Search

INTRODUCTION: This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early‐stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well‐established measures. METHODS: For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. RESULTS: Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test‐retest reliability) and stronger associations with AD‐related demographic, genetic, and brain risk markers than well‐established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early‐stage AD clinical trials. Highlights: Well‐established cognitive tests may not accurately detect subtle cognitive changes.No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties.NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains.Novel measures had better psychometric properties compared to established measures.Significant associations with Alzheimer's disease biomarkers were found with novel measures. [ABSTRACT FROM AUTHOR]

Objective: In this study, we examine how impairments in vision, hearing, touch, and olfaction relate to depression in older adults, considering both individual and multisensory impairments (MSIs). Study Design: Analysis of cross‐sectional data from a longitudinal investigation involving black and white older adults aged 70 to 79 at enrollment. Setting: We studied 1640 black and white participants in the Health ABC study using complete sensory evaluation data from years 3 to 5. Methods: Our MSI assessment utilized data obtained for visual acuity, hearing perception, olfactory performance, and tactile function. We performed multivariable logistic regression analyses to examine the associations between the presence of individual and MSIs and depression which was defined as the presence of antidepressants prescribed for depression, or a Center for Epidemiological Studies Depression Scale score of greater than 10. Results: We observed a possible dose‐response relationship between the number of sensory impairments and depression. In adjusted models, when compared to no impairments, vision (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.09‐1.93) and hearing impairments (OR = 1.49, 95% CI: 1.11‐1.99) were significantly associated with depression, whereas olfaction (OR = 1.11, 95% CI: 0.83‐1.47) and tactile impairments (OR = 1.28, 95% CI: 0.96‐1.70) were not. Participants with 3 sensory impairments had a higher rate of depression (OR = 2.05, 95% CI: 1.22‐3.54) compared to those without impairments, and this risk increased further for those with 4 sensory impairments (OR = 2.95, 95% CI: 1.48‐5.88). Conclusion: The findings suggest that individuals with MSI represent a high‐risk population for depression, warranting close monitoring to screen for depression. The study emphasizes the importance of considering multiple sensory impairments in the context of mental health and supports the early identification and monitoring of depression in this population. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The effects of sleep–wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep‐related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below‐mean CR. Therefore, improving sleep–wake regulation and leisure activities may protect against fatigability and cognitive decline. Highlights: Clinical fatigue and fatigability cannot be alleviated by rest.Clinical fatigability disrupts daily activities during preclinical Alzheimer's.High cognitive reserve mitigates sleep–wake disturbance effects.High cognitive reserve attenuates clinical fatigability effects on daily functioning.Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain. [ABSTRACT FROM AUTHOR]

Background: There is ample evidence in animal models that lithium increases Brain‐Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function. Objectives: To evaluate low‐dose lithium treatment of agitation in Alzheimer's disease (AD). Method: We measured levels of BDNF in patients treated with lithium prior to and after a 12‐week randomized placebo‐controlled trial. Results: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function. Conclusions: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia. Key points: Lithium is known to increase Brain‐Derived Neurotrophic Factor (BDNF) levels.BDNF has neuroprotective properties.Decreased levels of BDNF have been found in the brains of people with AD.Little is known about the association between the effects of Lithium on BDNF in patients with AD. [ABSTRACT FROM AUTHOR]

Background: The pathology of Alzheimer's disease (AD) is characterized by two types of proteins: intracellular neurofibrillary tau tangles and extracellular β‐amyloid (Aβ) plaques. In the present observational studies, spatial discrepancies between these two proteins across the brain regions are well‐documented. However, the association between these two proteins remains elusive in different stages of depositions. Methods: We aimed to investigate the remote association between tau and Aβ uptakes by using 572 elderlies 67.11 ± 6.08 (476 healthy control (HC) and 96 mild cognitive impairments (MCI)) Aβ and tau positron emission tomography (PET) scans. We leveraged 47 tau‐PET and 97 Aβ‐PET scans of healthy young individuals (aged 20‐40) to find the regional cut‐points for 68 cortical regions in the brain. Then by using these cut‐points and tau PET scans of all elderly individuals, we identified four groups of individuals (no tau phase, pre‐acceleration phase, acceleration phase, and post‐acceleration phase) (Table 1). Finally, a regional multiple linear regression model is performed for each group to detect the hubs region based on the remote association between each target region of tau and all other regions Aβ in the different phases of tau accumulations (controlling for gender, age, intracranial volume, and each target region Aβ). Results: First, we show that the left and right entorhinal cortex, and right parahippocampal tau are the hubs of remote association with Aβ in several cortical regions (especially temporal regions) in the early stage of aggregation (Figure 1). Second, we identify tau in the same regions, continuing to demonstrate the highest remote associations with cortical Aβ (Figure 2) in the acceleration phase. Conclusion: The remote association appears in medial temporal lobe (MTL) tau during the early stage, as well as the later stage of tau accumulation (pre‐acceleration and acceleration phases). While the cellular mechanism of remote association is still elusive, in vivo studies have demonstrated that the Aβ triggers tau deposition indirectly in distal regions. Understanding the association between tau and Aβ at the preclinical stage of AD is critically important for a better consideration of tau spreading, especially in disease‐related brain regions. [ABSTRACT FROM AUTHOR]

