chain. F.N.N. receives funding from e-Bio Copr. (regulation of uterine contractility) and Interactome Biotherapeutics Corp. (exosome-related). E.K. receives ongoing funding from Mithra Pharma, current funding from Womaness, and past funding from Astellas Pharma. N.S. receives ongoing funding from Astellas, Amazon project Ember, and Ansch Labs, and is a member of the Menogenix scientific advisory board. The other authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Introduction: Early-onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%-8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early-onset dementia., Methods: Data from 307 cognitively normal (CN) volunteer participants and those with amyloid-positive EOAD or amyloid-negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed-effects modeling., Results: The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD., Discussion: EOAD declined 2-4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease-modifying medications., Highlights: Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller-scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD., Methods: Z-score cognitive-domain composites for 311 amyloid-positive sporadic EOAD and 314 amyloid-positive LOAD participants were calculated from baseline data from age-appropriate control cohorts. Z-score composites were compared between AD groups for each domain., Results: After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory., Discussion: Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non-amnestic impairments in younger patients to ensure proper identification and intervention using disease-modifying treatments., Highlights: Both early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same-aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv-PPA), and frontal-variant AD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial., Methods and Findings: The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline., Conclusions: In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population., Competing Interests: K.K. served on the data safety monitoring board for Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid. MM-A received consulting fees from the Biomedical Research Alliance of New York. Radiopharmaceuticals, Eli Lilly. She consults for Biogen., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Practice effects (PE) are traditionally considered improvements in performance observed resulting from repeated exposure to test materials across multiple testing sessions. While PE are commonly observed for memory tests, this effect has only been considered in summary total scores. The current objective was to consider PE in summary total scores, individual learning trials, and learning slopes., Method: One-week PE for individual trial and learning slope performance was examined on the BVMT-R and HVLT-R in 151 cognitively intact participants and 131 participants with Mild Cognitive Impairment (MCI) aged 65 years and older., Results: One-week PE were observed across all trials and summary total scores for both memory measures and diagnostic classifications, despite the potential for ceiling effects to limit improvement on retesting. PE were largest on the first trial relative to subsequent learning trials. This effect was diminished - but not eliminated - in participants with MCI. Conversely, no PE were observed for learning slope scores, which was counter to expectations and likely confounded by ceiling effects., Conclusions: PE were present across learning trials but not learning slopes, and the initial learning trial at follow-up tended to benefit most from PE relative to subsequent learning trials. Ceiling effects appeared to influence PE for learning slopes more than learning trials. These results highlight the potential diagnostic utility of PE across individual learning trials and inform how they are distributed at follow-up, while also suggesting that learning slopes may be generally stable during longitudinal assessment.

Introduction: We examined the burden of neuropsychiatric symptoms (NPSs) in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD) and adjusted for age effects via the inclusion of cognitively unimpaired (CU) individuals., Methods: Cross-sectional data from 2940 EOAD, 8665 LOAD, and 8775 age-stratified CU individuals (early-CU, n = 2433; late-CU, n = 6342) from the National Alzheimer's Coordinating Center database were included. Fisher's exact tests compared EOAD and LOAD on the presence and severity of NPSs. Multiple logistic regression models included an age*diagnosis interaction to examine age effects., Results: Presence (ps < 0.0001) and severity (ps < 0.05) of NPS were greater in EOAD than in LOAD. However, after adjusting for base rates in NPS in CU individuals (age effects), only elation and eating behaviors were more frequent in EOAD (ps < 0.05) and nighttime behaviors more frequent and severe in LOAD (ps < 0.05)., Discussion: Few NPSs were specific to the EOAD versus LOAD. Previous findings of greater NPS burden in EOAD may partially reflect age effects., Highlights: Adjusting for age effect, elation and eating problems are more frequent in EOAD. Adjusting for age effect, sleep disturbances are more frequent and severe in LOAD. Age effects underlie higher neuropsychiatric symptom presentation in EOAD than in LOAD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Early-onset dementia (EOD, onset age < 65) and late-onset dementia (LOD, onset age ≥ 65) exhibit distinct features. Understanding the risk factors for dementia development and mortality in EOD and LOD respectively is crucial for personalized care. While risk factors are known for LOD development and mortality, their impact on EOD remains unclear. We aimed to investigate how hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and osteoporosis influence the development and mortality of EOD and LOD, respectively., Methods: Using the Korean National Health Insurance Service (NHIS) database, we collected 546,709 dementia-free individuals and followed up for 11 years. In the two study groups, the Younger group (< 65 years old) and the Older group (≥ 65 years old), we applied Cox proportional hazard models to assess risk factors for development of EOD and LOD, respectively. Then, we assessed risk factors for mortality among EOD and LOD., Results: Diabetes mellitus and osteoporosis increased the risk of EOD and LOD development. Hypertension increased the risk of EOD, while atrial fibrillation increased the risk of LOD. Conversely, hyperlipidemia exhibited a protective effect against LOD development. Additionally, diabetes mellitus increased mortality in EOD and LOD. Hypertension and atrial fibrillation increased mortality in LOD, while hyperlipidemia decreased mortality in EOD and LOD., Conclusions: Risk factors influencing dementia development and mortality differed in EOD and LOD. Targeted public health interventions addressing age-related risk factors may reduce dementia incidence and mortality., (© 2024. The Author(s).)

