Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) Îµ4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. DISCUSSION: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. HIGHLIGHTS: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

The Power of EEG to Predict Conversion from Mild Cognitive Impairment and Subjective Cognitive Decline to Dementia.

INTRODUCTION: The aim of this study was to examine if quantitative electroencephalography (qEEG) using the statistical pattern recognition (SPR) method could predict conversion to dementia in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). METHODS: From 5 Nordic memory clinics, we included 47 SCD patients, 99 MCI patients, and 67 healthy controls. EEGs analyzed with the SPR method together with clinical data recorded at baseline were evaluated. The patients were followed up for a mean of 62.5 (SD 17.6) months and reexamined. RESULTS: Of 200 participants with valid clinical information, 70 had converted to dementia, and 52 had developed Alzheimer's disease. Receiver-operating characteristic analysis of the EEG results as defined by a dementia index (DI) ranging from 0 to 100 revealed that the area under the curve was 0.78 (95% CI 0.70-0.85), corresponding to a sensitivity of 71%, specificity of 69%, and accuracy of 69%. A logistic regression analysis showed that by adding results of a cognitive test at baseline to the EEG DI, accuracy could improve. CONCLUSION: We conclude that applying qEEG using the automated SPR method can be helpful in identifying patients with SCD and MCI that have a high risk of converting to dementia over a 5-year period. As the discriminant power of the method is of moderate degree, it should be used in addition to routine diagnostic methods.

A signature pattern of cortical atrophy in dementia with Lewy bodies: A study on 333 patients from the European DLB consortium.

INTRODUCTION: We explored regional brain atrophy patterns and their clinical correlates in dementia with Lewy bodies (DLB). METHODS: In this multicentre study, we included a total of 333 patients with DLB, 352 patients with Alzheimer's disease (AD), and 233 normal controls and used medial temporal lobe atrophy, posterior atrophy, and frontal atrophy (GCA-F) visual rating scales. Patients were classified according to four atrophy patterns. RESULTS: Patients with DLB had higher scores on all the three atrophy scales than normal controls but had less medial temporal lobe atrophy than those with AD (all P values < .001). A signature hippocampal-sparing pattern of regional atrophy was observed in DLB. The magnetic resonance imaging measures showed 65% ability to discriminate between DLB and AD and marginally contributed to the discrimination over and above the core clinical features. DISCUSSION: The most common pattern of atrophy of DLB was hippocampal-sparing. Future studies should explore whether comorbid AD pathology underlies the atrophy patterns seen in DLB.

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-ß precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease ß-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the ß-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.

BACKGROUND: Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. METHODS AND RESULTS: Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. CONCLUSIONS: We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

Variant of TREM2 associated with the risk of Alzheimer's disease.

BACKGROUND: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. METHODS: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). CONCLUSIONS: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.).

Electroencephalography Is a Good Complement to Currently Established Dementia Biomarkers.

BACKGROUND/AIMS: Dementia biomarkers that are accessible and easily applicable in nonspecialized clinical settings are urgently needed. Quantitative electroencephalography (qEEG) is a good candidate, and the statistical pattern recognition (SPR) method has recently provided promising results. We tested the diagnostic value of qEEG-SPR in comparison to cognition, structural imaging, and cerebrospinal fluid (CSF) biomarkers. METHODS: A total of 511 individuals were recruited from the multicenter NORD EEG study [141 healthy controls, 64 subjective cognitive decline, 124 mild cognitive impairment, 135 Alzheimer's disease (AD), 15 dementia with Lewy bodies/Parkinson's disease with dementia (DLB/PDD), 32 other dementias]. The EEG data were recorded in a standardized way. Structural imaging data were visually rated using scales of atrophy in the medial temporal, frontal, and posterior cortex. RESULTS: qEEG-SPR outperformed structural imaging, cognition, and CSF biomarkers in DLB/PDD diagnosis, outperformed structural imaging in AD diagnosis, and improved the differential diagnosis of AD. In addition, qEEG-SPR allowed differentiation of two clinically different AD subtypes. CONCLUSION: Adding qEEG to the diagnostic workup substantially increases the detection of AD pathology even in pre-dementia stages and improves differential diagnosis. EEG could serve as a good complement to currently established dementia biomarkers since it is cheap, noninvasive, and extensively applied outside academic centers.

The acetylcholine index: an electroencephalographic marker of cholinergic activity in the living human brain applied to Alzheimer's disease and other dementias.

