Likelihood Of Alzheimer's Disease Research Articles

Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease.

Higher-educated patients with Alzheimer disease (AD) can harbor greater neuropathologic burden than those with less education despite similar symptom severity. In this study, we assessed whether this observation is also present in potential preclinical AD stages, namely in individuals with subjective cognitive decline and clinical features increasing AD likelihood (SCD+). Amyloid-PET information ([18F]Flutemetamol or [18F]Florbetaben) of individuals with SCD+, mild cognitive impairment (MCI), and AD were retrieved from the AMYPAD-DPMS cohort, a multicenter randomized controlled study. Group classification was based on the recommendations by the SCD-I and NIA-AA working groups. Amyloid PET images were acquired within 8 months after initial screening and processed with AMYPYPE. Amyloid load was based on global Centiloid (CL) values. Educational level was indexed by formal schooling and subsequent higher education in years. Using linear regression analysis, the main effect of education on CL values was tested across the entire cohort, followed by the assessment of an education-by-diagnostic-group interaction (covariates: age, sex, and recruiting memory clinic). To account for influences of non-AD pathology and comorbidities concerning the tested amyloid-education association, we compared white matter hyperintensity (WMH) severity, cardiovascular events, depression, and anxiety history between lower-educated and higher-educated groups within each diagnostic category using the Fisher exact test or χ2 test. Education groups were defined using a median split on education (Md = 13 years) in a subsample of the initial cohort, for whom this information was available. Across the cohort of 212 individuals with SCD+ (M(Age) = 69.17 years, F 42.45%), 258 individuals with MCI (M(Age) = 72.93, F 43.80%), and 195 individuals with dementia (M(Age) = 74.07, F 48.72%), no main effect of education (ß = 0.52, 95% CI -0.30 to 1.58), but a significant education-by-group interaction on CL values, was found (p = 0.024) using linear regression modeling. This interaction was driven by a negative association of education and CL values in the SCD+ group (ß = -0.11, 95% CI -4.85 to -0.21) and a positive association in the MCI group (ß = 0.15, 95% CI 0.79-5.22). No education-dependent differences in terms of WMH severity and comorbidities were found in the subsample (100 cases with SCD+, 97 cases with MCI, 72 cases with dementia). Education may represent a factor oppositely modulating subjective awareness in preclinical stages and objective severity of ongoing neuropathologic processes in clinical stages.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. To investigate the potential therapeutic benefit of sildenafil on AD. We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Neuropathology in the LifeAfter90 Study: 2023 update on an Ethnically Diverse Cohort Study of Oldest‐Old

AbstractBackgroundNeuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life. Most studies, however, have limited ethnoracial diversity with almost exclusively White decedents. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old decedents.MethodThe LifeAfter90 study is an ongoing cohort study of Kaiser Permanente Northern California members, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Interviews and cognitive assessments occur approximately every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v.10 and used NIA‐AA guidelines for Alzheimer’s diagnoses. As of January 2023, 304 participants (40%) were enrolled in autopsy (20% Asian, 18% African American, 17% Latino, 9% Multiracial/Other, and 36% White).ResultOf the 304 participants, 59 had died and neuropathological evaluations were completed. The median age of death was 93 years (range 90‐105), 33 (56%) were female, 8 Asian, 5 Black, 10 Latino, 31 White, and 5 Multiracial/Other. At final clinical exam, 17 participants had dementia (29%), 25 questionable/mild cognitive impairment (42%), and 16 were cognitively normal (27%). Alzheimer disease (AD) and vascular pathologies were the most frequent findings (Figure). Twenty two percent of participants did not have AD, one lacked neurofibrillary tangles (NFT). The most severe distributions/densities of NFTs and plaques were infrequent, with high likelihood of AD in two participants. For vascular pathologies, 98% had some level of arteriolosclerosis, 97% had atherosclerosis, 70% had amyloid angiopathy, and 26% had at least one old microinfarct. Other pathologies were less common: 27% had Lewy bodies, 18% had TDP‐43 deposits, and only one had Hippocampal sclerosis. Although data is sparse to test for associations, the proportion of individuals with dementia tended to increase with increasing pathology severity especially for AD pathologies.ConclusionThis diverse cohort of oldest‐old individuals reveal numerous brain pathologies are present with advanced age, with AD and select vascular pathologies being the most common. Future analyses will investigate their role with cognitive impairment.

Differential Associations of 6 Adiposity Indices With Dementia in Older Adults: The MIND-China Study.

