Biomarkers.

BackgroundWe aimed to assess differences in baseline and longitudinal tau PET tracer binding between early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) in the LEADS and ADNI cohorts, respectively.MethodWe analyzed amyloid‐beta PET‐positive, cognitively impaired participants from the LEADS (EOAD; n = 383) and ADNI (LOAD; n = 196) cohorts with available 18F‐Flortaucipir tau PET data (Table 1). A subset had longitudinal 18F‐Flortaucipir PET data from LEADS (n = 232) and ADNI (n = 94) with average follow‐up intervals of 1.95 and 2.44 years, respectively. All 18F‐Flortaucipir PET scans were processed using the CenTauR pipeline. Cognitively normal participants from LEADS (n = 94) and ADNI (n = 421) with baseline 18F‐Flortaucipir and amyloid‐beta PET scans were also analyzed for comparison. We performed EOAD vs. LOAD comparisons using multivariate linear and linear mixed‐effects models for cross‐sectional and longitudinal analyses, respectively.ResultBaseline comparisons revealed large effect‐size, significant differences in 18F‐Flortaucipir binding between EOAD and LOAD (Figure 1). EOAD participants had higher 18F‐Flortaucipir levels in widespread neocortical regions compared to LOAD, after adjusting for covariates. In both groups, tau load was negatively associated with age. In EOAD, a significantly steeper slope was found in the association between amyloid‐beta and 18F‐Flortaucipir load, as well as between cognitive scores and 18F‐Flortaucipir load. Longitudinally, EOAD participants exhibited a faster increase in 18F‐Flortaucipir binding than LOAD, predominantly in frontal and occipital areas (Figure 2), with both groups showing an inverse linear relationship between 18F‐Flortaucipir accumulation rates and age.ConclusionEOAD patients demonstrate significantly higher tau loads, broader neuroanatomical involvement and faster tau accumulation over time compared to LOAD, independent of disease stage. These findings suggest that earlier age‐of‐onset in AD is linked to a more aggressive tauopathy. The early, extensive tau spread in symptomatic EOAD, even at an early clinical stage, may also limit the efficacy of anti‐amyloid‐beta therapies in this population.

Neurodegeneration is presumed to be the pathological process measure most proximal to clinical symptom onset in Alzheimer Disease (AD). Structural MRI is routinely collected in research and clinical trial settings. Several quantitative MRI-based measures of atrophy have been proposed, but their low correspondence with each other has been previously documented. The purpose of this study was to identify which commonly used structural MRI measure (hippocampal volume, cortical thickness in AD signature regions, or brain age gap [BAG]) had the best correspondence with the Clinical Dementia Rating (CDR) in an ethno-racially diverse sample. 2870 individuals recruited by the Healthy and Aging Brain Study-Health Disparities completed both structural MRI and CDR evaluation. Of these, 1887 individuals were matched on ethno-racial identity (Mexican American [MA], non-Hispanic Black [NHB], and non-Hispanic White [NHW]) and CDR (27% CDR > 0). We estimated brain age using two pipelines (DeepBrainNet, BrainAgeR) and then calculated BAG as the difference between the estimated brain age and chronological age. We also quantified their hippocampal volumes using HippoDeep and cortical thicknesses (both an AD-specific signature and average whole brain) using FreeSurfer. We used ordinal regression to evaluate associations between neuroimaging measures and CDR and to test whether these associations differed between ethno-racial groups. Higher BAG (pDeepBrainNet = 0.0002; pBrainAgeR = 0.00117) and lower hippocampal volume (p = 0.0015) and cortical thickness (p < 0.0001) were associated with worse clinical status (higher CDR). AD signature cortical thickness had the strongest relationship with CDR (AICDeepBrainNet = 2623, AICwhole cortex = 2588, AICBrainAgeR = 2533, AICHippocampus = 2293, AICSignature Cortical Thickness = 1903). The relationship between CDR and atrophy measures differed between ethno-racial groups for both BAG estimates and hippocampal volume, but not for cortical thickness. We interpret the lack of an interaction between ethno-racial identity and AD signature cortical thickness on CDR as evidence that cortical thickness effectively captures sources of disease-related atrophy that may differ across racial and ethnic groups. Cortical thickness had the strongest association with CDR. These results suggest that cortical thickness may be a more sensitive and generalizable marker of neurodegeneration than hippocampal volume or BAG in ethno-racially diverse cohorts.

