MMSE Decline Research Articles

Differential Longitudinal Associations Between Depressive Symptoms and Cognitive Status by Living Situation in Older Adults.

This study explores whether living situation modifies longitudinal associations between depressive symptoms and changes in cognitive status across ten years in generally healthy, community-dwelling older adults. Participants (N = 687, Mage = 73.92years) from the no-contact control condition of a multisite longitudinal study completed the Mini-Mental State Examination, Center for Epidemiological Studies Depression scale, and self-reported living situation. Multilevel models revealed that for older adults living alone, having clinically meaningful depressive symptoms was associated with greater decline in MMSE over ten years. However, reporting clinically meaningful depressive symptoms was not associated with decline in MMSE for adults who were living with others. These results suggest that living situation may be a modifying factor of cognitive change over time for older adults with clinically meaningful depressive symptoms. This highlights the need for targeted interventions for adults who may be at a greater risk of cognitive decline across older adulthood.

Two-Year Longitudinal Outcomes of Subjective Cognitive Decline in Hispanics Compared to Non-hispanic Whites.

Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P = .040). Hispanic participants endorsed more depressive symptoms at baseline (P = .048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P = .023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (β = .40 SE: .17, P = .023), and in specific BCRS domains: concentration (β = .13, SE: .07, P = .047), past memory (β = .13, SE: .06, P = .039) and functional abilities (β = .10, SE: .05, P = .037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (β = -.27, SE: .13, P = .039), MoCA (β = -.80 SE: .34, P = .032), Trails A (β = 2.75, SE: .89, P = .002), Trails B (β = 9.18, SE: 2.71, P = .001) and Guild Paragraph Recall Delayed (β = -.80 SE: .28, P = .005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

A multicenter validation study on the diagnostic and prognostic value of CSF Neurogranin and BACE1

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). Currently, AD is still mostly diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Disease‐modifying treatments should be most effective in the earliest stages, before amyloid plaques and neurodegeneration become prevalent. Thus, further identification of biomarkers is required that can detect AD in the predementia stage. This study aimed to assess the clinical utility of synaptic proteins neurogranin and beta‐secretase 1 (BACE1) in the diagnosis and prognosis of AD.MethodWe enrolled 530 participants from DELCODE, a multicenter prospective cohort study, including healthy controls (HC), subjective cognitive decline (SCD) subjects, mild cognitive impairment (MCI) subjects, mild AD dementia and first‐degree relatives of AD patients. Based on amyloid and tau status, we divided the participants into four groups: A−T−; A−T+; A+T−; A+T+. Neurogranin and BACE1 levels across groups were assessed by ANCOVA after adjusted for age and sex. To test the correlation of the biomarkers to cognitive performance, we used linear mixed models to model baseline biomarker levels and 7 years longitudinal MMSE and PACC5 scores.ResultRegardless of amyloid status, CSF neurogranin and BACE1 levels were significantly higher in T+ group compared with T‐ (all p &lt; 0.0001). Furthermore, for participants with negative tau status, neurogranin and BACE1 levels were lower in A+ group compared with A‐ (both p &lt; 0.0001). After adjusting for covariates (Age, Sex, Education, APOEε4), linear mixed‐effect models indicated that higher neurogranin predicts faster decline in MMSE (β = ‐0.14, p &lt; 0.01) and PACC5 (β = ‐0.03, p &lt; 0.05) over 7 years.ConclusionThis study reveals that neurogranin and BACE1 could offer insight into identifying patients at early stages of AD and improve prediction of cognitive decline.

Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect.

