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Sensory functions of organs of the head and neck allow humans to interact with the environment and establish social bonds. With aging, smell, taste, vision, and hearing decline. Evidence suggests that accelerated impairment in sensory abilities can reflect a shift from healthy to pathological aging, including the development of Alzheimer's disease (AD) and other neurological disorders. While the drivers of early sensory alteration in AD are not elucidated, insults such as trauma and infections can affect sensory function. Herein, we review the involvement of the major head and neck sensory systems in AD, with emphasis on microbes exploiting sensory pathways to enter the brain (the "gateway" hypothesis) and the potential feedback loop by which sensory function may be impacted by central nervous system infection. We emphasize detection of sensory changes as first-line surveillance in senior adults to identify and remove potential insults, like microbial infections, that could precipitate brain pathology., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: There is a need for integration and comprehensive characterization of environmental determinants of Alzheimer's disease. The Environmental Justice Index (EJI) is a new measure that consolidates multiple environmental health hazards., Objective: This analysis aims to explore how environmental vulnerabilities vary by race/ethnicity and whether they predict cognitive outcomes in a clinical trial of mild cognitive impairment (MCI)., Methods: We used data from a clinical trial of 107 MCI participants (28% minorities). Using the EJI, we extracted 40 measures of neighborhood environmental and social vulnerability including air and water pollution, access to recreational spaces, exposure to coal and lead mines, and area poverty. We also examined the relationship of the EJI to the Area Deprivation Index (ADI). Data was analyzed using regressions, correlations, and t -tests., Results: Environmental Burden Rank (EBR) across the sample (0.53±0.32) was near the 50th percentile nationally. When divided by race/ethnicity, environmental ( p  = 0.025) and social ( p  < 0.0001) vulnerabilities were significantly elevated for minorities, specifically for exposure to ozone, diesel particulate matter, carcinogenic air toxins, and proximity to treatment storage and disposal sites. ADI state decile was not correlated with the EBR. Neither EBR nor ADI were a significant predictor of cognitive decline., Conclusions: To our knowledge, this is the first study to link the EJI to an MCI trial. Despite limitations of a relatively small sample size, the study illustrates the potential of the EJI to provide deeper phenotyping of the exposome and diversity in clinical trial subjects., Competing Interests: DPD has received research grants from the National Institute on Aging and the Alzheimer’s Association and has served as a consultant on scientific advisory boards to Acadia, Corium, Genentech, TauRx, and a DSMB for BioXcel. PMD has received research grants from the NIH, DARPA, DOD, ONR, Salix, Avanir, Avid, Cure Alzhaimer’s Fund, Karen L. Wrenn Trust, US Highbush Blueberry Council, Steve Aoki Foundation, and advisory/board fees from Apollo, Clearview, Lumos, Prospira, Keel Digital, Otsuka, Compass, Sermo, Nutricia, UMethod, and Transposon. PMD is a co-inventor on patents for the diagnosis or treatment of Alzheimer disease and a patent for infection detection. PMD owns shares in UMethod, Alzheon, Transposon and MarvelBiome whose products are not discussed here. Other authors have received grant support from NIH and report no other competing interests., (© 2024 – The authors. Published by IOS Press.)

