Aging as a target for the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD.

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

Learning slopes in early-onset Alzheimer's disease.

OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without ß-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. HIGHLIGHTS: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection.

OBJECTIVE: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. METHODS: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). RESULTS: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. CONCLUSIONS: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

Corrigendum: A 5-min Cognitive Task With Deep Learning Accurately Detects Early Alzheimer's Disease.

[This corrects the article DOI: 10.3389/fnagi.2020.603179.].

Class-Based Antiretroviral Exposure and Cognition Among Women Living with HIV.

Neurologic complications of the human immunodeficiency virus (HIV) are common in treated individuals, and toxicity of certain antiretroviral therapies (ART) may contribute to cognitive impairment. We investigated exposures to specific ART and cognition among women living with HIV (WLWH). Virologically suppressed (viral load <200 copies/mL during at least two semi-annual visits) WLWH and age/race matched HIV-seronegative controls enrolled in the Women's Interagency HIV Study who completed at least two biennial cognitive assessments were included. Analysis of WLWH was restricted to those with exposure to the drug class of interest and a nucleoside reverse transcriptase inhibitor (NRTI) backbone. Generalized estimating equations were used to evaluate repeated measures of cognition over time in association with ART class exposure. Among 1,242 eligible WLWH, 20% (n = 247) had isolated drug exposure to non-nucleoside reverse transcriptase inhibitors (NNRTI), 18% (n = 219) to protease inhibitors (PIs), and 6% (n = 79) to integrase inhibitors with a NRTI backbone. Cognitive assessments were performed at a median of 3 biennial visits {IQR 2-4 visits}. At the index assessment, 21% of WLWH demonstrated global cognitive impairment versus 29% at their last cognitive assessment. In multivariable analyses adjusted for hypertension, depression, diabetes mellitus, history of AIDS-defining illness, alcohol use, number of medications, and time on ART, WLWH exposed to NNRTIs demonstrated verbal learning improvements (mean T-score change 1.3, p = .020) compared to other treated women. Compared to HIV-seronegative women, WLWH exposed to PIs had worse verbal learning (mean T-score difference -2.62, p = .002) and verbal memory performance (mean T-score difference -1.74, p = .032) at baseline. Compared to HIV-seronegative women, WLWH exposed to PIs had improvements in verbal learning (mean T-score slope difference 0.36, p = .025) and verbal memory (mean T-score slope difference 0.32, p = .042). The index T-score and slope of change in the T-score were similar among other treated groups and the HIV-seronegative group. We noted emerging trends in cognition in WLWH exposed to specific drug classes. Ongoing study of this relatively young group is important to characterize long-term cognitive outcomes and effect of antiretrovirals as treatment guidelines evolve.

Spatial inhibition of return is impaired in mild cognitive impairment and mild Alzheimer's disease.

Spatial inhibition of return (IOR) refers to the phenomenon by which individuals are slower to respond to stimuli appearing at a previously cued location compared to un-cued locations. Here with a group of older adults (n = 56, 58-80 (67.9±5.2) year old, 31 females, 18.7±3.6 years of education), we provide evidence supporting the notion that spatial IOR is mildly impaired in individuals with mild cognitive impairment (MCI) or mild Alzheimer's disease (AD), and the impairment is detectable using a double cue paradigm. Furthermore, reduced spatial IOR in high-risk healthy older individuals is associated with reduced memory and other neurocognitive task performance, suggesting that the double cue spatial IOR paradigm may be useful in detecting MCI and early AD.

Low CD4+ cell count nadir exacerbates the impacts of APOE ε4 on functional connectivity and memory in adults with HIV.

OBJECTIVE: Nearly half of individuals living with HIV in the USA are now 50 or older. This rapidly ageing populace may be at an increasingly greater risk of Alzheimer's disease. However, the potential interaction between HIV-disease and Alzheimer's disease pathogenesis (i.e. Alzheimer's disease genetic risk factors) on brain function remains an open question. The present study aimed to investigate the impact of APOE ε4 on brain function in middle-aged to older people with HIV (PWH), as well as the putative interaction between ε4 and HIV disease severity. METHODS: Ninety-nine PWH participated in a cross-sectional study (56.3 ±â€Š6.5 years, range 41-70 years, 27 women, 26 ε4 carriers and 73 noncarriers). Structural MRI and resting-state functional MRI were collected to assess alterations in brain structure and functional connectivity, respectively. RESULTS: APOE ε4 was associated with worse memory performance and reduced functional connectivity in the memory network. The functional connectivity reduction was centred at the caudate nucleus rather than hippocampus and correlated with worse memory performance. In ε4 carriers, low CD4+ cell count nadir was associated with reduced functional connectivity in the memory network, but this association was absent in noncarriers. Furthermore, there was an indirect detrimental impact of ε4 on memory performance through memory network functional connectivity. However, this indirect effect was contingent on CD4+ cell count nadir, that is the indirect effect of ε4 on memory was only significant when CD4+ cell count nadir was low. INTERPRETATION: APOE ε4 is associated with reduced memory and reduced functional connectivity within the memory network, and low CD4+ cell count nadir -- indicating a history of severe immunosuppression -- may exacerbate the effects of ε4.

A 5-min Cognitive Task With Deep Learning Accurately Detects Early Alzheimer's Disease.

Introduction: The goal of this study was to investigate and compare the classification performance of machine learning with behavioral data from standard neuropsychological tests, a cognitive task, or both. Methods: A neuropsychological battery and a simple 5-min cognitive task were administered to eight individuals with mild cognitive impairment (MCI), eight individuals with mild Alzheimer's disease (AD), and 41 demographically match controls (CN). A fully connected multilayer perceptron (MLP) network and four supervised traditional machine learning algorithms were used. Results: Traditional machine learning algorithms achieved similar classification performances with neuropsychological or cognitive data. MLP outperformed traditional algorithms with the cognitive data (either alone or together with neuropsychological data), but not neuropsychological data. In particularly, MLP with a combination of summarized scores from neuropsychological tests and the cognitive task achieved ~90% sensitivity and ~90% specificity. Applying the models to an independent dataset, in which the participants were demographically different from the ones in the main dataset, a high specificity was maintained (100%), but the sensitivity was dropped to 66.67%. Discussion: Deep learning with data from specific cognitive task(s) holds promise for assisting in the early diagnosis of Alzheimer's disease, but future work with a large and diverse sample is necessary to validate and to improve this approach.

An individual with human immunodeficiency virus, dementia, and central nervous system amyloid deposition.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is found in 30%-50% of individuals with HIV infection. To date, no HIV+ individual has been reported to have a positive amyloid PET scan. We report a 71-year-old HIV+ individual with HAND. Clinical and neuropsychologic evaluations confirmed a progressive mild dementia. A routine brain MRI was normal for age. [18F]Fluorodeoxyglucose-PET revealed mild hypermetabolism in bilateral basal ganglia and hypometabolism of bilateral parietal cortex including the posterior cingulate/precuneus. Resting state functional MRI revealed altered connectivity as found with individuals with mild AD. CSF examination revealed a low Aß42/tau index but a low phospho-tau. An amyloid PET/CT with [18F]florbetaben revealed pronounced cortical radiotracer deposition. This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. HIV infection does not preclude CNS Aß/amyloid deposition. Amyloid PET imaging may be of value in distinguishing HAND from AD pathologies.