The cross-sectional association between late-life obesity and dementia is often explained by the obesity paradox. We assessed the potential differential associations of various adiposity indices with dementia and subtypes of dementia in rural Chinese older adults. A population-based cross-sectional study. A total of 5277 participants (age ≥60years; 57.23% female) who were living in rural communities and were examined in March-September 2018 for MIND-China. We used weight, height, and waist circumference (WC) to calculate 6 adiposity indices: body mass index (BMI), waist-to-height ratio (WHtR), weight-adjusted-waist index (WWI), A Body Shape Index (ABSI), body roundness index (BRI), and Conicity Index (ConI). Dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were clinically diagnosed following the international criteria. Data were analyzed with logistic regression models. Of the 5277 participants, 303 were diagnosed with dementia, including 193 with AD and 99 with VaD. The multivariable-adjusted odds ratio (95% CI) of dementia associated with the highest (vs lowest) quintile of adiposity index was 2.32 (1.40-3.85) for WWI, 1.56 (1.03-2.36) for ABSI, and 1.40 (0.92-2.11) for ConI. Similarly, higher levels of these 3 adiposity indices were significantly associated with an increased likelihood of AD, whereas a higher BMI was associated with a decreased likelihood of AD. None of the 6 examined adiposity indices was significantly associated with VaD when adjusting for multiple confounders. The adiposity index WWI is linearly associated with the likelihood of dementia and AD. An increased WWI may be a clinical marker for the dementia syndrome and Alzheimer's dementia.

A simulative deep learning model of SNP interactions on chromosome 19 for predicting Alzheimer's disease risk and rates of disease progression.

Identifying genetic patterns that contribute to Alzheimer's disease (AD) is important not only for pre-symptomatic risk assessment but also for building personalized therapeutic strategies. We implemented a novel simulative deep learning model to chromosome 19 genetic data from the Alzheimer's Disease Neuroimaging Initiative and the Imaging and Genetic Biomarkers of Alzheimer's Disease datasets. The model quantified the contribution of each single nucleotide polymorphism (SNP) and their epistatic impact on the likelihood of AD using the occlusion method. The top 35 AD-risk SNPs in chromosome 19 were identified, and their ability to predict the rate of AD progression was analyzed. Rs561311966 (APOC1) and rs2229918 (ERCC1/CD3EAP) were recognized as the most powerful factors influencing AD risk. The top 35 chromosome 19 AD-risk SNPs were significant predictors of AD progression. The model successfully estimated the contribution of AD-risk SNPs that account for AD progression at the individual level. This can help in building preventive precision medicine.

Genetic Effects of NDUFAF6 rs6982393 and APOE on Alzheimer's Disease in Chinese Rural Elderly: A Cross-Sectional Population-Based Study.

PurposeTo investigate the associations of genotypes of NDUFAF6 rs6982393 and APOE and their combined genotypes with the risk of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) in Chinese rural elderly.MethodsThis cross-sectional population-based study included 5096 older adults (age ≥60 years, 57.1% female). Genotypes of NDUFAF6 rs6982393 and APOE were detected using the multiple-polymerase chain reaction amplification. We diagnosed AD following the criteria of Diagnostic and Statistical Manual of Mental Disorders, the fourth edition and diagnosed MCI following the Petersen’s criteria MCI. Data were analyzed using the logistic regression model.ResultsThe overall prevalence of AD and MCI was 3.57% (95% confidence interval [CI]: 0.040, 0.053) and 22.65% (95% CI: 0.223, 0.247), separately. The TT versus CC/CT genotype of NDUFAF6 rs6982393 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 1.61 (1.02, 2.54) in the total sample, 3.36 (1.48, 7.60) in those aged 60–69, and 1.24 (0.71, 2.17) in those aged 70 years and above. The interaction between genotype of NDUFAF6 rs6982393 with age groups (60–69 versus ≥70 years) was significant on the risk of AD. The presence of APOE ε4 was not significantly associated with the risk of AD. Carrying both NDUFAF6 TT and APOE ε4 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 2.69 (1.10, 2.56). In addition, there was no significant association between the above genotypes and MCI.ConclusionIn Chinese rural elderly, the TT versus CT/CC genotype of NDUFAF6 rs6982393 was associated with an increased likelihood of AD; such an association only existed among young-old adults. Carrying both NDUFAF6 rs6982393-TT and APOE ε4 was related to a higher risk of AD. This finding highlights the importance of considering age and combined genotype in studying the genetic profiles of AD.

Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.

