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Objective: People with Alzheimer’s disease (AD) dementia have impaired sleep. However, the characteristics of sleep in the early stages of AD are not well known, and studies with the aid of biomarkers are lacking. We assessed the subjective sleep characteristics of non-demented older adults and compared their amyloid profiles. Methods: We enrolled 30 participants aged ≥ 60 years, with no dementia or major clinical and psychiatric diseases. They underwent [11C]PiB-PET-CT, neuropsychological evaluations, and completed two standardized sleep assessments (Pittsburgh Sleep Quality Inventory and Epworth Sleep Scale). Results: Comparative analysis of subjective sleep parameters across the two groups showed longer times in bed (p = 0.024) and reduced sleep efficiency (p = 0.05) in individuals with positive amyloid. No differences in other subjective sleep parameters were observed. We also found that people with multiple-domain mild cognitive impairment (MCI) had shorter self-reported total sleep times (p = 0.034) and worse overall sleep quality (p = 0.027) compared to those with single-domain MCI. Conclusions: Older adults testing positive for amyloid had a longer time in bed and lower sleep efficiency, regardless of cognitive status. In parallel, individuals with multiple-domain MCI reported shorter sleep duration and lower overall sleep quality.

Introduction: The early detection of cognitive impairment is one of the most important challenges in Alzheimer's disease (AD) research. The use of brief, short‐term repeated test sessions via mobile app has demonstrated similar or better reliability and validity compared to standard in‐clinic assessments in adult samples. The present study examined adherence, acceptability, and reliability for a remote, app‐based cognitive screening protocol in healthy older adults. Methods: Cognitively unimpaired older adults (N = 52, ages 60–80) completed three brief cognitive testing sessions per day within morning, afternoon, and evening time windows, for 8 consecutive days using a mobile app‐based cognitive testing platform. Cognitive tasks assessed visual working memory, processing speed, and episodic memory. Results: Participants completed an average of 93% (M = 22.3 sessions, standard deviation = 10.2) of the 24 assigned sessions within 8 to 9 days. Average daily adherence ranged from 95% of sessions completed on day 2 to 88% of sessions completed on day 8. There was a statistically significant effect of session time on adherence between the morning and afternoon sessions only F (1, 51) = 9.15, P =.004, η p 2 = 0.152, with fewer afternoon sessions completed on average. The within‐person reliabilities of average scores, aggregated across all 24 sessions, were exceptionally high, ranging from 0.89 to 0.97. Performance on the episodic memory task was positively and significantly associated with total score and word list recall score on the Telephone Interview for Cognitive Status. In an exit survey, 65% of participants reported that they "definitely" would complete the sessions again. Discussion: These findings suggests that remote, mobile app–based cognitive testing in short bursts is both highly feasible and reliable in a motivated sample of cognitively normal older adults. Limitations include the limited diversity and generalizability of the sample; this was a largely White, highly educated, and motivated sample self‐selected for AD research. [ABSTRACT FROM AUTHOR]

Objective: People with Alzheimer's disease (AD) dementia have impaired sleep. However, the characteristics of sleep in the early stages of AD are not well known, and studies with the aid of biomarkers are lacking. We assessed the subjective sleep characteristics of non-demented older adults and compared their amyloid profiles. Methods: We enrolled 30 participants aged X 60 years, with no dementia or major clinical and psychiatric diseases. They underwent [11C]PiB-PET-CT, neuropsychological evaluations, and completed two standardized sleep assessments (Pittsburgh Sleep Quality Inventory and Epworth Sleep Scale). Results: Comparative analysis of subjective sleep parameters across the two groups showed longer times in bed (p = 0.024) and reduced sleep efficiency (p = 0.05) in individuals with positive amyloid. No differences in other subjective sleep parameters were observed. We also found that people with multiple-domain mild cognitive impairment (MCI) had shorter self-reported total sleep times (p = 0.034) and worse overall sleep quality (p = 0.027) compared to those with single-domain MCI. Conclusions: Older adults testing positive for amyloid had a longer time in bed and lower sleep efficiency, regardless of cognitive status. In parallel, individuals with multiple-domain MCI reported shorter sleep duration and lower overall sleep quality. [ABSTRACT FROM AUTHOR]