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease with various clinical symptoms. Limited data have described the clinical subtypes of DLB. We aimed to compare clinical subtypes of DLB according to initial symptoms and to study the effect of Apolipoprotein E (APOE) gene in DLB. We included DLB patients classified into three groups based on initial symptoms: non-motor onset (cognitive and/or psychiatric) (NMO-DLB), motor onset (parkinsonism and/or gait disorders) (MO-DLB), and mixed onset (non-motor and motor symptoms) (MXO-DLB). Clinical and APOE genotype associations and survival were analyzed. A total of 268 patients were included (NMO-DLB = 75%, MXO-DLB = 15.3%, MO-DLB = 9.7%). Visual hallucinations were more frequent (p = 0.025), and attention was less commonly impaired in MXO-DLB (p = 0.047). When adjusting with APOE ɛ4 status (APOE genotype performed in 155 patients), earlier falls and frontal lobe syndrome were more common in MXO-DLB (p = 0.044 and p = 0.023, respectively). The median MMSE decline was 2.1 points/year and the median FAB decline was 1.9 points/year, with no effect of clinical subtypes. Median survival was 6 years. It was similar in DLB subtypes (p = 0.62), but shorter for patients with memory symptoms at onset (p = 0.04) and for males (p = 0.0058). Our study revealed a few differences between DLB clinical subtypes. APOE ɛ4 appears to be associated with earlier falls and a higher prevalence of frontal syndrome in MXO-DLB. However, DLB clinical subtypes did not impact on survival. Nevertheless, survival analysis identified other poor prognosis factors, notably inaugural memory impairment and male gender.

Serum brain-derived neurotrophic factor levels as a predictor for Alzheimer disease progression.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of Alzheimer's disease (AD), and decreased peripheral levels of this protein are associated with an increased risk of developing the disease. This study focuses on whether serum BDNF levels could be used as a predictor of AD progression. In this longitudinal observational study, we recruited cognition normal participants (N=98) and AD (N=442) from the Clinic at the Taipei Veterans General Hospital. We conducted a mini-mental status exam, a 12-item memory test, a categorical verbal fluency test, and a modified 15-item Boston naming test. A Serum BDNF level and Apolipoprotein E (APOE) allele status were measured. The AD patients were followed prospectively. Based on the difference of MMSE scores, these patients were divided into fast decliners (decline ≧ 3/year) and slow decliners (MMSE decline < 3/year). Logistic regression was conducted to examine the impact of serum BDNF levels and other factor on the likelihood of AD patients being slow decliners. Pearson's correlation was used to estimate the relationship between serum BDNF levels and the score of neuropsychological tests. In a logistic regression model containing serum BDNF levels, age, sex, APOE4 carrier status, education levels, and baseline MMSE score, higher serum BDNF levels were associated with a slower rate of cognitive decline in the AD group. Serum BDNF levels positively correlated with the results of multiple neuropsychological tests. BDNF is a protective factor against AD progression and likely plays a role in establishing a link between AD pathology and clinical manifestations.

The association among plasma p‐tau181, cognitive progression and structural brain change in early Alzheimer’s disease

AbstractBackgroundPlasma levels of phosphorylated tau 181 (p‐tau181) is one of the potential blood‐based biomarkers for the diagnosis of Alzheimer’s disease (AD). However, the association among plasma p‐tau181 and cognitive progression and structural brain change still needs to be investigated.MethodAD and mild cognitive impairment (MCI) patients diagnosed with a multidisciplinary consensus meeting were recruited. Cognitive function was assessed at baseline and at annual follow‐ups. Plasma p‐tau181 levels at baseline were measured using Quanterix SIMOA kits. The regional cortical thickness and volumes of baseline brain MRI were measured using the FreeSurfer image analysis suite. T‐tests and multiple regression were used for analyses. FDR tests were performed for multiple comparisons.ResultA total of 162 AD and 19 MCI patients were recruited (mean age = 77.4 ± 7.3 years, 42% male, 37% APOE ɛ4 carrier, and mean MMSE = 20 ± 5.4). There were 137 patients (75.7%) having at least two annual follow‐up and the mean follow‐up time was 2.1 ± 0.4 years. The baseline plasma p‐tau181 levels were correlated with the rates of MMSE decline per year (r = 0.284, p &lt; 0.001). After adjusting for age, gender, education, APOE ɛ4 status and baseline MMSE, the baseline plasma p‐tau181 levels were still correlated with the yearly MMSE decline (β = 0.292, p = 0.001) and was able to predict MMSE decline&gt;3 per year (OR = 4.03, 95% CI 1.47–11.05). There were 152 patients (135 AD and 17 MCI) with valid brain MRI. The cross‐sectional analyses with adjustments of age, gender, education and APOE ɛ4 status showed significant association between plasma p‐tau181 levels and left hippocampus volume (β = ‐0.205, p = 0.010), right hippocampus volume (β = ‐0.213, p = 0.009) and right middle temporal thickness (β = ‐0.292, p &lt; 0.001).ConclusionHigher plasma p‐tau181 levels were associated with the faster rate of MMSE decline in AD and MCI patients as well as the decreased volume and cortical thickness of several AD‐specific brain areas. Our study suggested that the plasma p‐tau181 could be a potential biomarker for tracking cognitive decline and reflecting structural brain changes in AD and MCI patients.