Alteration of a specific microRNA regulating neprilysin expression in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by accumulation of amyloid β (Aβ) plaques and aggregates of hyperphosphorylated tau protein. Genetic, epigenetic, and environmental factors play critical roles in AD etiology (Maloney & Lahiri-Lancet Neurol-15:760-774); however, underlying mechanisms of pathogenesis remain unclear. Both Aβ biogenesis pathways, involving APP and BACE1, and degradation pathways, involving membrane metallo-endopeptidase (MME), aka neprilysin, play critical roles in Aβ accumulation leading to AD. We posit that AD results from dysregulation of key biochemical pathways, particularly those involving non-coding microRNA (miRNA) (Chopra et al, Mol. Psychiatry-2020). We hypothesize that since MME is an important Aβ-clearing enzyme, disruption of miRNA regulation of MME would contribute to AD. Bioinformatics prediction revealed miRNA binding sites on the MME mRNA 3'-untranslated region (3'-UTR). Neuronally differentiated human neuroblastoma (SK-N-SH) cells were transfected with either siRNA against MME, candidate miRNA mimics, miRNA-inhibitors or negative controls. Levels of MME mRNA and protein were measured by qRT-PCR and western blotting, respectively. miR-181d emerged as a functional candidate. We tested sequence specificity and miR-181d activity with reporter gene- MME 3'-UTR fusion constructs. Levels of miR-181d were quantified in human brain tissue specimens from control, MCI, and AD subjects. Several human-specific miRNAs were predicted to target the MME 3'-UTR, including miR-9, miR-181d and miR-216. Notably, miR-181d treatment produced a significant reduction of MME mRNA and protein levels in neuronal cultures. Functional assays demonstrated miR-181d activity. MME is expressed in several human organs, the highest in kidney. Levels of miR-181d significantly influenced probability of AD diagnosis in human brain samples from temporal lobe and cerebellum but not posterior cingulate cortex. Overall, as miR-181d levels increased, likelihood of AD increased. This trend was particularly strong in female subjects vs. male subjects. Presence of the APOEε4 allele also increased likelihood of AD diagnosis, independent of miR-181d levels. In human neuronal cultures, miR-181d can down-regulate MME mRNA and protein, potentially through the MME 3'-UTR. Also, miR-181d is elevated in AD brains in multiple regions. Since MME is a key Aβ-degrading enzyme, its dysregulation by (presumably excess) miR-181d could contribute to AD pathogenesis. Supported by the NIA/NIH grant P01AG014449 to DKL and SEC.

Neuropathology in the LifeAfter90 study: A new ethnically diverse cohort study of oldest‐old

Persons over the age of 90 are the fastest growing segment of the population in the US, yet there is a dearth of studies investigating the underlying neuropathology of cognitive impairment and dementias, in ethnically diverse, non-white decedents. The Life after 90 study began enrollment in July 2018 and is an ongoing cohort study of members of Kaiser Permanente Northern California aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Participants are examined every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer's Coordinating Center Neuropathology form v. 10. As of January 2021, 173 (26%) participants enrolled in autopsy (18% Asian, 12% African American, 12% Latino, and 10% as multiracial) with 8 deceased and neuropathological evaluations completed. Average age of death was 96 years (range 91 to 105), 5 (62.5%) were female, 3 Latino, 3 Caucasian, and 2 multiracial. At the final clinical exam, which was on average 4 months before death (range: 2-8), 2 participant had dementia (25%), 3 questionable/mild cognitive impairment (37.5%), and 3 cognitively normal (37.5%). With respect to a neuropathologic diagnosis of Alzheimer's disease (AD), 2 met criteria for intermediate likelihood (25%), 4 low (50%), and 2 were considered not to have AD (25%). Notably, none had high likelihood of AD. All participants had some level of neurofibrillary tangles with Braak stages between II and IV. Two participants lacked plaques (Amyloid-Beta or neuritic types), and the highest Thal phase was 4. Four participants (50%) had Lewy bodies (LBs), 1 in olfactory bulb/tract only, 2 Transitional, and 1 with Diffuse. Hippocampal sclerosis was not seen in any whereas TDP-43 inclusions were detected in 2 participants (25%). Diffuse LB, TDP-43 inclusions, and intermediate AD co-occurred in one (50%) of the dementia participants while all lacking in the other. Preliminary results of the first 8 deaths in this multiethnic cohort of oldest-old individuals indicate that numerous brain pathologies are present with advanced age. Further work with this study will examine the clinical impact of this pathological heterogeneity.

Machine learning of brain structural biomarkers for Alzheimer's disease (AD) diagnosis, prediction of disease progression, and amyloid beta deposition in the Japanese population.