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear., Objective: In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition., Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration., Results: No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant., Conclusions: The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Background: Per cent slowing of decline is frequently used as a metric of outcome in Alzheimer's disease (AD) clinical trials, but it may be misleading. Our objective was to determine whether per cent slowing of decline or Cohen's d is the more valid and informative measure of efficacy., Methods: Outcome measures of interest were per cent slowing of decline; Cohen's d effect size and number-needed-to-treat (NNT). Data from a graphic were used to model the inter-relationships among Cohen's d, placebo decline in raw score units and per cent slowing of decline with active treatment. NNTs were computed based on different magnitudes of d. Last, we tabulated recent AD anti-amyloid clinical trials that reported per cent slowing and for which we computed their respective d's and NNTs., Results: We demonstrated that d and per cent slowing were potentially independent. While per cent slowing of decline was dependent on placebo decline and did not include variance in its computation, d was dependent on both group mean difference and pooled SD. We next showed that d was a critical determinant of NNT, such that NNT was uniformly smaller when d was larger. In recent AD associated trials including those focused on anti-amyloid biologics, d's were below 0.23 and thus considered small, while per cent slowing was in the 22-29% range and NNTs ranged from 14 to 18., Conclusions: Standardised effect size is a more meaningful outcome than per cent slowing of decline because it determines group overlap, which can directly influence NNT computations, and yield information on the likelihood of minimum clinically important differences. In AD, greater use of effect sizes, NNTs, rather than relative per cent slowing, will improve the ability to interpret clinical trial results and evaluate the clinical meaningfulness of statistically significant results., Competing Interests: Competing interests: LSS reports personal fees from AC Immune, Alpha-cognition, Athira, Corium, Cortexyme, BioVie, Eli Lilly, GW Research, Lundbeck, Merck, Neurim, Novo-Nordisk, Otsuka, Roche/Genentech, Cognition Therapeutics, Takeda; grants from Biohaven, Biogen, Eisai, Eli Lilly and Novartis. DPD reports research support from the National Institute on Aging, Alzheimer’s Association, is a scientific adviser to Acadia, TauRx, Corium, Genentech, and is a member of the Data and Safety Monitoring Board of BioXcel. TG and SL have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The association between sleep quality and cognition is widely established, but the role of aging in this relationship is largely unknown., Objective: To examine how age impacts the sleep-cognition relationship and determine whether there are sensitive ranges when the relationship between sleep and cognition is modified. This investigation could help identify individuals at risk for sleep-related cognitive impairment., Subjects: Sample included 711 individuals (ages 36.00-89.8359.66 ± 14.9155.7 % female) from the Human Connectome Project-Aging (HCP-A)., Methods: The association between sleep quality (Pittsburgh Sleep Quality Index, PSQI) and cognition (Crystallized Cognition Composite and Fluid Cognition Composite from the NIH Toolbox, the Trail Making Test, TMT, and the Rey Auditory Verbal Learning Test, RAVLT) was measured using linear regression models, with sex, race, use of sleep medication, hypertension, and years of education as covariates. The interaction between sleep and age on cognition was tested using the moderation analysis, with age as both continuous linear and nonlinear (quadratic) terms., Results: There was a significant interaction term between the PSQI and nonlinear age term (age 2 ) on TMT-B ( p = 0.02) and NIH Toolbox crystallized cognition ( p = 0.02), indicating that poor sleep quality was associated with worse performance on these measures (sensitive age ranges 50-75 years for TMT-B and 66-70 years for crystallized cognition)., Conclusions: The sleep-cognition relationship may be modified by age. Individuals in the middle age to early older adulthood age band may be most vulnerable to sleep-related cognitive impairment.

Objectives: Unexpected lucidity is a phenomenon of scientific, clinical, and psychological relevance to health professionals, to those who experience it, and their relatives. This paper describes qualitative methods used to develop an informant-based measure of lucidity episodes., Methods: The approach was refinement of the operationalization of the construct; review of seminal items, modification, and purification; and confirmation of the feasibility of reporting methodology. Modified focus groups were conducted with 20 staff and 10 family members using a web-based survey. Themes included reaction when hearing the term; words that come to mind; description of and first reaction to referenced or observed 'lucidity' events. Semi-structured cognitive interviews were conducted with 10 health professionals working with older adults with cognitive impairment. Data were extracted from Qualtrics or Microsoft 365 Word® for analysis using NVivo., Results: Conceptual issues, as well as issues regarding comprehension, interpretation, clarity, semantics, and standardization of definitions derived from an external advisory board, focus groups and cognitive interviews informed items' modification, and resulted in the final lucidity measure., Conclusions: An obstacle to understanding the mechanisms and estimating the prevalence of lucid events among individuals with dementia and other neurological conditions is the scarcity of reliable and valid measures. The substantive and varied data gathered from multiple methods including the collaborative work of an External Advisory Board, modified focus groups with staff and family caregivers, and structured cognitive interviews with health professionals were central in creating the revised version of the lucidity measure.