Introduction: Mild to moderate exercise may decrease Alzheimer's disease (AD) risk, but the effects of vigorous, regular physical exercise remain unclear. Methods: Two patients with initial diagnoses of amnestic mild cognitive impairment (MCI) demonstrated positive AD biomarkers throughout 16 and 8 years of follow‐up, with final diagnoses of mild AD and amnestic MCI, respectively. Results: Patient 1 was diagnosed with amnestic MCI at age 64. Neuropsychological testing, magnetic resonance imaging (MRI), fluorodeoxyglucose–positron emission tomography (FDG‐PET), amyloid imaging PET, and cerebrospinal fluid (CSF) biomarkers during follow‐ups remained consistent with AD. By age 80, progression was minimal with Montreal Cognitive Assessment (MoCA) 26 of 30. Patient 2 was diagnosed with amnestic MCI at age 72. Neuropsychological testing, MRI, FDG‐PET, and amyloid imaging PET during follow‐ups remained consistent with AD. At age 80, MoCA was 27 of 30 with no clinical progression. Both patients regularly performed vigorous, regular exercise that increased after retirement/work reduction. Discussion: Vigorous, regular exercise may slow disease progression in biomarker‐positive amnestic MCI and mild AD. [ABSTRACT FROM AUTHOR]

Background: The positron emission tomography (PET) radiotracer [18F]MK‐6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within‐brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK‐6240 use to identify and stage AD subjects versus non‐AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter‐reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30‐scan set, providing initial validation. Inter‐rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter‐rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131‐scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four‐class [18F]MK‐6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK‐6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter‐rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK‐6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. [ABSTRACT FROM AUTHOR]

Background: Odor identification deficits predict transition to dementia, whereas intact odor identification and global cognition may identify lack of transition. The purpose of this study is to examine intact odor identification and global cognitive functioning as prognostic indicators of lack of transition to dementia in a well‐characterized biracial (Black and White) cohort. Method: In a community‐dwelling sample of 2,270 older adults without dementia participating in the Health, Aging, and Body Composition (Health ABC) study, odor identification was measured using the Cross‐Cultural Smell Identification Test (BSIT) and global cognition was measured using the Teng Modified Mini‐Mental Status Examination (3MS), both in Year 3. Incident dementia was defined by diagnosis in medical/hospital records or prescription of anti‐Alzheimer's disease medications. Survival analyses for dementia transition over 4 years and 8 years were conducted using Cox proportional‐hazards models. Result: Survival analyses adjusted for demographic and medical covariates indicated that impaired odor identification (hazard ratio [HR] = 2.17, 95% confidence interval [CI] = 1.5‐3.1) and global cognition (HR = 2.75, 95% CI = 1.8‐4.3) each independently predicted transition to dementia (n = 287). Odor identification interacted with ApoE genotype, such that the effect of impaired odor identification on dementia transition risk was significantly greater in ApoE e4 carriers (HR = 4.0) than noncarriers (HR = 1.6). This interaction was significant for White participants, though not for Black participants. Among participants with intact odor identification (BSIT ≥ 11/12 correct) and global cognition (3MS ≥ 77/100 correct), 6.4% (49/765) transitioned to dementia over 8 years of follow‐up. Only 0.9% (4/451) of participants aged 70–75 with intact performance on both measures transitioned to dementia over 4 years of follow‐up. Conclusion: Odor identification testing paired with global cognitive screening identified individuals at low risk for transition to dementia in a biracial community cohort with this decrease in risk being pronounced in the seventh to eighth decade of life. Identification of such individuals can obviate the need for extensive investigation to establish a diagnosis and has potential for screening participants for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in MCI is unclear. Method: In a two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, computerized training with Web‐based cognitive games or Web‐based crossword puzzles, followed by six booster sessions. In mixed‐model analyses, the primary outcome was change from baseline in the 11‐item Alzheimer's Disease Assessment Scale‐Cognitive (ADAS‐Cog) score, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score and Functional Activities Questionnaire score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed. Result: Among 107 participants (n = 51 [games]; n = 56 [crosswords]), ADAS‐Cog11 score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, 21.44; 95% CI 22.83 to 20.06; P = 0.04). From baseline to week 78, mean ADAS‐Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, 22.45; SE, 0.89; 95% CI 24.21 to 20.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, 21.08; 95% CI 21.97 to 20.18, p = 0.02). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI 0.51 to 67.63, p <.05 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04, p =.02 [cortical thickness]). Conclusion: Home‐based computerized training with crosswords demonstrated superior efficacy to games at 78 weeks. Common directionality was observed in the primary outcome of ADAS‐Cog (cognition) and the secondary outcomes of FAQ (function) score and changes in MRI hippocampal volume and cortical thickness (neurodegeneration). If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzles training could become a home‐based, scalable, cognitive enhancement tool for individuals with MCI. [ABSTRACT FROM AUTHOR]