Quantifying learning deficits provides valuable information in identifying and diagnosing mild cognitive impairment and dementia. Previous research has found that a learning ratio (LR) metric, derived from the list learning test from the Neuropsychological Assessment Battery (NAB), was able to distinguish between those with normal cognition versus memory impairment. The current study furthers the NAB LR research by validating a NAB story LR, as well as an aggregate LR. The aggregate LR was created by combining the individual list and story LRs. Participants were classified as those with normal cognition ( n = 51), those with MCI ( n = 39) and those with dementia ( n = 35). Results revealed the story LR was able to accurately distinguish normal controls from those with mild cognitive impairment and those with dementia and offers enhanced discriminability beyond the story immediate recall score (sum of trial 1 and trial 2). Further, the aggregate LR provided superior discriminability beyond the individual list and story LRs and accounted for additional variance in diagnostic group classification. The NAB aggregate LR provides improved sensitivity in detecting declines in impaired learning, which may assist clinicians in making diagnoses earlier in a disease process, benefiting the individual through earlier interventions.

Background: Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD) remain understudied, especially with how they compare to biomarkers of AD., Objective: The current study sought to add to this growing literature., Methods: Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 status., Results: The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons., Conclusion: Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.

Objective: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS)., Methods: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits., Results: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance., Conclusions: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years., Competing Interests: Financial disclosure/conflicts of interest: Dr Kantarci served on the data safety monitoring board for Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid Radiopharmaceuticals, Eli Lilly. She consults for Biogen. Dr Santoro is a member of the Scientific Advisory Boards for Astellas, Que Oncology, Amazon (Ember), and Menogenix, Inc. She is a consultant for Ansh Labs and has received grant support (to her institution) from Menogenix, Inc. Dr Kapoor is funded in part by the National Institute on Aging (NIA grant U54 AG044170). Dr Kapoor has no conflicts of interest directly related to the subject of this manuscript. However, over the past 36 months, she has had the following conflicts of interest: She has been a consultant for Astellas and Mithra Pharmaceuticals, Scynexis, and Womaness. She receives grant support form Mithra Pharmaceuticals. She has received payment for development of educational content from Med Learning Group and Academy of Continued Healthcare Learning. She has received honoraria for CME activity from PriMed and OBG Management. Dr Pal is a member of advisory board for Flo Health, receives ongoing funding from Springer, and has received funding in the past from Ferring. Dr Fields receives institutional grant funding from the National Institute of Health for three additional projects. Dr Malek-Ahmadi receives grant funding from Biomedical Research Alliance of New York, LLC. The other authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Background: Identifying genetic patterns that contribute to Alzheimer's disease (AD) is important not only for pre-symptomatic risk assessment but also for building personalized therapeutic strategies., Methods: We implemented a novel simulative deep learning model to chromosome 19 genetic data from the Alzheimer's Disease Neuroimaging Initiative and the Imaging and Genetic Biomarkers of Alzheimer's Disease datasets. The model quantified the contribution of each single nucleotide polymorphism (SNP) and their epistatic impact on the likelihood of AD using the occlusion method. The top 35 AD-risk SNPs in chromosome 19 were identified, and their ability to predict the rate of AD progression was analyzed., Results: Rs561311966 (APOC1) and rs2229918 (ERCC1/CD3EAP) were recognized as the most powerful factors influencing AD risk. The top 35 chromosome 19 AD-risk SNPs were significant predictors of AD progression., Discussion: The model successfully estimated the contribution of AD-risk SNPs that account for AD progression at the individual level. This can help in building preventive precision medicine., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD)., Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated., Results: Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure., Discussion: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses., Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants., (© 2023 the Alzheimer's Association.)

Introduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)., Methods: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70)., Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD., Discussion: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants., Methods: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study., Results: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases., Discussion: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases., Highlights: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point., Methods: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70])., Results: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures., Conclusions: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant., Highlights: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present., (© 2023 the Alzheimer's Association.)

Introduction: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD)., Methods: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden., Results: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers., Discussion: The effects of sex and APOE ε4 must be considered when studying these populations., Highlights: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD., Methods: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables., Results: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time., Discussion: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores., Highlights: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD)., Methods: We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification., Results: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants., Discussion: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD., Highlights: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: In learning and memory tests that involve multiple presentations of the same material, learning slope refers to the degree to which examinees improve performances over successive learning trials. We aimed to quantitatively review the traditional raw learning slope (RLS), and the newly created learning ratio (LR) to understand the effects of demographic variables and clinical diagnoses on learning slope (e.g., limited improvement over multiple trials), and to develop demographically sensitive norms., Method: A systematic literature search was conducted to evaluate the potential for these aims to be examined across the most popular contemporary multi-trial learning tests. Two databases were searched. Following this, hierarchical linear modeling was used to examine how demographic variables predict learning slope indices. These results were in turn used to contrast the performance of clinical groups with the predicted performance of demographically similar healthy controls. Finally, preliminary normative estimates for learning slope indices were presented., Results: A total of 82 studies met criteria for inclusion in this study. However, the Rey Auditory Verbal Learning Test (RAVLT) was the only test to have sufficient trial-level learning and demographic data. Fifty-eight samples from 19 studies were quantitatively examined. Hierarchical linear models provided evidence of sex differences and a curvilinear decline in learning slope with age, with strongest and most consistent effects for LR relative to RLS. Regression-based norms for demographically corrected RLS and LR scores for the RAVLT are presented. The effect of clinical diagnoses was consistently stronger for LR, and Alzheimer's disease had the strongest effect, followed by invalid performances, severe traumatic brain injury, and seizures/epilepsy., Conclusion: Overall, LR enjoys both conceptual and demonstrated psychometric advantages over RLS. Replication of these findings can be completed by reanalyzing existing datasets. Further work may focus on the utility of using LR in diagnosis and prediction of clinical prognosis.