Abstract Aims/hypothesis Midlife obesity is a risk factor for dementia. We investigated the impact of obesity on brain structure, metabolism, and cerebrospinal fluid (CSF) core Alzheimer's disease (AD) biomarkers in healthy elderly. Methods We selected controls from ADNI2 with CSF AD biomarkers and/or fluorodeoxyglucose positron emission tomography (FDG‐PET) and 3T‐MRI. We measured cortical thickness, FDG uptake, and CSF amyloid beta (Aβ)1‐42, p‐tau, and t‐tau levels. We performed regression analyses between these biomarkers and body mass index (BMI). Results We included 201 individuals (mean age 73.5 years, mean BMI 27.4 kg/m2). Higher BMI was related to less cortical thickness and higher metabolism in brain areas typically not involved in AD (family‐wise error [FWE]

Alzheimer's disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of Aβ42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40-85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD. [ABSTRACT FROM AUTHOR]

Objective: Accumulation of cerebral amyloid-β (Aβ) is a risk factor for cognitive decline and defining feature of Alzheimer's disease (AD). Aβ is implicated in brain network disruption, but the extent to which these changes correspond with observable cognitive deficits in pre-clinical AD has not been tested. This study utilized individual-specific functional parcellations to sensitively evaluate the relationship between network connectivity and cognition in adults with and without Aβ deposition. Participants and Methods: Cognitively unimpaired adults ages 45-85 completed amyloid positron emission tomography, resting-state-functional magnetic resonance imaging (fMRI), and neuropsychological tests of episodic memory and executive function (EF). Participants in the upper tertile of mean standard uptake value ratio were considered Aβ+ ( n  = 50) while others were Aβ- ( n  = 99). Individualized functional network parcellations were generated from resting-state fMRI data. We examined the effects of group, network, and group-by-network interactions on memory and EF. Results: We observed several interactions such that within the Aβ+ group, preserved network integrity (i.e., greater connectivity within specific networks) was associated with better cognition, whereas network desegregation (i.e., greater connectivity between relative to within networks) was associated with worse cognition. This dissociation was most apparent for cognitive networks (frontoparietal, dorsal and ventral attention, limbic, and default mode), with connectivity relating to EF in the Aβ+ group specifically. Conclusions: Using an innovative approach to constructing individual-specified resting-state functional connectomes, we were able to detect differences in brain-cognition associations in pre-clinical AD. Our findings provide novel insight into specific functional network alterations occurring in the presence of Aβ that relate to cognitive function in asymptomatic individuals. Impact statement Elevated cerebral amyloid-β is a biomarker of pre-clinical Alzheimer's disease (AD). Associations between amyloidosis, functional network disruption, and cognitive impairment are evident in the later stages of AD, but these effects have not been substantiated in pre-clinical AD. Using individual-specific parcellations that maximally localize functional networks, we identify network alterations that relate to cognition in pre-clinical AD that have not been previously reported. We demonstrate that these effects localize to networks implicated in cognition. Our findings suggest that there may be subtle, amyloid-related alterations in the functional connectome that are detectable in pre-clinical AD, with potential implications for cognition in asymptomatic individuals.

The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ4 status, and Braak stage are taken into consideration. [ABSTRACT FROM AUTHOR]

To explore the hypothesis that alterations in cellular membrane lipids are present at the stage of pre-clinical Alzheimer's disease ( AD) (i.e., cognitively normal at death, but with AD neuropathology), we performed targeted shotgun lipidomics of lipid extracts from post-mortem brains of subjects with pre-clinical AD. We found sulfatide levels were significantly lower in subjects with pre-clinical AD compared to those without AD neuropathology. We also found that the level of ethanolamine glycerophospholipid was marginally lower at this stage of AD, whereas changes of the ceramide levels were undetectable with the available samples. These results indicate that cellular membrane defects are present at the earliest stages of AD pathogenesis and also suggest that sulfatide loss is among the earliest events of AD development, while alterations in the levels of ethanolamine glycerophospholipid and ceramide occur relatively later in disease. [ABSTRACT FROM AUTHOR]