IntroductionWe developed machine learning (ML) designed to analyze structural brain magnetic resonance imaging (MRI), and trained it on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In this study, we verified its utility in the Japanese population.MethodsA total of 535 participants were enrolled from the Japanese ADNI database, including 148 AD, 152 normal, and 235 mild cognitive impairment (MCI). Probability of AD was expressed as AD likelihood scores (ADLS).ResultsThe accuracy of AD diagnosis was 88.0% to 91.2%. The accuracy of predicting the disease progression in non‐dementia participants over a 3‐year observation was 76.0% to 79.3%. More than 90% of the participants with low ADLS did not progress to AD within 3 years. In the amyloid positron emission tomography (PET)–positive MCI, the hazard ratio of progression was 2.39 with low ADLS, and 5.77 with high ADLS. When high ADLS was defined as N+ and Pittsburgh compound B (PiB) PET positivity was defined as A+, the time to disease progression for 50% of MCI participants was 23.7 months in A+N+, whereas it was 52.3 months in A+N‐.ConclusionThese results support the feasibility of our ML for the diagnosis of AD and prediction of the disease progression.

A TOMM40/APOE allele encoding APOE-E3 predicts high likelihood of late-onset Alzheimer's disease in autopsy cases.

BackgroundThe APOE‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE‐ε4 are at variance.MethodsWe investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V‐VI), respectively, and in 150 controls without major neurodegenerative diseases.ResultsWe observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE‐E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE‐E3 was identified as risk haplotype of high‐ (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high‐, but not intermediate likelihood AD on the APOE‐ε3/ε3 background (p = .0230).ConclusionThe striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.

Event-related Potentials Improve the Efficiency of Cerebrospinal Fluid Biomarkers for Differential Diagnosis of Alzheimer's Disease.

The pathological process of Alzheimer's disease (AD) in the brain likely begins 20-30 years earlier than the emergence of its first clinical symptoms and symptoms of AD often overlap with the symptoms of other primary causes of dementia. Therefore, it is crucially important to improve early and differential diagnosis of the disease. Event-related potentials (ERP) measured non-invasively by electroencephalography have shown diagnostic potential in AD. The aim of this study was to compare the efficiency of P300 and N200 potentials and reaction time (RT) with commonly used protein biomarkers measured in the cerebrospinal fluid (CSF), including amyloid β peptide (β1-42), total tau (t-tau), tau protein phosphorylated at threonine 181 (p-tau181), tau protein phosphorylated at serine 199 (p-tau199), tau protein phosphorylated at threonine 231 (p-tau231), and visinin-like protein 1 (VILIP-1) in differential diagnosis of AD in mild cognitive impairment (MCI) and AD patients. The study involved 49 AD patients, 28 patients with MCI, 4 healthy control subjects and 16 patients with other primary causes of dementia. ERP (P300RT, N200RT, P300 counting and N200 counting) showed a moderate to strong correlation with protein CSF biomarkers. We confirmed previous observations of moderate to strong correlation between ERP and neuropsychological testing and showed that P300 latency and RT are shortened in AD patients on therapy with acetylcholinesterase inhibitors. Using ERP and RT, a predictive model for determination of AD likelihood in MCI patients was developed, detecting 56.3% of MCI patients with high risk for development of AD in our cohort. MCI patients with pathological levels of Aβ1-42 had prolonged P300 latency, indicating that a combination of ERP and CSF protein biomarkers could improve the differential diagnosis of AD in MCI patients. Additionally, the results suggested the potential of P300 latency in differentiating AD and FTD patients. Our data provide possible solutions for improvement of differential diagnosis of AD, and reveal that the diagnostic efficiency of CSF protein biomarkers t-tau, p-tau181, p-tau199, p-tau231 and VILIP-1 could be improved by adding ERP in clinical practice.