List-learning tasks provide a wealth of information about an individual's cognitive abilities: attention, encoding, storage, retrieval, recognition. A more recently developed metric, the Learning Ratio (LR), supplements information about cognitive ability and can assist the clinician in determining whether an individual has cognitive impairment. The LR is calculated by taking the difference between the individuals' raw score on the first learning trial and their raw score on the last learning trial, which is then divided by the number of words left to be learned after the first learning trial. A LR derived from the list-learning task from the Neuropsychological Assessment Battery (NAB) was evaluated to determine ability to distinguish those with normal cognition from those with mild cognitive impairment (MCI) and dementia. Results from the present study indicate the NAB LR is able to distinguish between clinical groups; recommended cutoffs for the NAB LR scores are provided. We also found a significant female sex-advantage for the NAB LR in those with normal memory ability and demonstrated the female sex advantage decreased with increasing memory impairment. Taken together, the NAB LR may assist clinicians in making an accurate and early diagnosis and may be helpful for tracking learning and functioning across multiple assessments. .

Background: The prevalence of dementia in Sub-Saharan Africa, particularly in French-speaking countries, has received limited attention. This study investigates the prevalence and risk factors of suspected dementia in elderly adults in Kinshasa, Democratic Republic of the Congo (DRC)., Methods: A community-based sample of 355 individuals over 65 years old was selected using multistage probability sampling in Kinshasa. Participants were screened using the Community Screening Instrument for Dementia, Alzheimer's Questionnaire, Geriatric Depression Scale, Beck Anxiety Inventory, and Individual Fragility Questionnaire, followed by clinical interview and neurological examination. Suspected dementia diagnoses were made based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria including significant cognitive and functional impairments. Prevalence and odds ratios (ORs) with 95% confidence interval (CI) were calculated using, respectively, regression and logistic regression., Results: Among 355 participants (mean age 74, SD = 7; 51% male), the crude prevalence of suspected dementia was 6.2% (9.0% in women and 3.8% in men). Female sex was a significant factor associated with suspected dementia [OR = 2.81, 95% CI (1.08-7.41)]. The prevalence of dementia increased with age (14.0% after 75 years and 23.1% after 85 years), with age being significantly associated with suspected dementia [OR = 5.42, 95% CI (2.86-10.28)]. Greater education was associated with a lower prevalence of suspected dementia [OR = 2.36, 95% CI (2.14-2.94), comparing those with ≥7.3 years of education to those with <7.3 years of education]. Other factors associated with the prevalence of suspected dementia included being widowed (OR = 1.66, 95% CI (1.05-2.61), being retired or semi-retired (OR = 3.25, 95% CI (1.50-7.03)], a diagnosis of anxiety [OR = 2.56, 95% CI (1.05-6.13)], and death of a spouse or a relative after age 65 [OR = 1.73, 95% CI (1.58-1.92)]. In contrast, depression [OR = 1.92, 95% CI (0.81-4.57)], hypertension [OR = 1.16, 95% CI (0.79-1.71)], body mass index (BMI) [OR = 1.06, 95% CI (0.40-2.79)], and alcohol consumption [OR = 0.83, 95% CI (0.19-3.58)] were not significantly associated with suspected dementia., Conclusions: This study found a prevalence of suspected dementia in Kinshasa/DRC similar to other developing countries and Central African countries. Reported risk factors provide information to identify high-risk individuals and develop preventive strategies in this setting., (© 2023 the Alzheimer's Association.)

Objective: Learning slopes represent serial acquisition of information during list-learning tasks. Although several calculations for learning slopes exist, the Learning Ratio (LR) has recently demonstrated the highest sensitivity toward changes in cognition and Alzheimer's disease (AD) biomarkers. However, investigation of learning slopes in cognitively unimpaired individuals with subjective memory concerns (SMC) has been limited. The current study examines the association of learning slopes to SMC, and the role of SMC in the relationship between learning slopes and AD biomarkers in cognitively unimpaired individuals., Method: Data from 950 cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (aged 55 to 89) were used to calculate learning slope metrics. Learning slopes among those with and without SMC were compared with demographic correction, and the relationships of learning slopes with AD biomarkers of bilateral hippocampal volume and β-amyloid pathology were determined., Results: Learning slopes were consistently predictive of hippocampal atrophy and β-amyloid deposition. Results were heightened for LR relative to the other learning slopes. Additionally, interaction analyses revealed different associations between learning slopes and hippocampal volume as a function of SMC status., Conclusions: Learning slopes appear to be sensitive to SMC and AD biomarkers, with SMC status influencing the relationship in cognitively unimpaired participants. These findings advance our knowledge of SMC, and suggest that LR - in particular - can be an important tool for the detection of AD pathology in both SMC and in AD clinical trials.

Despite extensive use of the Alzheimer's Disease (AD) Assessment Scale - Cognitive Subscale (ADAS-Cog) in AD research, exploration of memory subtests or process scores from the measure has been limited. The current study sought to establish validity for the ADAS-Cog Word Recall Immediate and Delayed Memory subtests and learning slope scores by showing that they are sensitive to AD biomarker status. Word Recall subtest and learning slope scores were calculated for 441 participants from the Alzheimer's Disease Neuroimaging Initiative (aged 55 to 90). All participants were categorized using the NIA-AA Research Framework - based on PET-imaging of β-amyloid (A) and tau (T) deposition - as Normal AD Biomarkers (A-T-), Alzheimer's Pathologic Change (A + T-), or Alzheimer's disease (A + T+). Memory subtest and learning slope performances were compared between biomarker status groups, and with regard to how well they discriminated samples with (A + T+) and without (A-T-) biomarkers. Lower Word Recall memory subtest scores - and scores for a particular learning slope calculation, the Learning Ratio - were observed for the AD (A + T+) group than the other biomarker groups. Memory subtest and Learning Ratio scores further displayed fair to good receiver operator characteristics when differentiating those with and without AD biomarkers. When comparing across learning slopes, the Learning Ratio metric consistently outperformed others. ADAS-Cog memory subtests and the Learning Ratio score are sensitive to AD biomarker status along the continuum of the NIA-AA Research Framework, and the results offer criterion validity for use of these subtests and process scores as unique markers of memory capacity.