Introduction: The early detection of cognitive impairment is one of the most important challenges in Alzheimer's disease (AD) research. The use of brief, short-term repeated test sessions via mobile app has demonstrated similar or better reliability and validity compared to standard in-clinic assessments in adult samples. The present study examined adherence, acceptability, and reliability for a remote, app-based cognitive screening protocol in healthy older adults., Methods: Cognitively unimpaired older adults ( N  = 52, ages 60-80) completed three brief cognitive testing sessions per day within morning, afternoon, and evening time windows, for 8 consecutive days using a mobile app-based cognitive testing platform. Cognitive tasks assessed visual working memory, processing speed, and episodic memory., Results: Participants completed an average of 93% (M = 22.3 sessions, standard deviation = 10.2) of the 24 assigned sessions within 8 to 9 days. Average daily adherence ranged from 95% of sessions completed on day 2 to 88% of sessions completed on day 8. There was a statistically significant effect of session time on adherence between the morning and afternoon sessions only  F  (1, 51) = 9.15,  P   = .004, η  p  2    = 0.152, with fewer afternoon sessions completed on average. The within-person reliabilities of average scores, aggregated across all 24 sessions, were exceptionally high, ranging from 0.89 to 0.97. Performance on the episodic memory task was positively and significantly associated with total score and word list recall score on the Telephone Interview for Cognitive Status. In an exit survey, 65% of participants reported that they "definitely" would complete the sessions again., Discussion: These findings suggests that remote, mobile app-based cognitive testing in short bursts is both highly feasible and reliable in a motivated sample of cognitively normal older adults. Limitations include the limited diversity and generalizability of the sample; this was a largely White, highly educated, and motivated sample self-selected for AD research., Competing Interests: Stephen Salloway has been study site investigator for the aducanumab trials; received consulting fees from Bolden Therapeutics, Ono, Genentech, Biogen, Prothena, Alnylam, ATRI, Roche, and Mayo; received payment/honoraria for Grand Rounds lecture at VA Providence, CME Talk for GME, CME Talk for PlatformQ, CME Talk for WebMD Medscape, CME Talk for PER, Biogen Master Class Series, from Biogen for RSNA Symposium, AD Comm Adv Board, Webinar for SNMMI, Genentech ‐ Adv Board, ATRI‐IMPACT AD seminar, and CTAD. He received travel payment from Acumen ‐ Sci Board, AMGEN, AAIC, GEMVAX, and AVID. All other authors no conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Aims/hypothesis: Midlife obesity is a risk factor for dementia. We investigated the impact of obesity on brain structure, metabolism, and cerebrospinal fluid (CSF) core Alzheimer's disease (AD) biomarkers in healthy elderly., Methods: We selected controls from ADNI2 with CSF AD biomarkers and/or fluorodeoxyglucose positron emission tomography (FDG-PET) and 3T-MRI. We measured cortical thickness, FDG uptake, and CSF amyloid beta (Aβ)1-42, p-tau, and t-tau levels. We performed regression analyses between these biomarkers and body mass index (BMI)., Results: We included 201 individuals (mean age 73.5 years, mean BMI 27.4 kg/m 2 ). Higher BMI was related to less cortical thickness and higher metabolism in brain areas typically not involved in AD (family-wise error [FWE] <0.05), but not to AD CSF biomarkers. It is notable that the impact of obesity on brain metabolism and structure was also found in amyloid negative individuals., Conclusions/interpretation: In the cognitively unimpaired elderly, obesity has differential effects on brain metabolism and structure independent of an underlying AD pathophysiology., Competing Interests: All authors declare no biomedical financial interests or potential conflicts of interest related to this work., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of Aβ42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40-85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD.

Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer´s Disease Neuroimaging Initiative (mean follow-up 50.5±30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss ≥ 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/AΔ 42 ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2-year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/AΔ 42 ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non-cognitive manifestation of pre-clinical AD., Competing Interests: CONFLICTS OF INTEREST All authors report no biomedical financial interests or potential conflicts of interest related to this work.

Prevention of dementia due to Alzheimer's disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of "normal" aging. A different approach involves testing of "central auditory processing" (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOEɛ4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.