Determinants of cognitive and brain resilience to tau pathology: A longitudinal analysis

AbstractBackgroundMechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease (AD) spectrum are insufficiently understood. Longitudinal data is necessary for revealing which factors contribute to maintaining cognition (cognitive resilience, CR) or preserving brain structure (brain resilience, BR) despite elevated tau, and for clarifying whether these factors provide a baseline advantage and/or moderate rates of brain structural and cognitive change. We therefore investigated whether age, sex, education, APOE‐e4 status, intracranial volume (ICV) and cortical thickness (in CR analysis) moderate the association between baseline tau load and subsequent changes in cognition and cortical thickness.MethodsThe study included 341 amyloid‐β‐positive individuals from a multi‐cohort dataset (BioFINDER‐1/AVID/ADNI/UCSF), diagnosed with MCI or AD dementia at the time of the baseline [18F]flortaucipir tau‐PET scan, who had longitudinal cognitive assessments (CR sample). A subset (n = 133) additionally underwent longitudinal structural MRI (BR sample). We used (separate) linear mixed‐effect models with MMSE as outcome to investigate the association of key baseline variables‐of‐interest (age, sex, APOE‐e4 status, education, ICV and global cortical thickness) with cognitive decline in the presence of tau (covaried for cohort). A three‐way interaction between time, tau and the predictor‐of‐interest was initially assessed. In the absence of a moderation effect, we subsequently assessed models including only the two‐way interaction between each predictor and time. These analyses were repeated with global cortical thinning as an outcome variable.ResultsCharacteristics of the CR sample and BR sub‐sample are described in Table‐1. Models revealed that younger age (βInteraction = ‐0.18, p&lt;0.01), higher education (βInteraction = ‐0.62, p&lt;0.001), larger ICV (βInteraction = ‐8.12, p&lt;0.01) and greater cortical thickness (βInteraction = ‐9.9, p&lt;0.05) were related to higher CR, as these factors moderated the relationship between tau pathology and decline in MMSE (Figure‐1,2). No predictor moderated tau effects on cortical thinning nor explained additional variance (Table‐2).ConclusionThis study indicates that tau pathology affects cognitive decline differently across age, education, ICV and cortical thickness levels. Understanding moderators of prospective cognitive decline and cortical thinning related to tau pathology, as well as their complex interactions, may be relevant for improving prognosis and clinical trial design in AD.

INTERMUSCULAR ADIPOSITY: A NOVEL RISK FACTOR FOR COGNITIVE DECLINE IN A BIRACIAL COHORT OF OLDER ADULTS

Abstract Skeletal muscle and brain health both decline with age. Poorer skeletal muscle characteristics may be early markers of cognitive decline. The Health ABC study obtained repeated measures of thigh intermuscular adiposity via CT (IMAT, Years 1 and 6) and Mini-Mental State Exam (MMSE, Years 1 through 10), in 1634 adults (69-79 years, 48% women, 35% black). Linear mixed effects models accounted for change (Years 1 and 6) in weight, muscle (strength, area), and adiposity characteristics (abdominal subcutaneous, visceral, total fat mass) and for dementia risk factors (education, APOE4, diabetes, hypertension, physical activity). IMAT increased by 0.97 cm2/year (SD:1.16), and MMSE declined by 0.4 points/year (0.02). Each SD of IMAT corresponded to a MMSE decline of 0.22 points/year (p&amp;lt;0.0001), similar in adjusted models and stratified by race or gender. Aging-related IMAT increase may be a novel predictor of cognitive decline beyond traditional risk factors, with potential implications for muscle-brain cross talk.

The impact of postoperative cognitive impairment on mid-term survival after heart transplantation.