A large scale multivariate parallel ICA method reveals novel imaging–genetic relationships for Alzheimer's disease in the ADNI cohort

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Caspase gene expression has previously been reported in terminal Alzheimer disease (AD) brain, but, currently, little is known about the temporal pattern of caspase gene expression relative to the onset and clinical progression of AD. To derive a profile of caspase gene expression and proapoptotic indexes as a function of the clinical and neuropathologic progression of AD dementia. Postmortem survey of nursing home patients characterized clinically by Clinical Dementia Rating (CDR) and neuropathologically by Consortium to Establish a Registry for Alzheimer's Disease criteria. To assess messenger RNA expression of caspase-1, -2L, -2S, -3, -5, -6, -7, -8, and -9; apoptotic cell death by TUNEL assay; and poly (ADP-ribose) polymerase cleavage in postmortem brain tissue samples from cognitively normal (CDR 0), high risk of developing AD dementia (CDR 0.5), and severe dementia (CDR 5) cases. Compared with CDR 0 cases, elevated messenger RNA expression of caspase-1 and caspase-7 in the entorhinal cortex of CDR 0.5 cases coincided with increased poly (ADP-ribose) polymerase cleavage but not apoptotic cell injury. In the entorhinal cortex of CDR 5 cases, we found elevation of caspase-1, -2L, -3, -5, -6, -7, -8, and -9 and a greater than 4-fold increase in TUNEL-positive cells. Caspase messenger RNA expression was closely associated with neurofibrillary tangle and, to a lesser extent, neuritic plaque density. Proapoptotic mechanisms may be at play early in the onset of AD (before overt signs of apoptosis) and may be a conditional factor for later apoptotic cell injury or death. These data have relevance to potential therapeutic interventions for AD using selective caspase inhibitors.

Mutations in the presenilin 1 (PS1) gene are responsible for the early onset of familial Alzheimer disease (FAD). Accumulating evidence shows that PS1 is involved in gamma-secretase activity and that FAD-associated mutations of PS1 commonly accelerate Abeta(1-42) production, which causes Alzheimer disease (AD). Recent studies suggest, however, that PS1 is involved not only in Abeta production but also in other processes that lead to neurodegeneration. To better understand the causes of neurodegeneration linked to the PS1 mutation, we analyzed the development of tau pathology, another key feature of AD, in PS1 knock-in mice. Hippocampal samples taken from FAD mutant (I213T) PS1 knock-in mice contained hyperphosphorylated tau that reacted with various phosphodependent tau antibodies and with Alz50, which recognizes the conformational change of PHF tau. Some neurons exhibited Congo red birefringence and Thioflavin T reactivity, both of which are histological criteria for neurofibrillary tangles (NFTs). Biochemical analysis of the samples revealed SDS-insoluble tau, which under electron microscopy examination, resembled tau fibrils. These results indicate that our mutant PS1 knock-in mice exhibited NFT-like tau pathology in the absence of Abeta deposition, suggesting that PS1 mutations contribute to the onset of AD not only by enhancing Abeta(1-42) production but by also accelerating the formation and accumulation of filamentous tau.

Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort

The Number of Trait Loci in Late-Onset Alzheimer Disease

Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

BackgroundSpeech impairments are an early feature of Alzheimer’s disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone.ObjectivesPROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts.DesignPROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD ‘probability-spectrum’, i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores.ParticipantsN= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months.MeasurementsThe speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure.Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum.ConclusionThe outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.

Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment. To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment. Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer's disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman's partial correlation scores between BPSD severity and regional amyloid uptake were calculated. Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r = 0.102; p = 0.009), cingulate (r = 0.083; p = 0.034), and global cerebral uptake (r = 0.099; p = 0.011); between irritability and frontal (r = 0.089; p = 0.023), cingulate (r = 0.085; p = 0.030), parietal (r = 0.087; p = 0.025), and global cerebral uptake (r = 0.093; p = 0.017); in the MCI subgroup, between anxiety and frontal (r = 0.126; p = 0.03) and global uptake (r = 0.14; p = 0.013); in the AD subgroup, between irritability and parietal uptake (r = 0.201; p = 0.03). Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD.