Background and Objectives: Odor identification deficits are associated with transition to dementia, whereas intact odor identification and global cognition test performance may identify lack of transition. The purpose of this study was to examine intact odor identification and global cognition as prognostic indicators of lack of transition to dementia in a biracial (Black and White) cohort., Methods: In a community-dwelling sample of older adults from the Health, Aging, and Body Composition study, odor identification was measured using the Brief Smell Identification Test (BSIT), and global cognition was measured using the Teng Modified Mini-Mental State Examination (3MS). Survival analyses for dementia transition over 4 and 8 years of follow-up used Cox proportional hazards models., Results: A total of 2,240 participants had an average age of 75.5 years (SD 2.8). Approximately 52.7% were female individuals. Approximately 36.7% were Black and 63.3% were White individuals. Impaired odor identification (hazard ratio [HR] 2.29, 95% CI 1.79-2.94, p < 0.001) and global cognition (HR 3.31, 95% CI 2.26-4.84, p < 0.001) were each independently associated with transition to dementia (n = 281). Odor identification remained robustly associated with transition to dementia for Black (HR 2.02, 95% CI 1.36-3.00, p < 0.001, n = 821) and White participants (HR 2.45, 95% CI 1.77-3.38, p < 0.001, n = 1,419), whereas global cognition was associated with transition among Black participants only (HR 5.06, 95% CI 3.18-8.07, p < 0.001). ApoE genotype was consistently associated with transition among White participants only (HR 1.75, 95% CI 1.20-2.54, p < 0.01). Among participants with intact performance on both odor identification (BSIT ≥9/12 correct) and global cognition (3MS ≥ 78/100 correct), 8.8% transitioned to dementia over 8 years. Intact performance on both measures had high positive predictive value for identifying individuals who did not transition to dementia over 4 years (0.98 for ages 70-75 years with only 2.3% transitioning, 0.94 for ages 76-82 years with only 5.8% transitioning)., Discussion: Odor identification testing paired with a global cognitive screening test identified individuals at low risk of transition to dementia in a biracial community cohort with a pronounced effect in the eighth decade of life. Identification of such individuals can reduce the need for extensive investigation to establish a diagnosis. Odor identification deficits showed utility in both Black and White participants, unlike the race-dependent utility of a global cognitive test and ApoE genotype., (© 2023 American Academy of Neurology.)

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., (© 2023 John Wiley & Sons Ltd.)

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., (© 2023 the Alzheimer's Association.)

Background: The positron emission tomography (PET) radiotracer [ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]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., Competing Interests: J. Shuping is a consultant to Enigma Biomedical Group. C. Wilde was a consultant to Cerveau Technologies. J. Evelhoch, W. Kreisl, K. Johnson, C. Rowe, and K. Van Laere are consultants/advisors to Cerveau Technologies. D. Matthews, A. Lukic, and R. Andrews are employees of ADM Diagnostics, Inc. D. Scott, K. Adamczuk, J. Barakos, and D. Purcell are employees of Clario. C. Rowe is an employee of Austin Health, Melbourne and University of Melbourne, Australia. S. Johnson is an employee of the University of Wisconsin Madison. W. Kreisl, A. Brickman, D. Devanand, J. Luchsinger, Y. Stern, and P. Lao are employees of Columbia University. P. Rosa‐Neto is an employee of McGill University. K. Van Laere is an employee of UZ Leuven. K. Johnson and J. Price are employees of Massachusetts General Hospital and Harvard University. A. Boxer is an employee of the University of California San Francisco. W. Klunk is an employee of the University of Pittsburgh. C. Sur was an employee of Merck & Co., Inc. L. Cordes is an employee of StatKing Clinical Services. L. Ward is an employee of Florey Department of Neuroscience and Mental Health and University of Melbourne. S. Mathotaarachchi is an employee of Enigma Biomedical Group. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer's disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks., Objective: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks., Methods: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks., Results: There were no differences between crosswords and games in the primary outcome, within-network DMN FC across all subjects. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p < 0.05), accompanied by lesser cognitive decline in the crosswords group., Conclusion: Results do not support a differential impact on within-network DMN FC between games and crossword puzzle interventions. However, crossword puzzles might result in cognitively beneficial remodeling between the DMN and other networks in more severely impaired MCI subjects, parallel to the observed clinical benefits.

Background and Objectives: Neuropsychiatric symptoms (NPS), including psychotic symptoms (hallucinations, illusions, delusions), agitation/aggression, and depressed mood, are common in individuals with Alzheimer's disease (AD) and predict poorer outcomes, including faster disease progression. We aimed to evaluate associations between NPS and cognition and dependence in a multi-ethnic sample of community-dwelling older adults with AD., Methods: Predictors 3 (P3) is a cohort study of AD disease courses recruiting older adults aged 65 and above residing in upper Manhattan. A total of 138 of 293 participants had probable AD at the study baseline. We fit linear mixed models to examine longitudinal associations of time-varying NPS (psychotic symptoms, agitation/aggression, and depressed mood) with dependence and cognition, adjusted for race-ethnicity, sex, education, age, clinical dementia rating score, APOE-ε4, and comorbidity burden; separate interaction models were fit for age, Hispanic ethnicity, and sex., Results: Psychotic symptoms were associated with faster rates of increasing dependence and declining cognition over time, agitation/aggression with faster rates of declining cognition, and depressed mood with faster rates of increasing dependence. Among psychotic symptoms, delusions, but not hallucinations or illusions, were associated with worse outcome trajectories. Depressed mood predicted an accelerated increase in dependence in males but not females., Conclusion: Our results confirm and extend prior results in clinic-based samples. The presence of NPS was associated with worse trajectories of dependence and cognition in this muti-ethnic sample of older adults with AD. Importantly, sex modified the association between depressed mood and dependence. Our results on NPS as predictors of differential AD progression in a community-dwelling, ethnically diverse sample serve to better inform the clinical care of patients and the future development of AD therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is defined by the presence of Amyloid-β (Aβ),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aβ deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aβ andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used 18 F-MK6240 and 18 F-Florbetaben/ 18 F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aβ, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aβ and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aβdeposition, Aβ uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aβandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aβ deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aβ and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aβ/tau synergy inAD pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Although clinicians caring for persons at the end of life recognize the phenomenon of paradoxical/terminal lucidity, systematic evidence is scant. The current pilot study aimed to develop a structured interview instrument for health care professionals to report lucidity. A questionnaire measuring lucidity length, degree, content, coinciding circumstances, and time from episode to death was expanded to include time of day, expressive and receptive communication, and speech during the month prior to and during the event. Thirty-three interviews were conducted; 73% of participants reported ever witnessing paradoxical lucidity. Among 29 events reported, 31% lasted several days, 20.7% lasted 1 day, and 24.1% lasted <1 day. In 78.6% of events, the person engaged in unexpected activity; 22.2% died within 3 days, and 14.8% died within 3 months of the event. The phenomenological complexity of lucidity presents challenges to eliciting reports in a systematic fashion; however, staff respondents were able to report lucidity events and detailed descriptions of person-specific characteristics. [ Journal of Gerontological Nursing, 49 (1), 18-26.].