BACKGROUND: The cholinergic hypothesis is well established and has led to the development of pharmacological treatments for Alzheimer's disease (AD). However, there has previously been no physiological means of monitoring cholinergic activity in vivo. METHODS: An electroencephalography (EEG)-based acetylcholine (Ach) index reflecting the cholinergic activity in the brain was developed using data from a scopolamine challenge study. The applicability of the Ach index was examined in an elderly population of healthy controls and patients suffering from various causes of cognitive decline. RESULTS: The Ach index showed a strong reduction in the severe stages of AD dementia. A high correlation was demonstrated between the Ach index and cognitive function. The index was reduced in patients with mild cognitive impairment and prodromal AD, indicating a decreased cholinergic activity. When considering the distribution of the Ach index in a population of healthy elderly subjects, an age-related threshold was revealed, beyond which there is a general decline in cholinergic activity. CONCLUSIONS: The EEG-based Ach index provides, for the first time, a physiological means of monitoring the cholinergic activity in the human brain in vivo. This has great potential for aiding diagnosis and patient stratification as well as for monitoring disease progression and treatment response.

Quantitative EEG Applying the Statistical Recognition Pattern Method: A Useful Tool in Dementia Diagnostic Workup.

BACKGROUND/AIM: The aim of this study was to examine the discriminatory power of quantitative EEG (qEEG) applying the statistical pattern recognition (SPR) method to separate Alzheimer's disease (AD) patients from elderly individuals without dementia and from other dementia patients. METHODS: The participants were recruited from 6 Nordic memory clinics: 372 unselected patients [mean age 71.7 years (SD 8.6), 54% women] and 146 healthy elderly individuals [mean age 66.5 years (SD 7.7), 60% women]. After a standardized and comprehensive assessment, clinical diagnoses were made according to internationally accepted criteria by at least 2 clinicians. EEGs were recorded in a standardized way and analyzed independently of the clinical diagnoses, using the SPR method. RESULTS: In receiver operating characteristic curve analyses, the qEEGs separated AD patients from healthy elderly individuals with an area under the curve (AUC) of 0.90, representing a sensitivity of 84% and a specificity of 81%. The qEEGs further separated patients with Lewy body dementia or Parkinson's disease dementia from AD patients with an AUC of 0.9, a sensitivity of 85% and a specificity of 87%. CONCLUSION: qEEG using the SPR method could be a useful tool in dementia diagnostic workup.

Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias.

Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of ß-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when ß-amyloid was included in the model. Instead, ß-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of ß-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on ß-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.

Sex differences in brain atrophy in dementia with Lewy bodies.

Background and objectives: Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods: We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results: We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions: This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.

Diagnostic accuracy of statistical pattern recognition of electroencephalogram registration in evaluation of cognitive impairment and dementia.

BACKGROUND: There is still a need for simple, noninvasive, and inexpensive methods to diagnose the causes of cognitive impairment and dementia. In this study, contemporary statistical methods were used to classify the clinical cases of cognitive impairment based on electroencephalograms (EEG). METHODS: An EEG database was established from seven different groups of subjects with cognitive impairment and dementia as well as healthy controls. A classifier was created for each possible pair of groups using statistical pattern recognition (SPR). RESULTS: A good-to-excellent separation was found when differentiating cases of degenerative disorders from controls, vascular disorders, and depression but this was less so when the likelihood of comorbidity was high. CONCLUSIONS: Using EEG with SPR seems to be a reliable method for diagnosing the causes of cognitive impairment and dementia, but comorbidity must be taken into account.

Validation of the Icelandic version of the Neuropsychiatric Inventory with Caregiver Distress (NPI-D).

BACKGROUND: Dementia is a complex and often debilitating illness, presenting with not only wide-ranging cognitive impairment but also neuropsychiatric challenges, which can have diverse consequences in quality of life for both patient and caregiver. AIM: Studying the validity and reliability of an Icelandic translation of the Neuropsychiatric Inventory with Caregiver Distress (NPI-D). METHODS: NPI-D was administered to 38 primary caregivers of dementia patients. The concurrent validity was explored by statistically comparing the NPI-D to the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Geriatric Depression Scale (GDS). Regarding caregiver distress, concurrent validity was established between NPI-D, BEHAVE-AD Global Rating and two other caregiver distress scales. RESULTS: Significant correlation was found when total score on the BEHAVE-AD was compared with total score on the NPI-D. All NPI-D subscales achieved significant correlation with the corresponding BEHAVE-AD subscales apart from the 'depression/dysphoria subscale'. This NPI-D subscale correlated however, significantly with the GDS depression scale, a frequent and well validated measure of depressive symptoms in the elderly population. Cronbach's alpha coefficient indicated a high degree of overall internal consistency among the items of the NPI-D. Interestingly, apathy was the most frequent neuropsychiatric disturbance and the only subscale that differed significantly between dementia severity levels. Finally, when studying caregiver distress, the NPI-D showed good concurrent validity with other measures of caregiver burden and distress. CONCLUSIONS: The results demonstrate an acceptable level of validity and reliability; therefore the Icelandic translation of the NPI-D is well suited for identifying neuropsychiatric symptoms in dementia and associated caregiver burden.