Objective: While Spencer's verbal incidental learning (IL) task-from Vocabulary and Similarities subtests of the WAIS-has been validated relative to traditional memory measures and Alzheimer's disease (AD) pathology, the effectiveness of the particular scoring method used has not been assessed relative to alternative scoring weightings. The purpose of this study was to compare original and alternative scoring methods of this IL task by using an AD biomarker-benchmark to arrive at an optimal approach. Methods: Fifty-five memory-clinic patients aged 59-87 received neuropsychological assessment, measures of IL, and quantitative brain imaging. Partial correlation coefficients with total hippocampal volume-controlling for age, sex, and intracranial volume-were assessed across several IL scoring methods, and partial correlations with measures of memory were examined to evaluate convergent validity. Results: IL scoring methods maximizing the contribution of paired-associate-recall-performance were significantly correlated with both hippocampal volumes and traditional memory measures, whereas discrimination-emphasized scoring methods were not. Conclusions: IL scoring methods emphasizing memory paired-associate recall appeared to be preferable to those emphasizing memory discrimination. Administration of the IL- Similarities subtest alone, without IL- Vocabulary, may strike a balance between strength of relationships with both hippocampal volumes and standard memory measures, while also limiting administration time.

Background: Utilization of NIA-AA Research Framework requires dichotomization of tau pathology. However, due to the novelty of tau-PET imaging, there is no consensus on methods to categorize scans into "positive" or "negative" (T+ or T-). In response, some tau topographical pathologic staging schemes have been developed., Objective: The aim of the current study is to establish criterion validity to support these recently-developed staging schemes., Methods: Tau-PET data from 465 participants from the Alzheimer's Disease Neuroimaging Initiative (aged 55 to 90) were classified as T+ or T- using decision rules for the Temporal-Occipital Classification (TOC), Simplified TOC (STOC), and Lobar Classification (LC) tau pathologic schemes of Schwarz, and Chen staging scheme. Subsequent dichotomization was analyzed in comparison to memory and learning slope performances, and diagnostic accuracy using actuarial diagnostic methods., Results: Tau positivity was associated with worse cognitive performance across all staging schemes. Cognitive measures were nearly all categorized as having "fair" sensitivity at classifying tau status using TOC, STOC, and LC schemes. Results were comparable between Schwarz schemes, though ease of use and better data fit preferred the STOC and LC schemes. While some evidence was supportive for Chen's scheme, validity lagged behind others-likely due to elevated false positive rates., Conclusions: Tau-PET staging schemes appear to be valuable for Alzheimer's disease diagnosis, tracking, and screening for clinical trials. Their validation provides support as options for tau pathologic dichotomization, as necessary for use of NIA-AA Research Framework. Future research should consider other staging schemes and validation with other outcome benchmarks.

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer's disease (AD). However, prior studies have typically utilized small and poorly characterized samples, and they have not analyzed the subtests of the RBANS. The current study sought to expand on prior work by examining the relationship between the Indexes and subtest scores of the RBANS and three AD biomarkers: amyloid deposition via positron emission tomography, hippocampal volume via magnetic resonance imaging, and APOE ε4 status., One-hundred twenty-one older adults across the AD continuum (intact, amnestic Mild Cognitive Impairment, mild AD), who were mostly Caucasian and well-educated, underwent assessment with the RBANS and collection of the three biomarkers., Greater amyloid deposition was significantly related to lower scores on all five Indexes and the Total Scale score of the RBANS, as well as 11 of 12 subtests. For bilateral hippocampal volume, significant correlations were observed for 4 of the 5 Indexes, Total Scale score, and 9 of 12 subtests, with smaller hippocampi being related to lower RBANS scores. Participants with at least one APOE ε4 allele had significantly lower scores on 3 of the 5 Indexes, Total Scale score, and 8 of the 12 subtests., In this sample of participants across the dementia spectrum, most RBANS Indexes and subtests showed relationships with the amyloid deposition, hippocampal volumes, and APOE status, with poorer performance on the RBANS being associated with biomarker positivity. Although memory scores on the RBANS have traditionally been linked to biomarkers in AD, other Index and subtest scores also hold promise as indicators of AD. Replication in a more diverse sample is needed.

Background: A novel learning slope score - the Learning Ratio (LR) - has recently been developed that appears to be sensitive to memory performance and AD pathology more optimally than traditional learning slope calculations. While promising, this research to date has been both experimental and based on group differences, and therefore does not aid in the interpretation of individual LR performance for either clinical or research settings. The objective of the current study was to develop demographically-corrected normative data on these LR learning slopes on verbal learning measures from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)., Method: The current study examined the influence of age and education on LR metrics for the List Learning, Story Memory, and an Aggregated RBANS score in 200 cognitively intact adults aged 65 or older using linear regression., Results: Age and education correlated with most LR metrics, but no sex differences were observed. Linear regression permitted the prediction of LR values from age and education, which are then compared to observed LR values. The result is demographically-corrected T scores for these LR metrics., Conclusions: By comparing observed and predicted LR scores calculated from regression-based prediction equations, this represents the first step towards interpretation of individual performances on this metric for clinical decision making and treatment planning purposes. With future replication in diverse and heterogenous samples, we hope to offer a new clinical tool for the examination of learning slopes in older adults.