Objective: Smell and taste alteration are closely linked to infection with SARS-CoV-2 and may be associated with a more indolent disease course. Serologic response rates among individuals with mild disease remains limited. We sought to identify whether chemosensory changes associated with COVID-19 were predictive of a serologic response., Study Design: Cross-sectional study., Methods: The sample consisted of 306 adults (≥18 years old) volunteering for convalescent plasma donation following perceived COVID-19 illness from April-June 2020. Documentation of COVID-19 PCR status, clinical symptoms at time of illness, and treatment course occurred at the time of serologic analysis, where we assessed chemosensory function using patient-perceived deficits. We implemented previously validated ELISA screening to determine serologic status regarding anti-Spike immunoglobulins. Statistical analysis using stepwise logistic models were employed to identify predictive factors of serologic response., Results: Of 306 patients undergoing serologic and chemosensory evaluation, 196 (64.1%) and 195 (63.7%) reported subjective olfactory and taste dysfunction, respectively, during the first two weeks of COVID-19 infection. In unadjusted models, the odds of developing suprathreshold IgG antibody titers were 1.98 times higher among those who reported altered smell (95% CI 1.14-3.42, p = 0.014) and 2.02 times higher among those with altered taste (95% CI 1.17-3.48, p = 0.011) compared to those with normal smell and taste. Multivariable logistic models adjusting for sex, age, race/ethnicity, symptom duration, smoking status and comorbidities index demonstrated that altered smell and taste remained significant predictors of positive anti-spike IgG response (smell OR = 1.90, 95% CI 1.05-3.44, p = 0.033; taste OR = 2.01, 95% CI = 1.12-3.61, p = 0.019)., Conclusion: Subjective chemosensory dysfunction, as self-reported smell or taste deficiency, is highly predictive of serologic response following SARS-CoV-2 infection. This information may be useful for patient counseling. Additional longitudinal research should be performed to better understand the onset and duration of the serologic response in these patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Overdevest et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Psychiatric symptoms, including changes in emotional processing, are a common feature of many neurodegenerative disorders, such as Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, and Huntington's disease. However, the neuroanatomical basis of emotional symptoms is not well defined; this stands in contrast to the relatively well-understood neuroanatomical correlates of cognitive and motor symptoms in neurodegenerative disorders. Furthermore, psychiatric diagnostic categories, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Statistical Classification of Diseases and Related Health Problems (ICD), may have limited applicability in patients with late-onset psychiatric symptoms in the context of neurodegenerative disorders. In this clinical review, we suggest that early-onset and late-onset psychiatric symptoms have distinct etiologies, and that late-onset changes in emotional processing are likely underpinned by neurodegenerative disease. Furthermore, we suggest that an improved understanding of the neuroanatomical correlates of emotional changes in neurodegenerative disease may facilitate diagnosis and future treatment development. Finally, we propose a novel clinical approach, in a preliminary attempt to incorporate late-onset emotional symptoms alongside cognitive and motor symptoms into a clinical "algorithm," with a focus on the neuroanatomy implicated when particular combinations of emotional, cognitive, and motor features are present. We anticipate that this clinical approach will assist with the diagnosis of neurodegenerative disorders, and our proposed schema represents a move towards integrating neurologic and psychiatric classification systems.