Heart transplantation is the definitive therapy for patients with end-stage heart failure. Antecedent studies reported that a substantial proportion of heart transplant recipients developed postoperative cognitive impairment in the long term. However, no studies have explored the association between postoperative cognitive impairment and survival after heart transplantation. The data of 43 adult patients who underwent heart transplantation were consecutively enrolled and assessed using the MMSE and MoCA neuropsychological tests. Kaplan-Meier curves and Cox proportional hazards models were used for survival analyses. Primary component analysis was performed to integrate MoCA subtests into the "Attention factor," "Naming factor," and "Orientation factor." About 30% of the patients were diagnosed with short-term postoperative cognitive impairment. The impairment group was older and had lower baseline cognitive performances, larger LV diameter, worse MMSE decline and higher ratio of significant MoCA decline. Postoperative cognitive impairment was significantly associated with worse survival (P=.028). Multivariate Cox analyses showed that higher postoperative MoCA score was significantly associated with lower mid-term post-transplant mortality (HR=.744 [.584, .949], P=.017), in which "Attention factor" contributed to this association most (HR=.345 [.123, .970], P=.044) rather than "Naming factor" or "Orientation factor." Notably, preoperative cognitive impairment was closely related with postoperative cognitive impairment and also indicated the worse post-transplant survival (P=.015). Postoperative as well as preoperative cognitive impairments were associated with a worse mid-term survival after heart transplantation, indicating that neuropsychological assessments before and after heart transplantation should be routinely performed for heart transplant recipients for better risk stratification.

Plasma phosphorylated tau181 predicts cognitive and functional decline.

To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort. Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N=91) or AD dementia (N=64), and NC (N=241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N=70), MCI (N=75), and AD dementia (N=50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p-tau181 was measured using the Quanterix SiMoA HD-X platform. Plasma p-tau181 differentiated pathology-confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p-Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p-tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia. Plasma p-tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p-tau181 are associated with faster cognitive and functional decline.

Subjective vs. Objective Memory Predictors of AD Biomarkers and Future Cognitive, Clinical, and Functional Decline

AbstractBackgroundSubjective and objective memory have been previously linked to Alzheimer’s disease (AD) biomarkers and future clinical and cognitive decline. We the ability of two subjective memory assessments and two objective memory assessments to predict cross‐sectional amyloid, tau, and neurodegenerative (A/T/N) biomarkers, as well as future cognitive, clinical, and functional decline.Methods298 participants from ADNI were included, specifically 128 with normal cognition without memory concerns (CN), 123 with significant memory concerns (SMC; defined as a score of ≥20 on the first 12 items of the Cognitive Change Index (CCI)), and 47 with early mild cognitive impairment (EMCI). Objective memory was defined as immediate and delayed scores of Logical Memory and the Rey AVLT (RAVLT). Subjective memory measures included the memory sub‐scores of the ECog and CCI. Baseline Aβ and tau positivity were defined as positive on either neuroimaging and/or CSF biomarkers using standard cut‐offs. Neurodegeneration positive was defined as a hippocampal volume w‐score of 1.5 standard deviations below all CNs with 3T MRI in ADNI (adjusted for age, sex, and total intracranial volume). Cognitive decline was defined as a negative slope on the MMSE, while functional decline was defined as a longitudinal increase on the CDR‐sum of boxes and/or FAQ. For CN/SMC, conversion from normal cognition to MCI was also assessed. ROC curves were calculated for each objective and subjective measure for predicting conversion, functional decline, MMSE decline, and A/T/N positivity.ResultsFigure 1 shows ROC curves for the best predictor of each outcome. Baseline Aβ positivity, MCI conversion, and MMSE decline were best predicted by RAVLT immediate recall. However, functional decline and N positivity were best predicted by the CCI‐12. Tau positivity was also best predicted by subjective memory, the ECog memory sub‐score.ConclusionObjective memory provided the best prediction of Aβ positivity, MCI conversion, and cognitive decline, while subjective memory was the best predictor of T and N positivity and functional decline. These findings suggest that objective and subjective performance provide complementary information about prognosis in preclinical and very mild symptomatic individuals. Future evaluations of prognostication of these measures in a clinical setting will expand these findings.