The Learning Ratio (LR) is a novel learning score examining the proportion of information learned over successive learning trials relative to information available to be learned. Validation is warranted to understand LR's sensitivity to Alzheimer's disease (AD) pathology. One-hundred twenty-three participants across the AD continuum underwent memory assessment, quantitative brain imaging, and genetic analysis. LR scores were calculated from the HVLT-R, BVMT-R, RBANS List Learning, and RBANS Story Memory, and compared to total hippocampal volumes, 18 F-Flutemetamol composite SUVR uptake, and APOE ε4 status. Lower LR scores were consistently associated with smaller total hippocampal volumes, greater cerebral β-amyloid deposition, and APOE ε4 positivity. This LR score outperformed a traditional learning slope calculation in all analyses. LR is sensitive to AD pathology along the AD continuum - more so than a traditional raw learning score - and reducing the competition between the first trial and subsequent trials can better depict learning capacity.

Objective: The current study sought to externally validate previously published standardized regression-based (SRB) equations for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Indexes administered twice over a one-year period. Method: Hammers and colleagues' SRB prediction equations were applied to two independent samples of community-dwelling older adults with amnestic Mild Cognitive Impairment (MCI), including those recruited from the community ( n  = 64) and those recruited from a memory disorders clinic ( n  = 58). Results: While Observed Baseline and Observed Follow-up performances were generally comparable for both MCI samples over one year, both samples possessed significantly lower Observed One-Year Follow-up scores than were predicted based on Hammers and colleagues' development sample across many RBANS Indexes. Relatedly, both amnestic MCI samples possessed a greater percentage of participants either "declining" or failing to exhibit a long-term practice effect over one year relative to expectation across most Indexes. Further, the clinic-recruited amnestic MCI sample displayed worse baseline performances, smaller long-term practice effects, and greater proportions of individual participants exhibiting a decline across one year relative to the community amnestic MCI sample. Conclusions: These findings validate Hammers and colleagues' SRB prediction equations by (1) indicating their ability to identify clinically meaningful change across RBANS Indexes in independent samples, and (2) discriminating rates of cognitive change among cognitively nuanced samples.

Background: The learning ratio (LR) is a novel learning slope score that was developed to identify learning more accurately by considering the proportion of information learned after the first trial of a multi-trial learning task. Specifically, LR is the number of items learned after trial one divided by the number of items yet to be learned. Although research on LR has been promising, convergent validation, clinical characterization, and demographic norming of this LR metric are warranted to understand its clinical utility when derived from the Rey Auditory Verbal Learning Test (RAVLT)., Method: Data from 674 robustly cognitively intact older participants from the Alzheimer's Disease Neuroimaging Initiative (aged 54- 89) were used to calculate the LR metric. Comparison of LR's relationship with standard memory measures was undertaken relative to other traditional learning slope metrics. In addition, retest reliability at 6, 12, and 24 months was examined, and demographically adjusted normative comparisons were developed., Results: Lower LR scores were associated with poorer performances on memory measures, and LR scores outperformed traditional learning slope calculations across all analyses. Retest reliability exceeded acceptability thresholds across time, and demographically adjusted normative equations suggested better performance for cognitively intact participants than those with mild cognitive impairment., Conclusions: These results suggest that this LR score possesses sound retest reliability and can better reflect learning capacity than traditional learning slope calculations. With the added development and validation of regression-based normative comparisons, these findings support the use of the RAVLT LR as a clinical tool to inform clinical decision-making and treatment., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Initial learning and learning slope are often acknowledged as important qualitative aspects of learning, but the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) contains discrete indices for neither. The traditional method of calculating learning slope involves a difference score between the last trial and first trial, which is referred to as raw learning score (RLS). However, this method does not account for initial Trial One performance and produces a ceiling effect that penalizes efficient first learners. We propose an alternative method of calculating learning score that accounts for initial learning performance, called learning ratio (LR), and we compared the psychometric and predictive properties of these methods. Performances from the List Learning and Story Memory subtests were used to create the indices, and composite learning scores were calculated by combining List Learning and Story Memory. The sample included 289 military veterans (mean age = 65.9 [12.6], education = 13.3 [2.4]), most of whom were male, undergoing neuropsychological assessments that included the RBANS. Results indicated that LR demonstrated superior correlations with criterion measures of memory when compared with RLS, and the LR composite score better discriminated between those with and without a neurocognitive diagnosis, AUC = 0.81 (0.76-0.87), than the RLS composite, AUC = 0.70 (0.64-0.76). We concluded that scores from the RBANS can be computed for initial learning and learning slope and that the LR method of calculating learning is superior to RLS in this older veteran sample.

Objective: Computerized cognitive training has been successful in healthy older adults, but its efficacy has been mixed in patients with amnestic Mild Cognitive Impairment (MCI)., Methods: In a randomized, placebo-controlled, double-blind, parallel clinical trial, we examined the short- and long-term efficacy of a brain-plasticity computerized cognitive training in 113 participants with amnestic MCI., Results: Immediately after 40-hours of training, participants in the active control group who played computer games performed better than those in the experimental group on the primary cognitive outcome (p = 0.02), which was an auditory memory/attention composite score. There were no group differences on 2 secondary outcomes (global cognitive composite and rating of daily functioning). After 1 year, there was no difference between the 2 groups on primary or secondary outcomes. No adverse events were noted., Conclusions: Although the experimental cognitive training program did not improve outcomes in those with MCI, the short-term effects of the control group should not be dismissed, which may alter treatment recommendations for these patients.