In this review, we comprehensively, qualitatively, and critically synthesized several features of APOE-e2, a known APOE protective variant, including its associations with longevity, cognition, and neuroimaging, and neuropathology, all in humans. If e2's protective effects-and their limits-could be elucidated, it could offer therapeutic windows for Alzheimer's disease (AD) prevention or amelioration. Literature examining e2 within the years 1994-2021 were considered for this review. Studies on human subjects were selectively reviewed and were excluded if observation of e2 was not specified. Effects of e2 were compared with e3 and e4, separately and as a combined non-e2 group. Our examination of existing literature indicated that the most robust protective role of e2 is in longevity and AD neuropathologies, but e2's effect on cognition and other AD imaging markers (brain structure, function, and metabolism) were inconsistent, thus inconclusive. Notably, e2 was associated with greater risk of non-AD proteinopathies and a disadvantageous cerebrovascular profile. We identified multiple methodological shortcomings of the literature on brain function and cognition that could have contributed to inconsistent and potentially misleading findings. We make careful interpretations of existing findings and provide directions for research strategies that could effectively examine the independent and unbiased effect of e2 on AD risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Devanand, Carlson and Goldberg.)

Importance: Understanding associations of Alzheimer disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) may have implications for diagnosis and management., Objective: To evaluate ADRD neuropathological diagnoses and NPS without consideration of clinical diagnosis., Design, Setting, and Participants: This retrospective cohort study evaluated 1808 brains from 39 sites in the US National Alzheimer Coordinating Center v. 10 collection for participants among whom the Neuropsychiatric Inventory Questionnaire (NPIQ) was administered annually. Brain autopsy diagnoses of AD, Lewy body disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration, cerebrovascular disease, hippocampal sclerosis, and no known pathology were examined. Autopsy data collected from January 2012 to January 2018 were deidentified and compiled into the publicly available v. 10 database. Data were analyzed from February 2021 to August 2021., Main Outcomes and Measures: The primary outcome was NPIQ domain score, if present at any time point, and mean NPIQ domain score during follow-up was secondary. Associations of ADRD diagnoses with 12 NPIQ symptom domains were examined in regression analyses, correcting for multiple comparisons., Results: The study sample of 1808 adults had a mean (SD) age of 80.0 (11.0) years, and 987 participants (54.6%) were male. Apathy was the most prevalent NPS, reaching 80% (203 of 254 individuals) in those with hippocampal sclerosis. Cerebrovascular disease showed few NPS associations. Frontotemporal lobar degeneration was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared with AD. Hippocampal sclerosis was associated with increased apathy (odds ratio, 2.60; 95% CI; 1.86-3.66, false discovery rate controlled P < .001) and disinhibition (odds ratio, 2.15; 95% CI, 1.63-2.84; false discovery rate controlled P < .001). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was consistently associated with increased NPS (eg, LBD was associated with an increase in hallucinations from brain stem [β, 0.23; 95% CI, 0.07-0.76; P = .02] to limbic [β, 1.69; 95% CI, 1.27-2.27; P < .001] to neocortical [β, 4.49; 95% CI, 3.27-6.16; P < .001] pathology). Hallucinations were more common in participants with AD and LBD (168 of 534 [31.5%]) compared with those with AD without LBD (152 of 704 [21.6%]) and those with LBD without AD (23 of 119 [19.6%])., Conclusions and Relevance: In this cohort study of 1808 brains from the US National Alzheimer Coordinating Center, patients with LBD and AD showed a higher prevalence of hallucinations compared with those with LBD without AD. Neuropsychiatric symptom criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported in this study. In hippocampal sclerosis, the findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was associated with NPS severity, indicating that NPS may reflect underlying ADRD pathology and highlighting the importance of diagnosing and treating NPS.