Background: Human neuroimaging efforts to understand the pathophysiology of Alzheimer's disease (AD) have solely focused on the amyloid‐beta (Aβ) deposition and tau neurofibrillary tangle formation. Until recently, the idea of a connectivity‐based molecular functional framework for understanding AD pathophysiology was missing, which eluded researchers from connecting functional connectivity (FC) with Aβ/Tau deposition. Method: The initial dataset includes 631 older (67.44 ± 6.48 years) adults (521 healthy controls and 110 mild cognitive impairment (MCI)) who have been imaged for Tau pathology as well as resting‐state functional magnetic resonance imaging (rsfMRI) and structural MRI scans. Using Schaefer's 200 parcellation atlas and a regional cutoff (SUVR = 1.25), we identified four groups of tau staging based on the number of regions having higher than cutoff tau SUVR (no tau stage (N = 193), pre‐acceleration stage (N = 222), acceleration stage (N = 149), and post‐acceleration stage (N = 67)). Since the entorhinal cortex (EC) is widely regarded as the epi‐center for tau accumulation, the left and right EC time series were derived from rsfMRI data using the Desikan‐Killiany atlas and used as seed regions for our Pearson correlation coefficient based functional connectivity analysis with all 200 regions in the Schaefer atlas. Finally, linear regression models were run to predict the mean regional accumulation of tau based on the strength of mean FC between that region and EC. Result: As shown in Fig. 1, left/right EC functional connectivity is strongly associated with the accumulation of tau in that region during the pre‐acceleration phase (left: t = 3.586, p < 0.0004; right: t = 4.404, p < 0.0001) and in the acceleration phase (left: t = 6.229, p < 0.0001; right: t = 7.577, p < 0.0001) (results not shown). The functional connectivity values from left/right EC for the pre‐acceleration phase are plotted on the surface of the brain, as shown in Fig. 2. Conclusion: Our results provide evidence of the role of functional connectivity in tau spreading from EC to the rest of the brain and can help throw light on the dynamic patterns of tau spreading in MCI/AD subjects in different disease stages. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluated acute change in odor identification following atropine nasal spray challenge, and 8-week change in odor identification ability, as a predictor of long-term improvement in patients with mild to moderate Alzheimer’s disease (AD) who received open-label cholinesterase inhibitor treatment. Methods: In patients with clinical AD, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Patients were then treated with donepezil for 52 weeks. Results: In 21 study participants, acute atropine-induced decrease in UPSIT was not associated with change in the Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) or Selective Reminding Test (SRT). Decline in odor identification performance from baseline to week 8 was indicative of a future decline in cognitive performance over 52 weeks. Discussion: Change in odor identification with atropine challenge is not a useful predictor of treatment response to cholinesterase inhibitors. Short-term change in odor identification performance needs further investigation as a potential predictor of cognitive improvement with cholinesterase inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background: Neural networks are increasingly being applied towards neuroimaging problems in AD, but performance is often limited by lack of adequate numbers of samples. This is commonly alleviated by pre‐training the model on a related task beforehand (i.e. 'transfer learning'). To our knowledge, there exists no set/standard of widely available pretrained model weights for 3D medical images. Tau PET radiotracers such as AV‐1451 and MK‐6240 have highly similar binding patterns, and so may be well suited to transfer learning tasks. Method: Subjects with AV‐1451 scans (n=446) were downloaded from ADNI, while subjects with MK‐6240 scans (n= 320) were pooled from multiple studies recruiting at CUIMC. We trained multiple 3D neural networks (all with the same modified InceptionV3 architecture) to differentiate patients (i.e. MCI/AD) from controls based on their tau PET scan, both with and without pretraining information from prior training iterations of our models. We compare performance on holdout sets for each validation fold (n= 64 for MK‐6240 and n=89 for AV‐1451) using DeLong's test for ROC curves and analyze features learned by models with t‐SNE plots. Result: The AV‐1451 Model pretrained on MK‐6240 scans had superior performance to the AV‐1451 model not using pretraining (AUC = 0.74 vs. 0.91, Z = ‐5.5, p < 0.0001), whereas there was no significant difference with pretraining for MK‐6240 models (AUC = 0.84 vs. 0.83, Z = 0.47 ,p = 0.6). Visually, there appears to be greater separation in model learned features following pretraining in the AV‐1451 model. Conclusion: 3D pretraining for neural networks involving PET imaging could be accomplished with related but structurally different radioligands, though more work is needed into determining why certain pretraining experiments are successful. This procedure can enable better training of complex models with fewer constraints due to sample size. [ABSTRACT FROM AUTHOR]

Introduction: Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia. Methods: In an urban community, 1037 older adults without dementia completed the 40‐item University of Pennsylvania Smell Identification Test, which includes the 12‐item Brief Smell Identification Test (B‐SIT). Data from 749 participants followed up for 4 years were analyzed. Results: In covariate‐adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B‐SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B‐SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow‐up with no transitions in the 70‐75 and 81‐83 years age group quartiles. Discussion: Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S‐CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. Methods: S‐CitAD is a NIH‐funded, investigator‐initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study ‐ Clinical Global Impression of Change (mADCS‐CGIC). Discussion: S‐CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S‐CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846). [ABSTRACT FROM AUTHOR]