Distinct features of rapidly progressive Alzheimer’s disease

AbstractBackgroundRapidly progressive Alzheimer’s disease (rpAD) has been recognized as a subtype of Late‐Onset Alzheimer’s disease (LOAD) characterized by accelerated cognitive decline and/or reduced survival. The cause of variable progression rates of AD is largely unknown, and information regarding unique clinical features of rpAD is limited in longitudinal cohorts.MethodA retrospective analysis was performed on AD patients in the National Alzheimer’s Coordinating Center (NACC) database from 2015 to 2021. Patients with rpAD were identified by reduced survival time (time from symptom onset to death &lt; = three years) or accelerated cognition decline (defined as Mini‐Mental State Exam [MMSE] decrease &gt; = 6 points/year or Clinical Dementia Rating scale [CDR] global score increase to 2 or 3 within three years). Demographic, clinical, and neuropsychological measurements were compared between patients with rpAD, typical “slow” progressive AD, and normal controls. rpAD patients and normal controls with Whole Genome Sequencing (WGS) data available from the Alzheimer’s Disease Sequencing Project (ADSP) were selected for a pilot genome‐wide association study (GWAS).ResultAmong 43,746 NACC participants, 983 patients met our criteria for rpAD. rpAD patients had a mean survival of 2.8±0.5 years and their decline in MMSE was 6.4±5.9 points/year. Compared to controls, rpAD patients were older (72.6±8.6 vs 70.0±8.6, p &lt; 0.001), more likely to be male (39% vs 33%, p &lt; 0.001) and had fewer years of education (14.6±3.6 vs 15.9±3.0, p &lt; 0.001). Compared to AD patients who progressed slowly, rpAD patients showed a more rapid decline in neuropsychological tests measuring working memory, language, attention, and executive function (p values &lt; 0.001). GWAS was performed on 175 rpAD patients and 525 age‐ and sex‐matched NACC controls. 49 genetic variants showed significant associations with rpAD (p‐values &lt; 1 × 10−5).ConclusionIn the longitudinal NACC cohort, rapidly progressive AD constitutes an important subset, featuring a short survival with rapid decline of cognitive and neuropsychological functions. Previously known genetic risk variants for AD were not found in this rpAD cohort. Further examination of rpAD cohort could help identify unique mechanisms that drive the rate progression in AD for different groups of patients.

Head‐to‐head comparison between plasma ptau‐217 and Flortaucipir‐PET in amyloid‐positive patients with cognitive impairment

AbstractBackgroundPlasma measurements of phosphorylated tau (ptau) have emerged as promising biomarkers for Alzheimer’s disease (AD). Studies have shown strong associations between ptau and tau‐PET that are mainly driven by the difference between amyloid‐positive and amyloid‐negative patients. However, the relationship between ptau and tau‐PET is not well characterized within patients with AD. We conducted a head‐to‐head comparison between plasma ptau‐217 and tau‐PET in patients at the clinical stage of AD and assessed biomarker relationships with demographic and clinical variables.MethodsEighty‐seven amyloid‐positive patients (age=66±10, 48% women) with mild cognitive impairment (n=53) or dementia (n=34) underwent structural MRI, amyloid‐PET (11C‐PIB), tau‐PET (18F‐flortaucipir, FTP), Mini‐Mental State Examination (MMSE, with 28 patients having longitudinal measures 1.5±0.7 years after baseline) and blood draw within a year. Mean cortical PET‐Standardized Uptake Value Ratio (SUVR) were extracted using FreeSurfer5.3. Plasma ptau‐217 concentrations were measured using an electrochemiluminescence‐based assay on the Meso Scale Discovery platform.ResultsPtau‐217 and cortical FTP‐SUVR were strongly correlated (r=0.61, p&lt;.001, Figure 1). Younger age and female sex, but not APOE4, were associated with higher ptau‐217 and FTP‐SUVR (Figure 2). Amyloid‐PET levels were mildly associated with FTP‐SUVR (r=0.26, p=0.02), not ptau‐217 (r=0.10, p=0.36, Figure 2). The relationship between ptau‐217 and cortical FTP‐SUVR was not modified by age, sex, APOE4, or PIB‐PET (interactions: p’s&gt;0.25). In the whole group, ptau‐217 was associated with FTP‐SUVR in temporo‐parietal and dorsal prefrontal cortices (Figure 3A). However, ptau‐217‐FTP association patterns varied with amyloid burden: in patients with moderate amyloid (&lt;97.7 Centiloids), ptau‐217 was more strongly associated with temporal FTP‐SUVR whereas associations were stronger in primary cortices in patient with higher amyloid levels (Figure 3B). Cross‐sectionally, higher ptau‐217 and FTP‐SUVR were independently associated with lower MMSE (Table 1; Figure 4A). In separate mixed effect models, higher baseline ptau‐217 and FTP‐SUVR were associated with more severe longitudinal decline in MMSE (Figure 4B); when both biomarkers were entered in the same model, only FTP‐SUVR remained significant (Table 2).ConclusionsIn amyloid‐PET‐positive patients with cognitive deficits, ptau‐217 and tau‐PET had comparable patterns of association with demographic and clinical variables. However, cross‐modal and clinical associations tended to be stronger for tau‐PET than ptau‐217.