Purpose of Review: We comprehensively examined recent advancements in developing novel cognitive measures that could significantly enhance detection of outcome changes in Alzheimer's disease clinical trials. Previously established measures were largely limited in their ability to detect subtle cognitive declines in preclinical stages of Alzheimer's disease, particularly due to weak psychometric properties (including practice effects and ceiling effects) and requirement of in-person visits that impacted ascertainment., Recent Findings: We present novel cognitive measures that were designed to exhibit reduced practice effects and stronger correlations with Alzheimer's disease biomarkers. In addition, we summarized some recent efforts in developing remote testing measures protocols that are aimed to overcome the limitations and inconvenience of in-person testing, and digital phenotyping, which analyses subtle forms of digital behaviour indicative of cognitive phenotypes. We discuss each measure's prognostic accuracy and potential utility in Alzheimer's disease research while also commenting on their limitations. We also describe our study, the Development of Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD), that employed a parallel group design in which novel measures and established measures are compared in a clinical trials armature., Summary: Overall, we believe that these recent developments offer promising improvements in accurately detecting clinical and preclinical cognitive changes in the Alzheimer's disease spectrum; however, further validation of their psychometric properties and diagnostic accuracies is warranted before reliably implementing these novel measures in Alzheimer's disease clinical trials., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Patients with dementia can experience hallucinations and delusions because of their underlying neurodegenerative condition, a syndrome known as dementia-related psychosis. Dementia-related psychosis contributes to morbidity and mortality among patients with dementia and increases the burden on caregivers and the health care system. With no pharmacological treatment currently approved in the United States for this condition, patients are often treated off-label with antipsychotics. Though typical and atypical antipsychotics have demonstrated variable to modest efficacy in dementia-related psychosis, serious safety concerns arise with their use. Accordingly, clinical and Centers for Medicare & Medicaid Services guidelines recommend trying antipsychotics only when other therapies have failed and encourage treatment discontinuation of antipsychotics after 4 months to assess whether ongoing therapy is needed. Discontinuation of effective antipsychotic treatment, however, may increase the risk for relapse of symptoms and the associated morbidities that accompany relapse. A randomized medication withdrawal clinical trial design allows assessment of relapse risk after discontinuation and can provide initial information on longer-term safety of therapy for dementia-related psychosis. Given the substantial unmet need in this condition, new, well-tolerated therapies that offer acute and sustained reduction of symptoms while also preventing recurrence of symptoms of psychosis are critically needed., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The development of automatic speech recognition (ASR) technology allows the analysis of temporal (time-based) speech parameters characteristic of mild cognitive impairment (MCI). However, no information has been available on whether the analysis of spontaneous speech can be used with the same efficiency in different language environments., Objective: The main goal of this international pilot study is to address the question of whether the Speech-Gap Test® (S-GAP Test®), previously tested in the Hungarian language, is appropriate for and applicable to the recognition of MCI in other languages such as English., Methods: After an initial screening of 88 individuals, English-speaking (n = 33) and Hungarianspeaking (n = 33) participants were classified as having MCI or as healthy controls (HC) based on Petersen's criteria. The speech of each participant was recorded via a spontaneous speech task. Fifteen temporal parameters were determined and calculated through ASR., Results: Seven temporal parameters in the English-speaking sample and 5 in the Hungarian-speaking sample showed significant differences between the MCI and the HC groups. Receiver operating characteristics (ROC) analysis clearly distinguished the English-speaking MCI cases from the HC group based on speech tempo and articulation tempo with 100% sensitivity, and on three more temporal parameters with high sensitivity (85.7%). In the Hungarian-speaking sample, the ROC analysis showed similar sensitivity rates (92.3%)., Conclusion: The results of this study in different native-speaking populations suggest that changes in acoustic parameters detected by the S-GAP Test® might be present across different languages., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Digital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment., Objective: The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Our objective was to examine its relationship with the Alzheimer's Disease Assessment Scale-Cognition Subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) as well as with established paper-pencil tests of cognition and daily functioning in mild cognitive impairment (MCI)., Methods: We used Spearman correlations, regressions and principal components analysis followed by a factor analysis (varimax rotated) to examine our objectives., Results: In MCI subjects, the NCPT composite is significantly correlated with both a composite measure of established tests (r = 0.78, p < 0.0001) as well as with the ADAS-Cog (r = -0.55, p < 0.0001). Both NCPT and paper-pencil test batteries had a similar factor structure that included a large "g" component with a high eigenvalue. The correlation for the analogous tests (e.g., Trails A and B, learning memory tests) were significant (p < 0.0001). Further, both the NCPT and established tests significantly (p < 0.0001) predicted the University of California San Diego Performance-Based Skills Assessment and Functional Activities Questionnaire, measures of daily functioning., Conclusion: The NCPT, a web-based, self-directed, computerized test, shows high concurrent validity with established tests and hence offers promise for use as a research or clinical tool in MCI. Despite limitations such as a relatively small sample, absence of control group and cross-sectional nature, these findings are consistent with the growing literature on the promise of self-directed, web-based cognitive assessments for MCI.