Background: The association between sleep quality and cognition is widely established but the role of aging in this relationship has been unclear due to inconsistent findings with heterogeneous methods and a lack of studies in wide age ranges. The current study examined how age impacts the sleep‐cognition relationship using a large‐scale dataset with adults from young adulthood to older adulthood. Furthermore, we tested non‐linear effect of age to investigate the presence of age ranges in which the association between sleep and cognition is modified. Method: Sample included 711 individuals (ages 36.00‐89.83, 59.66 ± 14.91, 55.7% female) from the Human Connectome Project‐Aging (HCP‐A). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI), and cognitive outcome measures included the NIH Toolbox fluid cognition (Dimensional change Card Sort Test, List Sorting Working Memory Test, Picture Sequence Memory Test, Pattern comparison Processing Speed Test, Flanker Inhibitory Control and Attention Test) and crystallized cognition composite scores (Oral Reading Recognition Test and Picture Vocabulary Test), the Trail Making Test (TMT) A and B, and the Rey Auditory Verbal Learning Test (RAVLT). The association between sleep quality and cognitive performance was measured using linear regression models, with sex, race, use of sleep medication, and years of education as covariates. Age moderation was tested via the interaction between sleep and age on cognition, with age as linear and non‐linear (quadratic) terms. Result: There was a significant interaction term between the PSQI and non‐linear age term (age2) on TMT‐B (p = 0.02) and NIH Toolbox crystallized cognition (p = 0.02), indicating that the association between poor sleep quality and cognitive performance was moderated by age. Further analyses indicated that there were "critical age ranges" in which the sleep‐cognition association was more salient (ages 50‐75 for TMT‐B and 66‐70 for crystallized cognition). Conclusion: The association between sleep quality and cognitive performance may be modified by age. Individuals of the middle‐age to early older adulthood may be more vulnerable to sleep‐related cognitive impairment, indicating the clinical importance of detection and treatment of sleep disturbance in this particular age group. [ABSTRACT FROM AUTHOR]

Objective: The classification of mild cognitive impairment (MCI) continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. Our aim was to examine baseline characteristics of DEP-CI patients in the DOTCODE trial, a randomized controlled trial of open antidepressant treatment for 16 weeks followed by add-on donepezil or placebo for 62 weeks.Methods/design: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HAM-D) score >14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics.Results: Seventy-nine DEP-CI patients were recruited of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9, and mean HAM-D was 23.0. Late mild cognitive impairment patients had significantly worse ADAS-Cog (P < .001), MMSE (P = .004), Block Design (P = .024), Visual Rep II (P = .006), CFL Animal (P = .006), UPSIT (P = .051), as well as smaller right hippocampal volume (P = .037) compared to EMCI patients. MRI indices of cerebrovascular disease did not differ between EMCI and LMCI patients.Conclusions: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Pimavanserin was investigated for the treatment of dementia‐related psychosis (DRP) in HARMONY (NCT03325556), a phase 3 randomized discontinuation study. As the study met the primary endpoint (one‐sided P = 0.0023), we evaluated the consistency of the efficacy for reducing the risk of relapse in the largest dementia patient subgroup (ie, Alzheimer's dementia psychosis [ADP] patients) treated with pimavanserin 34mg. Method: Enrolled DRP patients (N = 392) entered the 12‐week open‐label (OL) period and received pimavanserin 34mg daily. During weeks 1‐4, dose could be adjusted to 20mg at investigator discretion. Patients meeting prespecified response criteria at weeks 8 and 12 were randomized to continue pimavanserin or receive placebo for up to 26 weeks in the double‐blind (DB) period. The primary endpoint was time from randomization to adjudicated relapse. Efficacy analyses included patients at the interim analysis (IA); safety analyses included all dosed patients. Result: Of 260 ADP patients, 243 stayed on pimavanserin 34mg throughout the OL period; 17 patients received pimavanserin 20mg beyond OL week 4. At baseline, mean age in the pimavanserin 34mg group was 75.7 years; mean MMSE score was 16.0. Twenty‐nine patients were terminated with sponsor termination of the study; of the remaining 214 patients, 130 (60.7%) met response criteria at weeks 8 and 12 and were randomized. At the IA, 116 ADP patients were randomized to pimavanserin 34mg (N = 57) or placebo (N = 59). Hazard ratio for psychosis relapse risk with pimavanserin 34mg versus placebo was 0.466 (95% CI: 0.179, 1.214); 6/57 (10.5%) pimavanserin‐treated and 14/59 (23.7%) placebo‐treated patients met relapse criteria. Treatment‐emergent adverse events incidence rates were: OL, 29.6% (72/243); DB‐pimavanserin 34mg, 39.7% (25/63); DB‐placebo, 34.3% (23/67). Pimavanserin did not have a negative effect on Mini‐Mental State Examination or Extrapyramidal Symptom Rating Scale‐Abbreviated score change from baseline versus placebo in the DB period. Conclusion: In a study that met its primary endpoint, a post‐hoc subgroup analysis in ADP, although not statistically significant, demonstrated a clinically meaningful reduction in the risk of relapse was observed in patients treated with pimavanserin 34mg versus placebo. Pimavanserin was not associated with an adverse impact on cognition or motor function. [ABSTRACT FROM AUTHOR]