Objective: In a meta-analysis examining practice effects on repeated neuropsychological testing, Calamia et al. (2012) provided information to predict practice effects in healthy and clinical samples across a range of cognitive domains. However, these estimates have not been validated., Method: This study used these prediction estimate calculations to predict follow-up scores across one year on a brief battery of neuropsychological tests in a sample of 93 older adults with amnestic mild cognitive impairment. The predicted follow-up scores were compared to observed follow-up scores., Results: Using Calamia et al. model's intercept, age, retest interval, clinical status, and specific cognitive tests, three of the seven observed follow-up scores in this cognitive battery were significantly lower than the Calamia et al. predicted follow-up scores. Differences between individual participants' observed and predicted follow-up scores were more striking. For example, on Delayed Recall of the Hopkins Verbal Learning Test - Revised, 40% of the sample had Calamia et al. predicted scores that were one or more standard deviations above their observed scores. These differences were most notable on tests that were not in Calamia et al.'s cognitive battery, suggesting the meta-analysis results may not generalize as well to other tests., Conclusions: Although Calamia et al. provided a method for predicting practice effects and follow-up scores, these results raise caution when using them in MCI, especially on cognitive tests that were not in their meta-analysis.

Objective: Reliable change methods can aid in determining whether changes in cognitive performance over time are meaningful. The current study sought to develop and cross-validate 12-month standardized regression-based (SRB) equations for the neuropsychological measures commonly administered in the Alzheimer's Disease Neuroimaging Initiative (ADNI) longitudinal study., Method: Prediction algorithms were developed using baseline score, retest interval, the presence/absence of a 6-month evaluation, age, education, sex, and ethnicity in two different samples ( n = 192 each) of robustly cognitively intact community-dwelling older adults from ADNI - matched for demographic and testing factors. The developed formulae for each sample were then applied to one of the samples to determine goodness-of-fit and appropriateness of combining samples for a single set of SRB equations., Results: Minimal differences were seen between Observed 12-month and Predicted 12-month scores on most neuropsychological tests from ADNI, and when compared across samples the resultant Predicted 12-month scores were highly correlated. As a result, samples were combined and SRB prediction equations were successfully developed for each of the measures., Conclusions: Establishing cross-validation for these SRB prediction equations provides initial support of their use to detect meaningful change in the ADNI sample, and provides the basis for future research with clinical samples to evaluate potential clinical utility. While some caution should be considered for measuring true cognitive change over time - particularly in clinical samples - when using these prediction equations given the relatively lower coefficients of stability observed, use of these SRBs reflects an improvement over current practice in ADNI.

Objective : Changes to study protocols during longitudinal research may alter cognitive testing schedules over time. Unlike in prior Alzheimer's Disease Neuroimaging Initiative (ADNI) protocols, where testing occurred twice annually, participants enrolled in the ADNI-3 are no longer exposed to cognitive materials at 6 months. This may affect their 12-month performance relative to earlier ADNI cohorts, and potentially confounds data harmonization attempts between earlier and later ADNI protocols. Method : Using data from participants enrolled across multiple ADNI protocols, this study investigated whether test exposure during 6-month cognitive evaluation influenced scores on subsequent 12-month evaluation. Results : No interaction effects were observed between test exposure group and time at 12 months on cognitive performance. No improvements, and limited declines, were seen between baseline and 12-month follow-up scores on most measures. Conclusions : The 6-month testing session had minimal impact on 12-month performance in ADNI. Collapsing longitudinal data across ADNI protocols in future research appears appropriate., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: The learning ratio (LR) is a novel learning slope score that has been developed to reduce the inherent competition between the first trial and subsequent trials in traditional learning slopes. In essence, the LR is the number of items learned after the first trial divided by the number of items yet to be learned. Criterion and convergent validation of this LR score is warranted to understand its sensitivity along the Alzheimer's disease (AD) continuum., Method: The LR metric was calculated for 123 participants from standard measures of memory, including the Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) list learning, and RBANS story memory. All participants were categorized as normal cognition, mild cognitive impairment (MCI), or AD. LR performances were compared between groups, among other standard memory measures, and with regards to how well they discriminated cognitively impaired from unimpaired samples-and within diagnostic subgroups., Results: Lower LR scores were observed for the MCI and AD groups than the normal cognition group, with the AD group performing worse than the MCI group for several slope calculations. Lower LR scores were also consistently associated with poorer performances on traditional memory measures. LR scores further displayed excellent receiver operator characteristics when differentiating those with and without cognitive impairment-and MCI from normal cognition. Overall, LR scores consistently outperformed traditional learning slope calculations across all analyses., Conclusions: This LR score is sensitive to memory dysfunction along the AD continuum, and results offer criterion and convergent validity for use of the LR metric to understand learning capacity., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated, to varying degrees, with commonly used biomarkers of Alzheimer's disease (AD). Given the ease of RBANS administration as a screening tool for clinical trials and other applications, a better understanding of how RBANS performance is associated with presence of APOE ε4 allele[s], cerebral amyloid burden, and hippocampal volume is warranted., Method: One hundred twenty-one older adults who were classified as intact, amnestic Mild Cognitive Impairment, or mild AD underwent cognitive assessment with the RBANS, genetic analysis, and quantitative brain imaging. APOE ε4 carrier status, 18 F-Flutemetamol composite standardized uptake value ratio (SUVR), and hippocampal volume were each regressed on demographic variables and RBANS Total Scale score, Index scores, and subtest scores., Results: Lower RBANS Total Scale score or Delayed Memory Index (DMI) predicted the presence of APOE ε4 allele[s], higher cerebral amyloid burden, and lower hippocampal volumes. DMI was a slightly better predictor than Total Scale score for most AD biomarkers. No demographic variables consistently contributed to these models., Conclusions: The RBANS - DMI in particular - is sensitive to AD pathology. As such, it could be used as a predictive tool, particularly in clinical drug trials to enrich samples prior to less accessible AD biomarker investigation.

