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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. [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: 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 FC outcome. 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 nonspecifically engage multiple specialized cognitive networks at a low level, resulting in cognitively beneficial remodeling between the DMN and other networks, and within the DMN in subjects at higher risk of dementia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Distinguishing Mild Cognitive Impairment (MCI) subjects from healthy controls. • Cross-lingual study using English and Hungarian subjects. • Acoustic features are extracted using English and Hungarian ASR models (4 cases). • No difference was found in performance between the mono- and cross-lingual cases. Mild Cognitive Impairment (MCI) is a heterogeneous clinical syndrome, often considered as the prodromal stage of dementia. It is characterized by the subtle deterioration of cognitive functions, including memory, executive functions and language. Mainly due to the tenuous nature of these impairments, a high percentage of MCI cases remain undetected. There is evidence that language changes in MCI are present even before the manifestation of other distinctive cognitive symptoms, which offers a chance for early recognition. A cheap non-invasive way of early screening could be the use of automatic speech analysis. Earlier, our research team developed a set of speech temporal parameters, and demonstrated its applicability for MCI detection. For the automatic extraction of these attributes, a Hungarian-language ASR system was employed to match the native language of the MCI and healthy control (HC) subjects. In practical applications, however, it would be convenient to use exactly the same tool, regardless of the language spoken by the subjects. In this study we show that our temporal parameter set, consisting of articulation rate, speech tempo and various other attributes describing the hesitation of the subject, can indeed be reliably extracted regardless of the language of the ASR system used. For this purpose, we performed experiments both on English-speaking and on Hungarian-speaking MCI patients and healthy control subjects, using English and Hungarian ASR systems in both cases. Our experimental results indicate that the language on which the ASR system was trained only slightly affects the MCI classification performance, because we got quite similar scores (67-92%) as we did in the monolingual cases (67-92% as well). As our last investigation, we compared the proposed attribute values for the same utterances, utilizing both the English and the Hungarian ASR models. We found that the articulation rate and speech tempo values calculated based on the two ASR models were highly correlated, and so were the attributes corresponding to silent pauses; however, noticeable differences were found regarding the filled pauses (still, these attributes remained indicative for both languages). Our further analysis revealed that this is probably due to a difference regarding the annotation of the English and the Hungarian ASR training utterances. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated impaired odor identification and global cognition as simple, cost-effective alternatives to neuroimaging biomarkers to predict cognitive decline and dementia in the Mayo Clinic Study of Aging., Methods: Six hundred forty-seven participants (mean 8.1, standard deviation 3.4 years' follow-up) had the following baseline procedures: modified Blessed Information Memory Concentration Test (BIMCT), 12-item Brief Smell Identification Test (BSIT), structural brain magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging with 11C-Pittsburgh compound B (11C-PiB) and fluorodeoxyglucose (FDG; subset)., Results: Cognitive decline developed in 102 participants and dementia in 34 participants. In survival analyses, PiB PET showed robust prediction for cognitive decline. Impaired BSIT, impaired BIMCT, MRI, and FDG measures were also significant predictors. The combination of demographics + BSIT + BIMCT showed strong predictive utility (C-index 0.81), similar to demographics + PiB PET (C-index 0.80). Similar but stronger results were obtained for prediction of dementia., Discussion: Impairment in both odor identification test and global cognition was comparable to PiB PET for predicting cognitive decline and dementia., Highlights: In 647 participants in the population-based Mayo Clinic Study of Aging, several clinical markers and biomarkers each predicted cognitive decline or dementia during an average 8 years of follow-up. The combination of the demographic variables of age, sex, and education with a brief odor identification test (BSIT) and a global cognitive test (Blessed Information Memory Concentration Test) showed strong predictive utility (C-index 0.81) for cognitive decline that was similar to the demographic variables combined with Pittsburgh Compound B amyloid imaging (C-index 0.80). Combining a brief odor identification test with a brief cognitive test needs consideration as a simple, cost-effective option in the clinical assessment of individuals at risk of cognitive decline and dementia, as well as a potential tool to identify individuals who may benefit from disease-modifying treatments and to screen participants for prevention trials., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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: 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 36.00-89.83, 59.66 ± 14.91, 55.7 % 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.)

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 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.].

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.)

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.)

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.)

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: 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.

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., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

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 © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Multimodality classification of Alzheimer's disease (AD) and its prodromal stage, Mild Cognitive Impairment (MCI), is of interest to the medical community. We improve on prior classification frameworks by incorporating multiple features from MRI and PET data obtained with multiple radioligands, fluorodeoxyglucose (FDG) and Pittsburg compound B (PIB). We also introduce a new MRI feature, invariant shape descriptors based on 3D Zernike moments applied to the hippocampus region. Classification performance is evaluated on data from 17 healthy controls (CTR), 22 MCI, and 17 AD subjects. Zernike significantly outperforms volume, accuracy (Zernike to volume): CTR/AD (90.7% to 71.6%), CTR/MCI (76.2% to 60.0%), MCI/AD (84.3% to 65.5%). Zernike also provides comparable and complementary performance to PET. Optimal accuracy is achieved when Zernike and PET features are combined (accuracy, specificity, sensitivity), CTR/AD (98.8%, 99.5%, 98.1%), CTR/MCI (84.3%, 82.9%, 85.9%) and MCI/AD (93.3%, 93.6%, 93.3%).