Background: The No Practice Effects (NPE) battery is a novel set of neuropsychological measures designed to assess important cognitive domains and have robust psychometric properties for use in preclinical and early‐stage Alzheimer's disease clinical trials. The current study used exploratory factor analysis to examine cognitive domains in the NPE battery. We further examined the association between identified cognitive domains with demographic characteristics, brain imaging metrics, and genetic risk markers for Alzheimer's disease. Methods: A total of 116 older adults who are cognitively healthy or have early mild cognitive impairment (eMCI) (mean age 70.35 ± 6.53, 62.9% women) and have baseline cognitive assessments were included. The NPE battery contains seven primarily computerized tests of memory and attention. We conducted an exploratory factor analysis using an oblique rotation to identify different cognitive domains within the NPE, then composite scores were calculated for each domain. Simple correlation analyses were conducted to examine the association between these composite scores and demographic characteristics. The multiple regression analyses were performed to examine the association between composite scores and AD risk markers. Results: The exploratory factor analysis produced three factors within the NPE battery corresponding to 1) Cognitive Control/Executive Functions (including Letter and Category Verbal Fluency, Brown‐Peterson Paradigm, Digit Symbol Substitution Test, Letter‐Number Span, and N‐Back); 2) Response Monitoring (Recognition Memory Test [RMT] learning and correctly rejected recognition items) reflecting encoding process and post‐recollection cognitive monitoring; and 3) Recall/Retention (RMT total recall and hits on recognition items) that may be considered a "memory consolidation" factor. Greater performance on Response Monitoring was associated with younger age (r2 = ‐0.27, P = 0.004), higher education level (r2 = 0.29, P = 0.002), and APOE4 genotype (B = ‐0.27, SE = 0.13, P = 0.04). Recall/Retention was positively associated with the thickness of the entorhinal cortex (B = 0.58, SE = 0.28, P = 0.04), but not hippocampal or parahippocampal volumes. The general composite score encompassing all tests was associated with age (r2 = ‐0.29, P = 0.002), education (0.28, P = 0.003), and APOE4 (B = ‐0.25, SE = 0.10, P = 0.01). Conclusion: These results provide preliminary evidence that the NPE battery identifies domains characteristic of cognition. These cognitive domains were associated with demographic factors, such as age and education, along with APOE4 genotype, and brain structural measures. [ABSTRACT FROM AUTHOR]

Background: There is no consensus in the field regarding the relationship between AD pathologies (Aβ, and Tau) and neurodegeneration. One reason that may contribute to this disagreement is the definition of cut‐point to categorize participants with or without significant pathologies. This approach overlooks an important early stage of pathological accumulation. In this study, we take advantage of Florbetaben/MK6240 PET scans from 61/21 young (<40) and healthy participants to redefined the cut‐point of Aβ/Tau uptake and investigate their association with cortical thickness as a measurement of neurodegeneration. Method: To capture the early effect of pathologies, we quantify global pathologies by averaging AD‐related regions uptake; global Aβ: frontal, parietal, temporal, anterior and posterior cingulate, and precuneus, global Tau: fusiform, amygdala, parahippocampal, entorhinal, inferior temporal, middle temporal, and medial temporal lobe (MTL) Tau: entorhinal and parahippocampal. We redefied the cut‐point of AD pathologies using 95% percentile of the fitted normal distribution to the young subject's uptakes. Using newly defined cut‐points (1.01

Background: The associations of Alzheimer's disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) is not well‐established. Method: This retrospective cohort study used 1,808 brains from 39 sites in the National Alzheimer's Coordinating Center (NACC) V.10 collection for participants with the Neuropsychiatric Interview‐Questionnaire (NPI‐Q) administered annually and without consideration of clinical diagnosis. Brain autopsy diagnoses of AD, Lewy Body Disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration (FTLD), cerebrovascular disease (CVD), hippocampal sclerosis, and "no known pathology" were examined. NPI‐Q domain score if present at any timepoint was the primary outcome and average NPI‐Q domain score during follow‐up was secondary. The associations of ADRD diagnoses with twelve NPI‐Q symptom domains were examined in regression analyses, correcting for multiple comparisons. Result: The study sample of 1,808 adults had a mean [SD] age 80.0 [11.0] years and 54.6% were male. Apathy was the most prevalent NPS, reaching 80% in hippocampal sclerosis. CVD showed few NPS associations. FTLD was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared to AD. Hippocampal sclerosis was associated with increased apathy (OR 2.60, 95%CI 1.86‐3.66, pfdr<.05) and disinhibition (OR 2.15, 95% CI 1.63‐2.84, pfdr<.05). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was associated consistently with increased NPS, e.g., LBD showed increase in hallucinations from brainstem (β=0.23, 95% CI 0.07‐0.76, p<.05) to limbic (β=1.69, 95% CI 1.27‐2.27, p<.01) to neocortical (β=4.49, 95% CI 3.27‐6.16, p<.001) pathology. Hallucinations were more common in participants with AD+LBD (168/534=31.5%) compared to AD without LBD (152/704=21.6%) and LBD without AD (23/119=19.6%). Conclusion: Visual hallucinations may characterize LBD with AD more than LBD without AD. NPS criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported. In hippocampal sclerosis, the novel findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was related to NPS severity, indicating that NPS reflect underlying ADRD pathology and highlight the importance of diagnosing and treating NPS. [ABSTRACT FROM AUTHOR]

