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Alzheimer's disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of chromosome Y (LOY) in leukocytes is strongly associated with AD. We studied here DNA methylation and RNA expression in sorted monocytes and granulocytes with and without LOY from male AD patients. Through multi-omic analysis, we identified new candidate genes along with those previously associated with AD. Global analyses of DNA methylation in samples with LOY vs. normal state showed that hypomethylation dominated both in granulocytes and monocytes. Our findings highlight LOY-related differences in DNA methylation that occur in gene regulatory regions. Specifically, we observed alterations in key genes involved in leukocyte differentiation: FLI1, involved in early hematopoiesis; RUNX1, essential for blood cell development; RARA, regulating gene expression in response to retinoic acid; CANX, crucial for protein folding; CEBPB, a transcription factor important for immune responses; and MYADM, implicated in cell adhesion and migration. Moreover, protein-protein interaction analysis in granulocytes identified that products of two of these genes, CANX and CEBPB, are key hub proteins. This research underscores the potential of multi-omic approach in pure hematopoietic cell populations to uncover the molecular underpinnings of AD. Finally, our results link previous analysis showing impact of LOY on leukocyte differentiation, LOY-associated transcriptional dysregulation and GWAS studies of LOY.

Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events with implications for aging and Alzheimer disease (AD). LOY is linked to increased AD risk, whereas CHIP may be protective, and their co-occurrence remains unclear. We conducted whole-exome sequencing of CD4+ T cells, NK cells, and myeloid cells from AD patients and controls exhibiting LOY or retention of Y chromosome. We identified 39 variants in known myeloid and lymphoid driver genes, with up to 35% co-occurring with LOY in the same clone. In addition, we detected 192 unknown drivers of clonal hematopoiesis, enriched in AD-LOY individuals (odds ratio 4.8, P = 0.041). In myeloid cells, total driver burden correlated with LOY (rho = 0.52, P = 0.00041). These results indicate that LOY is a primary driver of clonal hematopoiesis in AD, seeding myeloid clones that accumulate unknown driver variants, whereas most canonical CHIP mutations arise independently. Our study reveals distinct, partially overlapping clonal architectures for LOY and CHIP and highlights LOY-driven myeloid expansion as a contributor to AD pathogenesis.

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics. 

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

Background: Depression and dementia are known to be associated. The identification of characteristics distinguishing depression prodromal to dementia from other depressive symptoms would be of value for early identification of dementia. The study of risk factors for depressive symptoms prodromal to dementia could improve preventive care and provide clues to the causes of dementia.

Method: Dementia-free 82-year-old participants were stratified into groups that did (n = 126) and did not (n = 378) subsequently develop dementia. Examinations took place from 2003 to 2005 and follow-up ended 1 January 2015. Their baseline characteristics and depressive symptoms, measured using the 15-item Geriatric Depression Scale (GDS-15), were compared. Multivariate regression analyses were performed for the two groups separately, with the total GDS-15 score as the dependent variable.

Results: The groups did not differ significantly in answers to any of the GDS-15 questions, or mean +/- SD score, which was 2.4 +/- 2.5 among those who developed dementia and 2.1 +/- 2.3 among those who did not. (p = 0.33). Stroke before the age of 82 years and the inability to use stairs had significant impacts on the GDS-15 scores in both groups. For those who did not develop dementia, age, dependence in activities of daily living, and cancer also had significant impacts. Cancer had opposite associations with depressive symptoms in the two groups.

Conclusions: No difference was found in depressive symptoms preceding and not preceding dementia using the GDS-15. The results suggest that risk factors for depressive symptoms may differ depending on whether they precede dementia.

Background: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD). Objective: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to antiherpesvirus treatment and potential APOE epsilon 4 carriership interaction. Methods: This studywas conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied. Results: CumulativeADand all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE epsilon 4 or anti-CMV IgG. Similar results were obtained for HSV-1. Conclusions: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) during rapid eye movement (REM) sleep is often characterized with more frequent and lengthy breathing events and greater oxygen desaturation than during other sleep stages. Current evidence suggests an association between OSA and cognitive decline, however whether OSA during REM sleep plays a vital role in this link is understudied.