Baseline blood amylin levels predict longitudinal cognitive decline in participants at risk for or with mild cognitive impairment and dementia

AbstractBackgroundAmylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells that co‐aggregates with parenchymal and vascular b‐amyloid in the CNS. Cross‐sectional data shows that higher CSF and blood amylin levels are associated with increased frequency of cognitive impairment and dementia. The present study sought to determine whether baseline blood amylin levels are associated with longitudinal cognitive decline.MethodWhole blood amylin levels were ascertained from 83 participants in a longitudinal cohort spanning the cognitive continuum from normal to MCI and dementia who were evaluated initially in 2017 and followed to present. Cognitive change data including MMSE, MoCA, CDR global and sum‐of‐box scores at baseline and longitudinal follow‐up were analyzed in relation to baseline amylin levels.ResultParticipants were followed for a mean 2.0 ± 1.1 years. Baseline whole blood amylin levels varied widely (mean of 8.8 ± 12.2 pg/ml). Seventy‐one participants had complete baseline and follow‐up data were included in this analysis. Of these, 20 had objective evidence for longitudinal decline. Participants with above vs below modal baseline amylin levels scored lower on baseline and follow‐up assessment scores including MMSE, MoCA, CDR global and CDR sum‐of box scores (p‐values all &lt; 0.05). Annualized cognitive change scores (loss) for the MMSE (1.4 ± 2.4 vs. 0.3 ± 1.3; p &lt; 0.05) and MoCA (1.5 ± 2.5 vs. 0.4 ± 1.8; p &lt; 0.05) were greater in the above median baseline amylin level vs below median groups.ConclusionBaseline amylin whole blood levels are predictive of objective decline in MMSE and MoCA scores over periods as short as 2 years. These data suggest that the higher pancreatic hormone amylin may accelerate disease pathogenesis and cognitive decline as a result of altered pancreatic β‐cell function, potentially explaining, at least in part, the strong epidemiologic link between diabetes and dementia found across global observational cohorts. These data further suggest that the use of amylin biomarkers may serve as a useful tool for identifying subjects at high risk for short term cognitive decline. Additional work elucidating the role of amylin in degenerative disease cascades is warranted.

Differential responsiveness of outcome measures according to biomarker inclusion criteria: implications for trial design

AbstractBackgroundAccurate selection of outcome measures, sensitive to the earliest cognitive changes, is essential to demonstrate treatment efficacy in secondary prevention trials in preclinical Alzheimer’s disease(AD). These outcome measures may differ according to biomarker inclusion criteria. We aimed to determine sensitivity to change over time, of commonly used cognitive measures.MethodParticipants with longitudinal neuropsychological assessments with available baseline biomarkers were included, from the SCIENCe project. We created different (overlapping) target groups based on inclusion criteria in pre‐clinical AD trials; (1)amyloid PET or CSF (A+, n = 114), (2)CSF p‐tau (T+, n = 124), (3)AT(N)+ (n = 41), (4)APoE4 carriers(E4+, n = 195) and (5)APoE4 carriers with amyloid(E4+A+,n = 65). As a control population, we included 150 controls with normal biomarkers. Linear mixed models, adjusting for age, sex and education, were used to investigate the sensitivity to change of 14 individual (standardized) neuropsychological tests and two composites with time as the variable of interest. Composites were based on Preclinical Alzheimer Cognitive Composite; PACC(1) and the Cognitive‐Functional Composite; CFC(2).ResultA total of 556 participants where included(Age = 61.7±8.7, 44%F, follow‐up 3.1y ±2.7y)(Table 1). Linear mixed models in controls showed improvement over time in several tests, perhaps reflecting a learning effect: Stroop II/III, Wordlist Immediate Recall, Wordlist Delayed Recall and Letter Fluency. In contrast, all target groups showed significant decline in MMSE(Beta[‐0.09–0.26]), Digit‐Span‐Backwords (Beta[‐0.04‐ ‐0.06]), Trailmaking‐A (Beta[‐0.06–0.19]),‐B (Beta[‐0.15–0.29]), Stroop‐I (Beta[‐0.04–0.09]), Word‐List‐Recognition (Beta[‐0.09–0.16]) and Category‐Fluency (Beta[‐0.06–0.12])(Table 2). Linear mixed models showed a steeper decline on tests in AT(N)+ group. The composite measures showed significant decline in A+, AT(N)+ and E4+A+, (Beta[‐0.08–0.26]). With a sensitivity analyses we limited the follow up time to 2 years, leading to fewer neuropsychological tests showing decline and no decline in the composite measures.ConclusionWe demonstrated that in preclinical AD, commonly‐used neuropsychological tests capture cognitive decline dependent on biomarker profiles. Tests for memory, attention and executive functioning were sensitive to decline, as were composite measures. When follow‐up time was limited to 2 years, fewer tests were sensitive to change including the composite measures. Therefore, careful selecting cognitive outcome measures and an appropriate period of time is important when defining the target population for the clinical trial.