Background: The learning slope is typically represented as the raw difference between the final score and the score of the first learning trial. A new method for calculating the learning slope, the learning ratio (LR), was recently developed; it is typically represented as the number of items that are learned after the first trial divided by the number of items that are yet to be learned., Objective: To evaluate the convergent and criterion validity of the LR in order to understand its sensitivity to Alzheimer disease (AD) pathology., Method: Fifty-six patients from a memory clinic underwent standard neuropsychological assessment and quantitative brain imaging. LR scores were calculated from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised and were compared with both standard memory measures and total hippocampal volumes, as well as between individuals with AD and those with mild cognitive impairment., Results: Lower LR scores were consistently associated with poorer performances on standard memory measures and smaller total hippocampal volumes, generally more so than traditional learning slope scores. The LR scores of the AD group were smaller than those of the group with mild cognitive impairment. Furthermore, the aggregation of LR scores into a single metric was partially supported., Conclusion: The LR is sensitive to AD pathology along the AD continuum. This result supports previous claims that the LR score can reflect learning capacity better than traditional learning calculations can by considering the amount of information that is learned at trial 1., Competing Interests: The authors declare no conflicts of interest.

Objective: Reliable change methods can assist the determination of whether observed changes in performance are meaningful. The current study sought to validate previously published standardized regression-based (SRB) equations for commonly administered cognitive tests using a cognitively intact sample of older adults, and extend findings by including relevant demographic and test-related variables known to predict cognitive performance. Method: This study applied previously published SRB prediction equations to 107 cognitively intact older adults assessed twice over one week. Prediction equations were also updated by pooling the current validation sample with 93 cognitively intact participants from original development sample to create a combined development sample. Results: Significant improvements were seen between observed baseline and follow-up scores on most measures. However, few differences were seen between observed follow-up scores and those predicted from these SRB algorithms, and the level of practice effects observed based on these equations were consistent with expectations. When SRBs were re-calculated from this combined development sample, predicted follow-up scores were mostly comparable with these equations, but standard errors of the estimate were consistently smaller. Conclusions: These results help support the validity of of these SRB equations to predict cognitive performance on these measures when repeated administration is necessary over short intervals. Findings also highlight the utility of expanding SRB models when predicting follow-up performance serially to provide more accurate assessment of reliable change at the level of the individual. As short-term practice effects are shown to predict cognitive performance annually, they possess the potential to inform clinical decision-making about individuals along the Alzheimer's continuum.

Objective: Reliable change methods can aid neuropsychologists in understanding if performance differences over time represent clinically meaningful change or reflect benefit from practice. The current study sought to externally validate the previously published standardized regression-based (SRB) prediction equations developed by Duff for commonly administered cognitive measures., Method: This study applied Duff's SRB prediction equations to an independent sample of community-dwelling participants with amnestic mild cognitive impairment (MCI) assessed twice over a 1-week period. A comparison of MCI subgroups (e.g., single v. multi domain) on the amount of change observed over 1 week was also examined., Results: Using pairwise t-tests, large and statistically significant improvements were observed on most measures across 1 week. However, the observed follow-up scores were consistently below expectation compared with predictions based on Duff's SRB algorithms. In individual analyses, a greater percentage of MCI participants showed smaller-than-expected practice effects based on normal distributions. In secondary analyses, smaller-than-expected practice effects were observed in participants with worse baseline memory impairment and a greater number of impaired cognitive domains, particularly for measures of executive functioning/speeded processing., Conclusions: These findings help to further support the validity of Duff's 1-week SRB prediction equations in MCI samples and extend previous research by showing incrementally smaller-than-expected benefit from practice for increasingly impaired amnestic MCI subtypes., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study attempted to clarify the applicability of standard error (SE) terms in clinical research when examining the impact of short-term practice effects on cognitive performance via reliable change methodology., Method: This study compared McSweeney's SE of the estimate (SEest) to Crawford and Howell's SE for prediction of the regression (SEpred) using a developmental sample of 167 participants with either normal cognition or mild cognitive impairment (MCI) assessed twice over 1 week. One-week practice effects in older adults: Tools for assessing cognitive change. Using these SEs, previously published standardized regression-based (SRB) reliable change prediction equations were then applied to an independent sample of 143 participants with MCI., Results: This clinical developmental sample yielded nearly identical SE values (e.g., 3.697 vs. 3.719 for HVLT-R Total Recall SEest and SEpred, respectively), and the resultant SRB-based discrepancy z scores were comparable and strongly correlated (r = 1.0, p < .001). Consequently, observed follow-up scores for our sample with MCI were consistently below expectation compared to predictions based on Duff's SRB algorithms., Conclusions: These results appear to replicate and extend previous work showing that the calculation of the SEest and SEpred from a clinical sample of cognitively intact and MCI participants yields similar values and can be incorporated into SRB reliable change statistics with comparable results. As a result, neuropsychologists utilizing reliable change methods in research investigation (or clinical practice) should carefully balance mathematical accuracy and ease of use, among other factors, when determining which SE metric to use., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background : The Learning Ratio (LR) is a novel learning slope score that has been developed to reduce the inherent competition between the first trial and subsequent trials in traditional learning slopes. Recent findings suggest that LR is sensitive to AD pathology along the AD continuum - more so than the traditional learning calculations that employ raw changes across trials. However, research is still experimental and not yet directly applicable to clinical settings. Consequently, the objective of the current study was to develop demographically-corrected normative data on these LR learning slopes. Method : The current study examined the influence of age and education on LR scores for the HVLT-R, BVMT-R, and an Aggregated HVLT-R/BVMT-R in 200 cognitively intact adults aged 65 years and older using linear regression. Results : Age negatively correlated with all LR metrics, and education positively correlated with most. No sex differences were identified. LR values were predicted from age and education, which can be compared to observed LR values and converted into demographically-corrected T scores. Conclusions : By comparing observed and predicted LR scores calculated from regression-based prediction equations, interpretations are permitted that aid in clinical decision making and treatment planning. Co-norming of the HVLT-R and BVMT-R also allows for comparisons between verbal and visual learning slope scores in individual patients. We hope normative data for LR enhances its utility as a clinical tool for examining learning slopes in older adults administered the HVLT-R and/or BVMT-R.