METHODS: A cross-sectional sample of 728 men and women (aged 59.1 ± 11.3 years) underwent a full night polysomnography for determining apnea-hypopnea index (AHI) and sleep stages. Trail Making Test (TMT) part A and B were conducted during the following day for assessing participants' cognitive function. Linear regression analyses were performed to test the possible association between AHI and AHI during REM sleep with TMT-A and B results. Similar analyses were carried out in a subsample involving participants aged ≥60 years with ≥30 min of REM sleep (n = 356).

RESULTS: Despite a slight difference in TMT-B between participants with and without OSA (AHI ≥5 vs AHI <5, β-coefficient: 4.83, 95 % CI: [-9.44, -0.22], P = 0.040), no other association between AHI or REM-AHI and TMT results were found in the full sample. In older participants (aged ≥60 years), a REM-AHI ≥5 events/hour was associated with longer time taken to finish TMT-A (vs REM-AHI <5 events/hour, 3.93, [0.96, 6.90], P = 0.010). There was no association between REM-AHI and time taken to finish TMT-B in older participants.

CONCLUSIONS: The results indicate that OSA during REM sleep may be of particular concern for attention-related cognitive function in older adults.

Bsckground and Purpose: Differentiating idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative disorders such as progressive supranuclear palsy (PSP), Multiple System Atrophy-parkinsonian type (MSA-P), and vascular dementia (VaD) is challenging due to overlapping clinical and neuroimaging findings. This study assesses if quantitative brain stem and cerebellum metrics can aid in this differentiation.

Methods: We retrospectively compared the sagittal midbrain area, midbrain to pons ratio, MR parkinsonism index (MRPI), and cerebellar atrophy in 30 PSP patients, 31 iNPH patients, 27 MSA-P patients, 32 VaD patients, and 25 healthy controls. Statistical analyses determined group differences, sensitivity, specificity, and the area under the receiver operating characteristic curves.

Results: There was an overlap in midbrain morphology between PSP and iNPH, as assessed with MRPI, midbrain to pons ratio, and midbrain area. A cutoff value of MRPI > 13 exhibited 84% specificity in distinguishing PSP from iNPH and 100% in discriminating PSP from all other conditions. A cutoff value of midbrain to pons ratio at <0.15 yielded 95% specificity for differentiating PSP from iNPH and 100% from all other conditions. A cutoff value of midbrain area at <87 mm² exhibited 97% specificity for differentiating PSP from iNPH and 100% from all other conditions. All measures showed low sensitivity. Cerebellar atrophy did not differ significantly among groups.

Conclusion: Our study questions MRPI's diagnostic performance in distinguishing PSP from iNPH. Simpler indices such as midbrain to pons ratio and midbrain area showed similar or better accuracy. However, all these indices displayed low sensitivity despite significant differences among PSP, MSA-P, and VaD.

Computerized cognitive tests have the potential to cost-effectively detect and monitor cognitive impairments and thereby facilitate treatment for these conditions. However, relatively few of these tests have been validated in a variety of populations. Brain on Track, a self-administered web-based test, has previously been shown to have a good ability to differentiate between healthy individuals and patients with cognitive impairment in Portuguese populations. The objective of this study was to validate the differential ability and evaluate the usability of Brain on Track in a Swedish memory clinic setting. Brain on Track was administered to 30 patients with mild cognitive impairment/mild dementia and 30 healthy controls, all scheduled to perform the test from home after one week and after three months. To evaluate the usability, the patient group was interviewed after completion of the testing phase. Patients scored lower than healthy controls at both the first (median score 42.4 vs 54.1, p<0.001) and the second test (median score 42.3 vs 55.0, p<0.001). The test-retest intra-class correlation was 0.87. A multiple logistic regression model accounting for effects of age, gender and education rendered an ability of Brain on Track to differentiate between the groups with an area under the receiver operation characteristics curve of 0.90 for the first and 0.88 for the second test. In the subjective evaluation, nine patients left positive comments, nine were negative whereas five left mixed comments regarding the test experience. Sixty percent of patients had received help from relatives to log on to the platform. In conclusion, Brain on Track performed well in differentiating healthy controls from patients with cognitive impairment and showed a high test-retest reliability, on par with results from previous studies. However, the substantial proportion of patients needing help to log in could to some extent limit an independent use of the platform.