Phenotypic Displays of Cholinergic Enzymes Associate With Markers of Inflammation, Neurofibrillary Tangles, and Neurodegeneration in Pre- and Early Symptomatic Dementia Subjects.

Background: Cholinergic drugs are the most commonly used drugs for the treatment of Alzheimer's disease (AD). Therefore, a better understanding of the cholinergic system and its relation to both AD-related biomarkers and cognitive functions is of high importance. Objectives: To evaluate the relationships of cerebrospinal fluid (CSF) cholinergic enzymes with markers of amyloidosis, neurodegeneration, neurofibrillary tangles, inflammation and performance on verbal episodic memory in a memory clinic cohort. Methods: In this cross-sectional study, 46 cholinergic drug-free subjects (median age = 71, 54% female, median MMSE = 28) were recruited from an Icelandic memory clinic cohort targeting early stages of cognitive impairment. Enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was measured in CSF as well as levels of amyloid-ß1-42 (Aß42), phosphorylated tau (P-tau), total-tau (T-tau), neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B), and glial fibrillary acidic protein (GFAP). Verbal episodic memory was assessed with the Rey Auditory Verbal Learning (RAVLT) and Story tests. Results: No significant relationships were found between CSF Aß42 levels and AChE or BuChE activity (p > 0.05). In contrast, T-tau (r = 0.46, p = 0.001) and P-tau (r = 0.45, p = 0.002) levels correlated significantly with AChE activity. Although neurodegeneration markers T-tau and NFL did correlate with each other (r = 0.59, p < 0.001), NFL did not correlate with AChE (r = 0.25, p = 0.09) or BuChE (r = 0.27, p = 0.06). Inflammation markers S100B and YKL-40 both correlated significantly with AChE (S100B: r = 0.43, p = 0.003; YKL-40: r = 0.32, p = 0.03) and BuChE (S100B: r = 0.47, p < 0.001; YKL-40: r = 0.38, p = 0.009) activity. A weak correlation was detected between AChE activity and the composite score reflecting verbal episodic memory (r = -0.34, p = 0.02). LASSO regression analyses with a stability approach were performed for the selection of a set of measures best predicting cholinergic activity and verbal episodic memory score. S100B was the predictor with the highest model selection frequency for both AChE (68%) and BuChE (73%) activity. Age (91%) was the most reliable predictor for verbal episodic memory, with selection frequency of both cholinergic enzymes below 10%. Conclusions: Results indicate a relationship between higher activity of the ACh-degrading cholinergic enzymes with increased neurodegeneration, neurofibrillary tangles and inflammation in the stages of pre- and early symptomatic dementia, independent of CSF Aß42 levels.

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.

Cerebrospinal Fluid C18 Ceramide Associates with Markers of Alzheimer's Disease and Inflammation at the Pre- and Early Stages of Dementia.

BACKGROUND: Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer's disease (AD) pathology might be critical in developing effective treatments. OBJECTIVE: To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia. METHODS: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n = 34) or non-AD (n = 26) pathology profiles. Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory. RESULTS: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aß42: st.ß= -0.36, p = 0.007; T-tau: st.ß= 0.41, p = 0.005) and inflammatory marker S100B (st.ß= 0.51, p = 0.001) with C18 ceramide levels. CONCLUSION: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target.

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.

Evaluating differences in linkage disequilibrium between populations.

We propose two methods to evaluate the statistical significance of differences in linkage disequilibrium (LD) between populations, where LD is measured by the standardised parameter D'. The first method is based on bootstrapping individuals within populations in order to test LD differences for each pair of loci. Using this approach we propose a solution to the problem of testing multiple locus-pairs by means of a single test for the number of pairs that exhibit significant LD differences among populations. The second method provides the Bayesian posterior probability that one population has greater LD than the other for each locus pair. Both methods can handle genotypes with unknown phase, and are demonstrated using two data sets. For the purpose of demonstration, we apply the methods to two different sets of data from humans. First, we explore the issue of LD differences between reproductively isolated populations using a new data set of twelve Xq25 microsatellites, typed in four European populations. Second, we examine evidence for LD differences between Alzheimer cases and controls from the Icelandic population using 19 single nucleotide polymorphisms (SNPs) from a 97 kb region flanking the Apolipoprotein E (APOE) gene on chromosome 19.