Background: We examined the association between sleep health consequences and perceived fatigability within the context of carrying out everyday activities in non‐demented older adults and investigated whether cognitive reserve (CR; individual differences in susceptibility to cognitive decline due to brain aging, pathology, or insult) moderated this relationship. Method: This was a cross‐sectional study. We prospectively screened adults age 55‐90 years at a Memory Research Clinic. An IRB approved the study protocol, and informed consent was obtained. Patients with cognitive concerns underwent neurocognitive testing to determine cognitive status based on the ADNI criteria. Inclusion criteria: the ADNI criteria for cognitively normal or MCI. Exclusion criteria: 1) depression assessed with the Geriatric Depression Scale (GDS>5) and DSM‐5 criteria, 2) history of primary psychiatric illnesses, 3) medical conditions associated with fatigue, and 4) a history of obstructive sleep apnea diagnosed by a clinical sleep physician. Measures included the PROMIS Sleep‐related Impairment (SRI); the Neuro‐QOL Cognitive function (CogF) and Fatigue measure, which yields "fatigue symptom severity (Fat_Sx)" and "perceived fatigability (Fatiga)" subscales. CR was assessed with the CR Index questionnaire (CRIq). Linear regression models were fit to the fatigue outcomes and included the SRI, CR, and their interaction as predictors. If the interaction was significant, SRI slopes were assessed at CR=mean and mean ±1SD. All analyses were adjusted for age, sex, and education. Result: There were 37 subjects in this study; mean age of 70.8 years (SD=9.3); 70.3% subjects were female; 86.5% white, 10.8% Hispanic, and 2.7% others. CR significantly moderated the relationship between SRI and perceived fatigability (F (1,32)=18.64, p=0.011). A higher SRI score was associated with a higher perceived fatigability severity with a low CR (CRIq mean‐1SD)=108.6; b(se)=.493(.089), p<0.001) and a mean CR (CRIq mean=128.0; b(se)=.274(.076); p=0.001), but not a high CR (CRIg mean+1SD=147.4; b(se)=0.1278; p=0.636). Moreover, higher perceived fatigability was associated with lower cognitive function (b(se)=‐.24 2(0.077), p=0.004), controlling for age, gender, and education. Conclusion: Poorer cognitive function was significantly associated with greater fatigability within the context of managing everyday activities. Greater cognitive reserve may reduce the detrimental influence of poor sleep health on perceived fatigability in managing daily function during the preclinical stages of dementia. [ABSTRACT FROM AUTHOR]

Background: There is limited information on the impact of specific neuropathologies on neuropsychiatric symptoms (NPS). We evaluated the impact of neuropathologically defined subtypes of Alzheimer's Disease and Related Dementias (ADRD) on neuropsychiatric symptoms (NPS) during life. Method: The study design used a direct and unbiased approach that did not consider clinical diagnoses and included all brains with neuropathological diagnoses in the V.10 collection of the National Alzheimer's Coordinating Center (NACC) database that also had Neuropsychiatric Interview‐Questionnaire (NPI‐Q) data collected during life. Data from 1,808 patients from 39 sites were examined. We utilized pairwise, ordinal and multiple logistic regression analyses to assess the effects of 8 neuropathological diagnoses on 12 domains in the Neuropsychiatric Inventory Questionnaire (NPI‐Q), correcting for multiple statistical comparisons. For NPS, average NPI‐Q domain scores during annual follow‐ups was the primary measure and NPI‐Q domain ever present/always absent was the secondary measure. Result: The neuropathological diagnosis of Alzheimer's disease (AD) using ABC criteria showed moderate associations with increased delusions, agitation/aggression and hallucinations. Cerebral amyloid angiopathy showed associations with NPS that were similar to AD. Lewy Body Disease (LBD) showed increased hallucinations. Infarcts/lacunes and microinfarcts showed weak associations with mood and motivational symptoms. Frontotemporal Dementia (FTD) was associated with marked increase in apathy and significantly decreased psychotic features and agitation. Hippocampal sclerosis was associated with less depression and increased apathy and disinhibition; these associations persisted after controlling for vascular neuropathology and FTD. In multiple regression analyses that controlled for other neuropathologies, the main findings were not altered. Conclusion: The associations of ADRD neuropathologies with specific NPS support current diagnostic criteria for behavioral symptoms in specific disorders. The findings on apathy and disinhibition in hippocampal sclerosis are novel and unique, and may explain inconsistent findings for depression treatment in dementia. Further investigation is needed to clarify the impact of hippocampal sclerosis on medial temporal lobe function and NPS, which may help eventually with diagnosis and clinical management. [ABSTRACT FROM AUTHOR]