Head‐to‐head comparison between plasma ptau‐217 and Flortaucipir‐PET in amyloid‐positive patients with cognitive impairment

AbstractBackgroundPlasma measurements of phosphorylated tau (ptau) have emerged as promising biomarkers for Alzheimer’s disease (AD). Studies have shown strong associations between ptau and tau‐PET that are mainly driven by the difference between amyloid‐positive and amyloid‐negative patients. However, the relationship between ptau and tau‐PET is not well characterized within patients with AD. We conducted a head‐to‐head comparison between plasma ptau‐217 and tau‐PET in patients at the clinical stage of AD and assessed biomarker relationships with demographic and clinical variables.MethodsEighty‐seven amyloid‐positive patients (age=66±10, 48% women) with mild cognitive impairment (n=53) or dementia (n=34) underwent structural MRI, amyloid‐PET (11C‐PIB), tau‐PET (18F‐flortaucipir, FTP), Mini‐Mental State Examination (MMSE, with 28 patients having longitudinal measures 1.5±0.7 years after baseline) and blood draw within a year. Mean cortical PET‐Standardized Uptake Value Ratio (SUVR) were extracted using FreeSurfer5.3. Plasma ptau‐217 concentrations were measured using an electrochemiluminescence‐based assay on the Meso Scale Discovery platform.ResultsPtau‐217 and cortical FTP‐SUVR were strongly correlated (r=0.61, p&lt;.001, Figure 1). Younger age and female sex, but not APOE4, were associated with higher ptau‐217 and FTP‐SUVR (Figure 2). Amyloid‐PET levels were mildly associated with FTP‐SUVR (r=0.26, p=0.02), not ptau‐217 (r=0.10, p=0.36, Figure 2). The relationship between ptau‐217 and cortical FTP‐SUVR was not modified by age, sex, APOE4, or PIB‐PET (interactions: p’s&gt;0.25). In the whole group, ptau‐217 was associated with FTP‐SUVR in temporo‐parietal and dorsal prefrontal cortices (Figure 3A). However, ptau‐217‐FTP association patterns varied with amyloid burden: in patients with moderate amyloid (&lt;97.7 Centiloids), ptau‐217 was more strongly associated with temporal FTP‐SUVR whereas associations were stronger in primary cortices in patient with higher amyloid levels (Figure 3B). Cross‐sectionally, higher ptau‐217 and FTP‐SUVR were independently associated with lower MMSE (Table 1; Figure 4A). In separate mixed effect models, higher baseline ptau‐217 and FTP‐SUVR were associated with more severe longitudinal decline in MMSE (Figure 4B); when both biomarkers were entered in the same model, only FTP‐SUVR remained significant (Table 2).ConclusionsIn amyloid‐PET‐positive patients with cognitive deficits, ptau‐217 and tau‐PET had comparable patterns of association with demographic and clinical variables. However, cross‐modal and clinical associations tended to be stronger for tau‐PET than ptau‐217.

A synergistic association of diabetes and AD biomarkers on cognitive decline in persons without dementia?