Objective: reliable change methods can assist in the determination of whether observed changes in performance are meaningful. The current study sought to validate previously published 1-year standardized regression-based (SRB) equations for commonly administered neuropsychological measures that incorporated baseline performances, demographics, and 1-week practice effects., Method: Duff et al.'s SRB prediction equations were applied to an independent sample of 70 community-dwelling older adults with either normal cognition or mild cognitive impairment, assessed at baseline, at 1 week, and at 1 year., Results: minimal improvements or declines were seen between observed baseline and observed 1-year follow-up scores, or between observed 1-year and predicted 1-year scores, on most measures. Relatedly, a high degree of predictive accuracy was observed between observed 1-year and predicted 1-year scores across cognitive measures in this repeated battery., Conclusions: these results, which validate Duff et al.'s SRB equations, will permit clinicians and researchers to have more confidence when predicting cognitive performance on these measures over 1 year., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Despite expansion of telecommunication strategies across health services and data supporting feasibility of videoconference-based neuropsychological assessment, relatively little is known about teleneuropsychology (TeleNP) use in practice. The current COVID-19 pandemic provides an opportunity for greater use of TeleNP and understanding of neuropsychologists' experience with this unique assessment medium. Methods: During the course of a no-cost global webinar related to practical/ethical considerations of TeleNP practice, attendees were invited to engage in a 26-question survey about their TeleNP use and related COVID-19 concerns. TeleNP practices before the COVID-19 pandemic and early on during the global outbreak were queried among survey participants, along with examination of TeleNP intentions following COVID-19. Results: Multiple countries were represented across five continents, with two-thirds of respondents being from the United States. Approximately one-fourth of respondents reported using TeleNP for clinical interview, feedback, and intervention prior to the onset of the COVID-19 pandemic, and approximately one-tenth of individuals used TeleNP for testadministration. Increased use of TeleNP for clinical interview, feedback, and intervention was reported within the first few weeks of the global COVID-19 outbreak, though the use of TeleNP for testing remained relatively unchanged. Most respondents indicated an intention for future use of TeleNP. Conclusions: Our findings suggest the use of TeleNP is increasing, although use of remote TeleNP testing is still developing. Findings also illustrate increasing use of TeleNP in the context of the COVID-19 pandemic and encourage follow-up investigation in future studies to understand the changing practices and rates of TeleNP provision over time.

Objective : Reliable change methods can assist neuropsychologists in determining whether observed changes in a patient's performance are clinically meaningful. The current study sought to validate previously published standardized regression-based (SRB) equations for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Indexes and subtests. Methods : Duff and colleagues's SRB prediction equations, developed from 223 cognitively intact primary care patients, were applied to an independent sample of robustly cognitively intact ( n = 129) community-dwelling older adults assessed with the RBANS twice over a one-year period. Results : Results suggest that the cognitively intact participants in the current validation sample possessed significantly better Observed Follow-up scores than was predicted based on Duff's developmental sample across most RBANS Indexes and many RBANS subtests, though significantly lower Observed Follow-up scores were observed for the Visuospatial/Constructional Index than was predicted. As a result of these findings, the current study calculated updated prediction algorithms for the RBANS Index and subtest scores from the sample of 129 cognitively intact participants. Conclusions : Duff's 2004 and 2005 SRB prediction equations for the RBANS Index and subtest scores failed to generalize to a sample of cognitively intact community-dwelling participants recruited from senior living centers and independent assisted living facilities. These updated SRB prediction equations - being developed from a more medically "clean" sample of cognitively intact older adults who remained stable over 12 months - have the potential to provide a more accurate assessment of reliable change in an individual patient.

Convergent validation of a verbal incidental learning (IL) task from the WAIS-IV using neuroimaging biomarkers is warranted to understand its sensitivity to Alzheimer's disease (AD) pathology. Fifty-five memory clinic patients aged 59 to 87 years received neuropsychological assessment, and measures of IL and quantitative brain imaging. Worse IL-Total Score and IL-Similarities performances were significantly associated with smaller hemispheric hippocampal volumes. IL measures were not significantly correlated with cerebral β-amyloid burden, though a trend was present and effect sizes were mild. These hippocampal volume results suggest that this IL task may be sensitive to AD pathology along the AD continuum.