Traumatic brain injury (TBI) has been proposed as a risk factor for Alzheimer's disease (AD), although the mechanisms underlying the putative association are poorly understood. We investigated elderly individuals with a remote history of TBI, aiming to understand how this may have influenced amyloidosis, neurodegeneration, and clinical expression along the AD continuum. Total of 241 individual datasets including amyloid beta (Aβ) positron emission tomography ([18F]-AV45), structural MRI, and neuropsychological measures, were obtained from the Alzheimer's Disease Neuroimaging Initiative. The data were stratified into groups with (TBI +) or without (TBI-) history of head injury, and by clinical dementia rating (CDR) scores, into subgroups with normal cognition (CDR = 0) and those with symptomatic cognitive decline (CDR ≥ 0.5). We contrasted the TBI + and TBI- subgroups with respect to the onset age and extent of cognitive decline, cortical thickness changes, and Aβ standard uptake value (SUVr). Compared to the TBI-/CDR ≥ 0.5 subgroup, the TBI + /CDR ≥ 0.5 subgroup showed a 3-4year earlier age of cognitive impairment onset (ACIO, p = 0.005). Among those participants on the AD continuum (Aβ + , as defined by a cortical SUVr ≥ 1.23), irrespective of current CDR, a TBI + history was associated with greater Aβ deposition and more pronounced cortical thinning. When matched for severity of cognitive status, the TBI + /CDR ≥ 0.5 group showed greater Aβ burden, but earlier ACIO as compared to the TBI-/CDR ≥ 0.5, suggesting a more indolent clinical AD progression in those with TBI history. Remote TBI history may alter the AD onset trajectory, with approximately 4years earlier ACIO, greater amyloid deposition, and cortical thinning.

INTRODUCTIONWe evaluated the long‐term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD).METHODSOver 2 years, patients received 1‐h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S‐PLEX assay measured plasma pTau217.RESULTSNo adverse events occurred over the study period. Three female patients with late‐onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini‐Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants – both with LOAD – and both showed pTau217 reductions of 47% and 19%.DISCUSSIONThese findings suggest that long‐term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation.CLINICAL TRIAL REGISTRATION INFORMATIONClinicalTrials.gov (NCT04055376).HighlightsFive mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years.Late‐onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores.National Alzheimer's Coordinating Center (NACC) data enhanced early‐phase analysis and support precision medicine in AD studies.Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use.This small pilot is the first to link long‐term 40 Hz therapy to AD biomarker change.

BackgroundImaging, cognitive and fluid data have been widely studied to identify quantitative biomarkers that can help predict the status and progression of Alzheimer’s disease (AD). However, it is still an underexplored topic whether there exist subpopulations with different genetic profiles across which the biomarker‐based prediction models may vary. We propose to use the Chow test (Chow 1960 Econometrica 28(3)) to perform genetically stratified analyses for identifying SNP‐based subpopulations coupled with precision AD biomarkers with varying effects on future diagnosis in these subpopulations. The investigation of such SNPs and precision biomarkers may eventually pave the way for increased customization of AD care.MethodParticipants included 1,324 subjects from the ADNI cohort with both AD biomarker and genotyping data available (http://www.pi4cs.org/qt‐pad‐challenge). 30 significant (P &lt; 1.5E‐278) AD SNPs were sourced from (Jansen 2019 NatGen). Chow tests were performed to determine whether each of baseline visit measures of 16 AD biomarkers predicted AD diagnosis at the three‐year visit with varying slopes when stratifying upon the allelic dosage of each of 30 chosen SNPs. Bonferroni correction (P &lt; 1.04E‐4) was employed to correct for multiple comparisons.ResultMultiple SNP‐biomarker pairs showed significant genetically driven deviations in the regression coefficients when predicting diagnosis in three years using baseline biomarkers (Figure 1). Top SNP hits involved rs769449 (Chr 19, APOE) and rs7561528 (Chr 2, LOC105373605), and almost all 16 studied biomarkers demonstrated differential slopes in different genotype groups to predict diagnosis in three years. To examine the details of these top findings, the regression coefficients calculated for each of the five most significant biomarkers of both SNPs were bootstrapped and plotted in Figure 2.ConclusionGenetic analysis of AD candidate SNPs in conjunction with AD biomarker data via the Chow test identified several SNPs coupled with precision AD biomarkers with varying prognosis effects in the corresponding genotype groups. These findings provide valuable information to reveal disease heterogeneity and help facilitate precision medicine.

Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD). To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis. A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy. An AD research center. All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia. Progression to the stage of CDR 1, which characterizes mild definite DAT. Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%). Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.