Objective To examine the association between odor identification deficits and future mortality in a multiethnic community cohort of older adults. Methods Participants were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Follow-up occurred at 2-year intervals with information on death obtained from informant interviews and the National Death Index. Results During follow-up (mean = 4.1 years, standard deviation = 2.6), 349 of 1,169 (29.9%) participants died. Participants who died were more likely to be older ( p < 0.001), be male ( p < 0.001), have lower UPSIT scores ( p < 0.001), and have a diagnosis of dementia ( p < 0.001). In a Cox model, the association between lower UPSIT score and mortality (hazard ratio [HR] = 1.07 per point interval, 95% confidence interval [CI] = 1.05-1.08, p < 0.001) persisted after controlling for age, gender, education, ethnicity, language, modified Charlson medical comorbidity index, dementia, depression, alcohol abuse, head injury, smoking, body mass index, and vision and hearing impairment (HR = 1.05, 95% CI = 1.03-1.07, p < 0.001). Compared to the fourth quartile with the highest UPSIT scores, HRs for mortality for the first, second, and third quartiles of UPSIT scores were 3.81 (95% CI = 2.71-5.34), 1.75 (95% CI = 1.23-2.50), and 1.58 (95% CI = 1.09-2.30), respectively. Participant mortality rate was 45% in the lowest quartile of UPSIT scores (anosmia) and 18% in the highest quartile of UPSIT scores. Interpretation Impaired odor identification, particularly in the anosmic range, is associated with increased mortality in older adults even after controlling for dementia and medical comorbidity. Ann Neurol 2015;78:401-411 [ABSTRACT FROM AUTHOR]

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled “Sensory and Motor Dysfunctions in Aging and AD.” The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses. [ABSTRACT FROM AUTHOR]

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is associated with an elevated risk of progressing to Alzheimer's disease. Much less is known about the course of dysexecutive mild cognitive impairment (dMCI). The goals of this study were to determine how the profile of cognitive deficits differs over time between patients with dMCI and aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with stroke and white matter hyperintensity on magnetic resonance imaging (MRI) than aMCI. Methods: The authors undertook a prospective evaluation of an inception cohort of 1167 ethnically diverse elders recruited from an urban community-based sample monitored with clinical and neuropsychological testing for an average of 4.5 years (standard deviation, 0.8 year). A subset of the subjects underwent MRI. We compared four groups of MCI patients: single-domain amnestic and dysexecutive MCI, and multiple-domain MCI with and without executive dysfunction. Results: Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single-domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple-domain MCI did not increase risk of progression to dementia. Patients with multiple-domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer's–type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to experience stroke, but not white matter hyperintensity, detected via MRI than patients with aMCI. Conclusions: dMCI appears to follow a different course, and is less associated with Alzheimer's disease and more associated with stroke than aMCI. [Copyright &y& Elsevier]

Background: Dementia‐related psychosis (DRP) is common in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), vascular dementia (VaD), and frontotemporal dementia (FTD). However, no therapies have been approved. Current guidelines and real‐world practice involve a trial of off‐label antipsychotics when other interventions fail, with assessment of response in an individual patient and taper within 4 months in patients who have responded. Pimavanserin is an inverse agonist/antagonist at the 5‐HT2A receptor and is approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis. The objective of this analysis was to examine the response (≥30% reduction on the SAPS‐H+D Total Score AND a CGI‐I score of 1=very much improved or 2=much improved) to pimavanserin during open‐label treatment of patients with DRP. Method: HARMONY was a placebo‐controlled, randomized, Phase 3, relapse prevention study in patients with dementia (NIA‐AA criteria) and moderate to severe psychosis associated with PDD, DLB, AD, FTD or VaD. Eligible patients who failed brief psychosocial therapy during screening entered into a 12‐week open‐label (OL) period where they received pimavanserin 34 mg once daily. Patients were assessed for response at Weeks 8 and 12. Only patients who demonstrated sustained response (response at both Weeks 8 and 12) were eligible to randomize into the double‐blind portion of the trial. OL response rates and changes in psychotic symptoms were assessed in various subgroups within the study population Result: 392 patients were enrolled into the open‐label period; 41 patients were ongoing at the time of early study termination. Overall, 61.8% of patients demonstrated sustained response (59.8% AD, 71.2% PDD, 71.4% VaD, 45.5% DLB, and 50.0% FTD). Mean change in the SAPS scores across the OL period was similar regardless of dementia subtype or baseline characteristics. The response rate was similar regardless of age, dementia severity, or previous drug therapy, with more than 50% patients meeting response criteria at Week 4 across most factors. Conclusion: In this Phase 3 study, during the OL treatment phase, pimavanserin produced a robust reduction in psychosis symptoms, irrespective of most likely clinical diagnosis of dementia subtype or baseline MMSE/dementia severity. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the efficacy of antidepressants in people with depression and dementia. DESIGN: A systematic review and meta-analysis based on a literature search of Medline and Cochrane Trials Registry for acute-phase, double-blind, placebo-controlled, parallel-design, random-assignment trials of antidepressants marketed in the United States. SETTING: Outpatient clinics, inpatient units, residential settings. PARTICIPANTS: People with criterion-based diagnoses of dementia and depression. MEASUREMENTS: Numbers of participants randomized; baseline and end point depression scale scores; and response, remission, and discontinuation rates were extracted. Random-effects meta-analyses were performed for response and remission rates, change scores using standardized mean differences, and discontinuation rates. Sensitivity analyses were planned to examine effects of depression diagnosis, severity, and trial duration. RESULTS: Seven trials with 330 participants met selection criteria. The odds ratio (OR) for six trials reporting response rates with antidepressant and placebo was 2.12 (95% confidence interval (CI)=0.95-4.70; Z=1.84, P=.07). The OR for five trials reporting remission rates was 1.97 (95% CI=0.85-4.55; Z=1.59, P=.11). Both analyses demonstrated heterogeneity. The standardized mean difference in trials was 0.29 (95% CI=0.02-0.60, Z=1.86, P=.06). This analysis did not demonstrate significant heterogeneity. Adverse event discontinuation rates (9.0%) were not significantly higher with drug than placebo (6.0%), and were low. CONCLUSION: The evidence for antidepressant treatment of people with depression and dementia, although suggestive, does not confirm efficacy. All of the trials were significantly underpowered to detect differences, resulting in inconclusive findings. Variable trial methods, comorbid conditions, and differences in antidepressants employed further confounded findings. [ABSTRACT FROM AUTHOR]