AbstractBackgroundTo improve prognostic procedures, we aimed to explore whether diabetes mellitus and Alzheimer’s disease (AD) biomarkers are synergistically associated with cognitive decline in persons without dementia.MethodWe included 1.737 persons with normal cognition (NC) and 634 with mild cognitive impairment (MCI) from 8 European memory clinic and aging cohorts as part of the PRIME project. We examined cognitive decline in MMSE (raw scores), memory (delayed recall), attention, executive functioning, and language domains (Z‐scores). AD biomarkers included CSF amyloid‐beta42 (data‐driven cut‐offs) or amyloid PET (center‐specific cut‐offs) as measure of amyloid positivity, CSF p‐tau as measure of tau tangle positivity and CSF t‐tau as measure of neurodegeneration (both center‐specific cut‐offs). We performed generalized linear mixed models with random intercepts and slopes, all adjusted for demographics.ResultMean age was 65.9 (SD=8.9) years, 54% were women, and diabetes was diagnosed in 7% of NC and 12% of MCI. Mean follow‐up time was 1.8 years (range 0.5‐8).In NC, we found decline in memory and attention in persons with both diabetes and t‐tau positivity. This was not shown in persons with only diabetes or only t‐tau positivity (Figure 1). We also found this interaction between diabetes and p‐tau on attention decline (Table 1). When stratifying for amyloid status, we found that this was only significant in amyloid negative individuals (memory t‐tau: p=0.005, attention p‐tau: p=0.033, attention t‐tau: p=0.039). A higher baseline language performance was found in persons with both diabetes and p‐tau or t‐tau positivity (p=0.011; p=0.034) compared to those with only diabetes or tau positivity. We found steeper decline in language in persons with both diabetes and amyloid positivity, compared to other groups (Figure 2). A similar synergism with diabetes was found for p‐tau. No interaction was found for executive functioning.In persons with MCI with both diabetes and t‐tau positivity, we found higher baseline MMSE scores (p=0.041) compared to other groups. Diabetes was not associated with cognitive decline in any domain in MCI.ConclusionDiabetes may affect non‐AD‐related decline in memory and attention as well as AD‐related decline in language at an early clinical stage. This may help improve prognostic procedures.

Lipophilic Statins in Subjects with early Mild Cognitive Impairment and Low Serum Cholesterol: Association with Long‐Term Cerebral Metabolic and Cognitive Decline in a Prospective Longitudinal Multi‐Center Study

AbstractBackgroundWe recently reported that lipophilic statins, known to penetrate the blood‐brain barrier, were associated with accelerated decline in regional cerebral metabolism in subjects with early Mild Cognitive Impairment (eMCI) who had relatively low serum cholesterol levels (J Nucl Med. 2021;62:Suppl 1). In this study, we expand upon our past results by studying the relationship between metabolic decline in lipophilic statin users and their decline in neuropsychological test scores.MethodsSubjects with eMCI were drawn from a consecutive series enrolled in the Alzheimer's Disease Neuroimaging Initiative, identifying 70 having serum cholesterol levels below the 206 mg/dl median of non‐statin users and with clear histories of time‐frames of prescriptions and types of statins used – 41 taking lipophilic statins throughout the 2‐year follow‐up period (LS), and 29 demographically similar non‐statin users (nonS). FDG‐PET scans acquired at baseline and 2 years later were compared for each group, and standardized Volume of Interest (sVOI) methods were used to calculate rates of regional metabolic decline. Correlations between changes in regional metabolism and changes in neuropsychological test scores were assessed by linear regression.ResultsThe strongest association occurred between declining metabolism in the left parietotemporal cortex (PTC) and declining function, as indexed by the Functional Activities Questionnaire (FAQ), which was highly significant among LS users (p=0.0004), but not among nonS subjects (p=0.56). Decline of left PTC was also a significant correlate of decline in LS memory performance (p= 0.001), but not nonS (p = 0.11). Both the left posterior cingulate and right PTC declines correlated with LS MMSE decline (p = 0.01 for both), while that metabolic decline was again uncorrelated for nonS subjects.ConclusionSubjects with eMCI with low serum cholesterol levels , who nevertheless were persistently prescribed lipophilic statins over two years, underwent accelerated metabolic decline in the brain regions most significantly hypometabolic in patients with Alzheimer's disease that was in turn significantly correlated with decline in key measures of both function and cognition, in a manner specific to statin use.