Background: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD., Objective: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline., Methods: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models., Results: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition., Conclusion: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

Objective: Social isolation and emotional isolation, i.e. loneliness, have been associated with dementia or cognitive decline. In contrast, the relationship of restriction of physical and instrumental activities of daily living to cognitive decline and dementia has been less studied., Design: We examined multiple quality of life (QoL) indicators, including isolation and restriction of activities, utilizing two validated scales in elders without dementia to determine their associations with cognitive decline and incident dementia that were followed longitudinally over 6 years. We comprehensively controlled for other symptom constellations, including depression and anergia., Setting: A large multi-ethnic prospective study was conducted in northern Manhattan, NYC., Participants: An ethnically diverse sample of 855 non-demented individuals at baseline participated., Measures: The following QoL scales were utilized: Restriction, Anergia, Isolation, Loneliness, and Affective Suffering., Results: Both Restriction (HR = 2.22, 95% CI [1.42, 3.47], P < .001) and Isolation (HR = 1.78, 95% CI [1.17, 2.70], P = 0.007) were associated with episodic memory and incident dementia, controlling for age, sex, and education. Loneliness and Affective Suffering (depression) were not associated with these outcomes (P's > .1) with both Restriction and Isolation in the same model for the prediction of dementia, only Restriction remained significant (HR = 1.97, 95% CI [1.24, 3.14], P = 0.004). In cross-lagged panel analyses, Restriction and Isolation had reciprocal influences (P's < .001), indicating that Restriction at the previous time point influenced current Isolation. Importantly, Restriction (but not Isolation) and Selective Reminding total recall memory demonstrated highly significant direct and reciprocal influences over time (P's < .001)., Conclusions: Restriction and Isolation were associated with incident dementia. Restriction played a more prominent role in its impact on memory decline. The development of these impairments in QoL, particularly Restriction, may provide warning signs of future cognitive decline and dementia and provide multiple and novel avenues for therapeutic interventions with the goal of delaying the development of cognitive decline and dementia.

Background: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT 2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear., Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis., Results: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin., Conclusions: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.)., (Copyright © 2021 Massachusetts Medical Society.)

Importance: People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy., Objective: To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI)., Design, Setting, and Participants: This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020., Main Outcomes and Measures: Dementia was defined using the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria., Results: The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age., Conclusions and Relevance: In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use.

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., Competing Interests: D. P. Devanand: Consultant to Eisai, Genentech, Axovant, Astellas, Acadia. Research support: NIA, DOD, Avanir., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: We assessed the association of apolipoprotein E (APOE) genotype with cerebrovascular disease (CVD) in a large neuropathological database maintained by the National Alzheimer's Coordinating Center (NACC). Such a comprehensive investigation of APOE and CVD pathology has not heretofore been conducted. We focused on APOE e2, an established neuroprotective genetic variant against Alzheimer's disease., Methods: To implement these objectives APOE associations in the NACC database of 1275 brains with 11 CVD pathologies, including old and recent infarcts, haemorrhages, cerebral amyloid angiopathy (CAA) and arteriosclerosis, were examined. These pathologies were uniformly and semiquantitatively measured across 39 Alzheimer's Disease Center sites. We used χ2 statistics and ordinal regression to assess the significance of associations and Bonferroni corrected for multiple comparisons., Results: Of the cases, 98 were e2/e3 or e2/e2 genotypes ('e2' carriers), 621 were e3 homozygotes ('e3' group), and 556 were e4/e3 (442) or e4/e4 (114) genotypes ('e4' group). Results indicated that the APOE e4 allele significantly increased risk for CAA. After stratification by CAA presence/absence, we found that in those cases in which CAA was present, APOE e2 significantly increased risk for gross haemorrhage. All other associations were negative., Conclusions: In this, the largest study of APOE e2 effects on pathologically verified CVD, e2 was not protective against any CVD pathology compared with e3 homozygotes, including CAA. Regarding the latter pathology, e4 was associated with increases in its severity. Furthermore, and perhaps unexpectedly, e2 significantly increased risk of acute/subacute gross haemorrhage in the presence of CAA. Thus, there were limits to e2 neuroprotection against amyloidosis, despite its known and large protective effects against diffuse and neuritic amyloid plaques compared with e3/e3 and e4 carriers in this very collection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2019 the Alzheimer's Association.)