Background: To evaluate low‐dose lithium treatment of agitation in Alzheimer's disease (AD). Method: In a four‐site trial, patients with AD and agitation/aggression on the Neuropsychiatric Inventory (NPI) were randomized, double‐blind, to lithium carbonate 150‐600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response defined by 30% reduction in NPI combined score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved. Somatic, cognitive, metabolic, and neurological side effects were assessed. Result: Fifty‐eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium did not differ from placebo in agitation/aggression change scores. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p=0.26). Moderate or marked improvement on global CGI change, which incorporated behavior, cognition, and function, was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher's exact test p<0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p's<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (β=5.06; 95%CI, 1.18 to 8.94, p=0.01). Oral dose and serum lithium levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on any safety outcome. Conclusion: Low dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted with precision pharmacological targeting of likely lithium‐responsive behavioral symptoms that overlap with mania. [ABSTRACT FROM AUTHOR]

Background: Olfactory dysfunction consistently occurs in patients with Alzheimer's disease (AD), beyond the mild and gradual decline in olfactory ability found in normal aging. This dysfunction begins early in the disease course, typically before clinical diagnosis, and progresses with disease severity. While odor identification and detection deficits clearly differentiate AD from controls, there remains uncertainty as to whether these are determined by olfactory threshold. The primary purpose of the current fMRI study was to examine the neural correlates of olfactory processing in healthy young and old adults and compare them with AD patients. Method: Health young adults (n=10), healthy old adults (n=10), and AD patients (n=12) participated in psychophysical olfactory testing and an fMRI odorant detection paradigm. We analyzed the interplay between age and disease‐related psychophysical olfactory declines and odorant‐induced brain activation. This tested whether odor threshold deficits reflect disease progression and explain group differences in detection, identification and brain activity. Result: AD patients had decreased odor detection task‐related signal in all regions of the primary olfactory cortex, with activity in the entorhinal cortex best differentiating the groups. Within the secondary olfactory regions, AD patients showed decreased activity in orbitofrontal cortex compared to healthy age matched individuals. Moderated‐mediation analyses on neuro‐psychophysical relationships found that increased brain activation in the entorhinal cortex moderated the negative effect of disease‐related threshold decline on olfactory detection. Conclusion: Even in the face of declining olfactory thresholds, older adults compensated for this effect with increased brain activation in a primary olfactory brain region. This was the case for odor detection but not odor identification. fMRI activation induced by an olfactory identification task may eventually be useful in improving early detection of AD and may, eventually, facilitate early treatment interventions in subjects at risk for AD. [ABSTRACT FROM AUTHOR]

Background: Fatigue is associated with neuroinflammation of the brain, one of the signatures of neurodegenerative disorders across preclinical and clinical stages. Substantial research evidence demonstrates a bidirectional link between Alzheimer's neuropathology and poor sleep. Whether neuroinflammation mediates the association between sleep disturbances and cognitive decline remains to be determined. In this pilot study, we examined whether fatigue impacts the relationship between sleep quality and cognitive function ability. Method: We prospectively recruited adults aged 55‐90 years with mild cognitive impairment to evaluate their symptoms of Fatigue, Sleep, and Cognitive Function Abilities (CFA), using the NIH PROMIS Fatigue short form (v1.0), Sleep Disturbances (SD, v2.0) and Sleep‐related Impairment short form (SRI v2.0), as well as the NIH Neuro‐QOL Cognitive Function Abilities short form (v1.0). The Poor‐sleep group was defined as a T‐score of >50 on either SD or SRI scale. Depression was defined as a Geriatric Depression Scale score of 5 or greater and was a study exclusion criterion. Result: Twenty‐seven patients enrolled in the study, including 14 women and 13 men. The mean age was 67.37+/‐ 9.00 years. The Poor‐sleep group had significantly lower CFA compared to the Good‐sleep group (b=‐6.28, p=0.019). Greater Fatigue scores were significantly associated with lower Cognitive Function Abilities scores (r=.49, p=0.010). These results remained significant after controlling for age. Further, total scale SRI score was significantly associated with total scale Fatigue score (r=.72, p<0.001). Conclusion: Both fatigue and sleep disturbances were significantly associated with low CFA independently, along with a significant correlation between fatigue and poor sleep. The mechanisms by which fatigue and sleep disturbances contribute to cognitive test performance need to be elucidated in future research. [ABSTRACT FROM AUTHOR]