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Alzheimer's disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards "energy metabolism" as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments., (© 2024. The Author(s).)

Objective: Type 2 diabetes and glucose metabolism have previously been linked to Alzheimer disease (AD). Yet, findings on the relation of glucose metabolism with amyloid-β and tau pathology later in life remain unclear., Research Design and Methods: We included 288 participants (mean age 43.1 years, SD 10.7, range 20-70 years) without dementia, from the Framingham Heart Study, who had available measures of glucose metabolism (i.e., one-time fasting plasma glucose and insulin) and positron emission tomography (PET) measures of amyloid-β and/or tau 14 years later. We performed linear regression analyses to test associations of plasma glucose (continuously and categorically; elevated defined as >100 mg/dL), plasma insulin, homeostatic model assessment for insulin resistance (HOMA-IR) with amyloid-β or tau load on PET. When significant, we explored whether age, sex, and APOE ε4 allele carriership (AD genetic risk) modified these associations., Results: Our findings indicated that elevated plasma glucose was associated with greater tau load 14 years later (B [95% CI] = 0.03 [0.01-0.05], P = 0.024 after false discovery rate [FDR] correction) but not amyloid-β. APOE ε4 carriership modified this association (B [95% CI] = -0.08 [-0.12 to -0.03], P = 0.001), indicating that the association was only present in APOE ε4 noncarriers (n = 225). Plasma insulin and HOMA-IR were not associated with amyloid-β or tau load 14 years later after FDR correction., Conclusions: Our findings suggest that glucose metabolism is associated with increased future tau but not amyloid-β load. This provides relevant knowledge for prevention strategies and prognostics to improve health care., (© 2024 by the American Diabetes Association.)

Conflicting evidence exists on the relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) biomarkers. Therefore, we conducted a random-effects meta-analysis to evaluate the correlation of glucose metabolism measures (glycated hemoglobin, fasting blood glucose, insulin resistance indices) and DM status with AD biomarkers of amyloid-β and tau measured by positron emission tomography or cerebrospinal fluid. We selected 37 studies from PubMed and Embase, including 11,694 individuals. More impaired glucose metabolism and DM status were associated with higher tau biomarkers (r=0.11[0.03-0.18], p=0.008; I2=68%), but were not associated with amyloid-β biomarkers (r=-0.06[-0.13-0.01], p=0.08; I 2 =81%). Meta-regression revealed that glucose metabolism and DM were specifically associated with tau biomarkers in population settings (p=0.001). Furthermore, more impaired glucose metabolism and DM status were associated with lower amyloid-β biomarkers in memory clinic settings (p=0.004), and in studies with a higher prevalence of dementia (p<0.001) or lower cognitive scores (p=0.04). These findings indicate that DM is associated with biomarkers of tau but not with amyloid-β. This knowledge is valuable for improving dementia and DM diagnostics and treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alzheimer's disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline., Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population., Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ 42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions., Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ - 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions., Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 – The authors. Published by IOS Press.)

Clinical and genomic studies have shown an overlap between neuropsychiatric disorders and insulin resistance (IR)-related somatic conditions, including obesity, type 2 diabetes, and cardiovascular diseases. Impaired cognition is often observed among neuropsychiatric disorders, where multiple cognitive domains may be affected. In this review, we aimed to summarise previous evidence on the relationship between IR-related diseases/traits and cognitive performance in the large UK Biobank study cohort. Electronic searches were conducted on PubMed, Scopus, and Web of Science until April 2022. Eighteen articles met the inclusion criteria and were qualitatively reviewed. Overall, there is substantial evidence for an association between IR-related cardio-metabolic diseases/traits and worse performance on various cognitive domains, which is largely independent of possible confoundings. The most consistent findings referred to IR-related associations with poorer verbal and numerical reasoning ability, as well as slower processing speed. The observed associations might be mediated by alterations in immune-inflammation, brain integrity/connectivity, and/or comorbid somatic or psychiatric diseases/traits. Our findings provide impetus for further research into the underlying neurobiology and possible new therapeutic targets., Competing Interests: Declarations of interest AS is or has been consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. BF discloses having received educational speaking fees from Medice GmbH. CF was a speaker for Janssen. GP is director of Drug Target ID (DTID), Ltd. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain "insulinopathies" were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (r g  = -0.315, p = 3.9 × 10 -8 ), OCD and obesity (r g  = -0.379, p = 3.4 × 10 -5 ), and OCD and T2DM (r g  = -0.172, p = 3 × 10 -4 ). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10 -4 ). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10 -4 ). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain., (© 2022. The Author(s).)

Background: The relation between vascular risk factors (VRFs) and Alzheimer's disease (AD) is important due to possible pathophysiological association., Objective: To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context., Methods: We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site., Results: We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aβ42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition., Conclusion: VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia.

Background . Sleep is important for consolidation of motor learning, but brain injury may affect sleep continuity and therefore rehabilitation outcomes. Objective . This study aims to assess the relationship between sleep quality and motor recovery in brain injury patients receiving inpatient rehabilitation. Methods . Fifty-nine patients with brain injury were recruited from 2 specialist inpatient rehabilitation units. Sleep quality was assessed (up to 3 times) objectively using actigraphy (7 nights) and subjectively using the Sleep Condition Indicator. Motor outcome assessments included Action Research Arm test (upper limb function), Fugl-Meyer Assessment (motor impairment), and the Rivermead Mobility Index. The Functional Independence Measure (FIM) was assessed at admission and discharge by the clinical team. Fifty-five age- and gender-matched healthy controls completed one assessment. Results . Inpatients demonstrated lower self-reported sleep quality ( P < .001) and more fragmented sleep ( P < .001) than controls. For inpatients, sleep fragmentation explained significant additional variance in motor outcomes, over and above that explained by admission FIM score ( P < .017), such that more disrupted sleep was associated with poorer motor outcomes. Using stepwise linear regression, sleep fragmentation was the only variable found to explain variance in rate of change in FIM ( R 2 adj = 0.12, P = .027), whereby more disrupted sleep was associated with slower recovery. Conclusions . Inpatients with brain injury demonstrate impaired sleep quality, and this is associated with poorer motor outcomes and slower functional recovery. Further investigation is needed to determine how sleep quality can be improved and whether this affects outcome.