DEVELOPMENT OF A NOVEL MULTI-BIOMARKER ASSESSMENT SCORE FOR ALZHEIMER’S DISEASE

There is an unmet need for laboratory tools that detect Alzheimer's disease (AD) in its early stages. Biomarkers in cerebrospinal fluid (CSF) have shown great potential in fulfilling this need. The ratio of the peptides β-amyloid (Aβ) 40 and 42 in CSF predicts disease progression. The levels of apolipoprotein E (ApoE) in CSF, and the presence of 1 or more ε4 alleles (APOE4), indicate disease likelihood. Here, we describe a novel algorithm that combines these biomarkers. We have used the algorithm to develop an assessment score that categorizes an individual's likelihood of having AD as higher, lower, or intermediate. Aβ42/ Aβ40 ratio, APOE4allele count, and total ApoE (μg/mL) were determined using mass spectrometry in a training set of 151 specimens from clinically-diagnosed AD and non-AD patients (supplied by UC San Diego ADRC Neuropathology Core and Brain Bank). A diagnosis of AD was based on imaging and cognition tests. The results from the training set were used to develop a logistic regression model. The linear predictor from the regression model was used to create an AD likelihood score. The score was partitioned into 3 groups: higher, intermediate, and lower likelihood. The higher likelihood threshold was selected to allow for a 10% false positive rate, while the lower likelihood threshold was selected to allow for a 10% false negative rate. We validated the model in an initially-blinded separate test cohort of 159 patients independently diagnosed as AD or non-AD using combined genomic and immunochemical methodology. Of the 159 test subjects, 79 were previously diagnosed as AD and 80 were diagnosed as non-AD. Categorization based on logistic regression analysis results is presented in Table 1. Of those in the higher likelihood category, 85.7% (36/42) had at least one APOE4 allele: 47.6% ε2/ε4 or ε3/ε4 (20/42), and 38.1% ε4/ε4 (16/42). The remaining higher likelihood samples, 14.3% (6/42), were APOE4-negative. We have devised a logistic regression model using biomarkers in CSF that has potential to stratify the likelihood of Alzheimer's disease.

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5–2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.

Appetite and Weight Loss Symptoms in Late-Life Depression Predict Dementia Outcomes

Identify depression symptoms during active late-life depression (LLD) that predict conversion to dementia. The authors followed a cohort of 290 participants from the Neurocognitive Outcomes of Depression in the Elderly study. All participants were actively depressed and cognitively normal at enrollment. Depression symptom factors were derived from prior factor analysis: anhedonia and sadness, suicidality and guilt, appetite and weight loss, sleep disturbance, and anxiety and tension. Cox regression analysis modeled time to Alzheimer disease (AD) and non-AD dementia onset on depression symptom factors, along with age, education, sex, and race. Significant dementia predictors were tested for interaction with age at depression onset. Higher scores on the appetite and weight loss symptom factor were associated with an increased hazard of both AD and non-AD dementia. This factor was moderated by age at first depression onset, such that higher scores were associated with higher risk of non-AD dementia when depression first occurred earlier in life. Other depression symptom factors and overall depression severity were not related to risk of AD or non-AD dementia. Results suggest greater appetite/weight loss symptoms in active episodes of LLD are associated with increased likelihood of AD and non-AD dementia, but possibly via different pathways moderated by age at first depression onset. Results may help clinicians identify individuals with LLD at higher risk of developing AD and non-AD dementia and design interventions that reduce this risk.

Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers.

Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients. We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis. With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure. After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86). The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.

Clinical features of Alzheimer disease with and without lewy bodies

Importance Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings. Objective To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD. Design, Setting, and Participants Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging–Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013. Exposures Standardized neuropathologic assessment and then brain autopsy after death. Main Outcomes and Measures Clinical and neuropsychiatric test scores. Results The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) ( P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) ( P = .03). More men than women had AD with Lewy bodies ( P = .01). The frequency of having at least 1 APOE e4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies ( P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric Inventory Questionnaire score (6.59 [1.44] [95% CI, 3.75-9.42] vs 5.49 [1.39] [95% CI, 2.76-8.23]; P = .04) and a statistically significantly higher mean (SD) Unified Parkinson Disease Rating Scale motor score (0.81 [0.18] [95% CI, 0.45-1.17] vs 0.54 [0.18] [95% CI, 0.19-0.88]; P Conclusions and Relevance Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE e4 allele suggest potential common mechanisms for AD and Lewy body pathologies.

Clinical Features of Alzheimer Disease With and Without Lewy Bodies.

Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings. To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD. Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging-Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013. Standardized neuropathologic assessment and then brain autopsy after death. Clinical and neuropsychiatric test scores. The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric Inventory Questionnaire score (6.59 [1.44] [95% CI, 3.75-9.42] vs 5.49 [1.39] [95% CI, 2.76-8.23]; P = .04) and a statistically significantly higher mean (SD) Unified Parkinson Disease Rating Scale motor score (0.81 [0.18] [95% CI, 0.45-1.17] vs 0.54 [0.18] [95% CI, 0.19-0.88]; P < .001) than did participants who had AD without Lewy bodies. Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.

Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum.

Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.