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)., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to determine the long-term test-retest reliability of the University of Pennsylvania Smell Identification Test (UPSIT), and its individual items, in cognitively intact older adults. A community sample of older adults received a neuropsychological test battery, including the 12-item, 6-trial Selective Reminding Test (SRT). The UPSIT was administered at baseline and follow-up that occurred between 1 and 4 years after baseline. UPSIT scores of participants who were cognitively intact and did not decline cognitively were examined for test-retest reliability. In 92 older adults with mean age 77.6 years followed for 2.79 (standard deviation [SD] 0.69) years, mean UPSIT score declined from 30.29 (SD 5.83) to 27.80 (SD 5.50). In linear mixed models that adjusted for time, age, sex, and education, intraclass correlation coefficients for UPSIT were 0.65, SRT delayed recall 0.59, and SRT total immediate recall 0.49. Among 4 possible response combinations, the largest proportion of participants had correct responses at both visits for 35 out of 40 items. Consistency of item responses ranged from 50% to 90% across the 2 time points. The long-term test-retest reliability of the UPSIT was moderately strong without practice effects over long periods of time in older adults. These results provide indirect support to prior findings on odor identification impairment predicting cognitive decline and dementia, and suggest potential use of olfactory testing as a biomarker in prevention and treatment trials of cognitive enhancers., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The first National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers was held on October 16-17, 2017, at the National Institutes of Health. In this paper, participants from the Summit Session on Research on Care Needs and Supportive Approaches for Persons with Dementia summarize the state of the science, identify gaps in knowledge, and offer recommendations to improve science and practice in long-term care. Recommendations cover 4 areas focused on persons living with dementia: (1) symptoms (behavioral and psychological symptoms of dementia, function, cognition, and sleep); (2) dementia care settings (physical and social environments, home, and residential care); (3) living with dementia (living well with dementia, living alone with dementia, and living with dementia and intellectual and developmental disabilities); and (4) technology as a cross-cutting theme. The participants identify 10 of the most pressing research issues based on the findings from their collective papers. Final Summit recommendations included those presented by session participants and will be used to advise federal agencies and other organizations that fund research., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

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., (© 2018 John Wiley & Sons, Ltd.)

The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale-Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate.

Objective: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment., Methods: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire)., Results: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo., Conclusion: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood., Objective: To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms., Methods: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS)., Results: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates., Conclusion: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD.

Background: The utility of functional deficits in patients with mild cognitive impairment is not established., Materials and Methods: In 3886 individuals with mild cognitive impairment evaluated and followed at 34 National Alzheimer Coordinating Center sites, informant-reported Pfeffer Functional Activities Questionnaire (FAQ) items associated with progression to dementia were derived in a training set (n=1943) and tested in the validation set (n=1943)., Results: In the training set, the optimal combination comprised 6 FAQ items (FAQ6): difficulties with finances (2 items), remembering events/appointments, playing games of skill, current events, and travel. In the validation set, hazard ratio for dementia increased from 2.00 for 1 FAQ6 deficit to 5.56 for 6 FAQ6 deficits. In patients 50 to 67 years old with high Mini Mental State Exam scores, dementia risk rose from 12.06% for no FAQ6 deficits to 56.75% for 6 functional deficits. Likelihood of progression to dementia reached 80% to 89% in older age groups with low Mini Mental State Exam and severe FAQ6 deficits., Conclusions: Specific functional deficits increased dementia risk and, with age and global cognition, constituted a validated clinical algorithm to estimate dementia risk. Clinicians can use this clinically important algorithm to personalize decision-making about further investigation and identify high-risk patients for early treatment or inclusion in clinical trials.

Objective: To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory., Method: We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures., Results: Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks., Discussion: Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation., Competing Interests: Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article, (© The Author(s) 2015.)

Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

Objective: Depression is common, frequently resistant to antidepressant treatment, and associated with impairments in cognition and everyday functioning. Computerized cognitive training (CCT) paradigms offer potential to improve cognition, mood and everyday functioning, but their effectiveness is not well established. The goal of this article was to conduct a systematic review and meta-analysis to determine the efficacy of CCT in depressive disorders., Method: A search was conducted to identify high quality randomized controlled CCT trials per PRISMA guidelines using PsycINFO and MEDLINE with the keywords "Cognitive training" or "Cognitive remediation" or "Cognitive rehabilitation" and "Depression". 9 randomized trials for depressed adults met inclusion criteria. Effect sizes (Hedge's g) were calculated for key outcome measures of mood symptom severity, daily functioning, and cognition. A 3-level Bayesian hierarchical linear model was used to estimate effect sizes for each domain and study. Publication bias was assessed using Classic Fail Safe N's and homogeneity was evaluated using Q and I(2) indexes., Results: Significant small-moderate effects for Symptom Severity (0.43) and Daily Functioning (0.72), and moderate-large effects for Attention (0.67), Working Memory (0.72), and Global Functioning (1.05) were found. No significant effects were found for Executive Functioning or Verbal Memory. Moderator variable analysis revealed decreased effect of CCT with age. Gender and concurrent medication treatment did not affect the results., Limitations: Small sample size, short duration, pseudo-specificity, and high heterogeneity for Verbal Memory measures., Conclusions: CCT is associated with improvement in depressive symptoms and everyday functioning, though produces inconsistent effects on cognition., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (© 2015 American Neurological Association.)