Journal of Alzheimer's Disease - Volume 98, issue 4

Authors: Robinson, Andrew C. | Bin Rizwan, Tawfique | Davidson, Yvonne S. | Minshull, James | Tinkler, Phillip | Payton, Antony | Mann, David M.A. | Roncaroli, Federico

Article Type: Research Article

Abstract: Background: While mid-life hypertension represents a risk factor for the development of Alzheimer’s disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use …of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria—even after controlling for sex, level of education and presence of APOE ɛ 4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow. Show more

Keywords: Alzheimer’s disease, dementia, hypertension, neuropathology

DOI: 10.3233/JAD-231429

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1457-1466, 2024

Authors: Hojjati, Seyed Hani | Chiang, Gloria C. | Butler, Tracy A. | de Leon, Mony | Gupta, Ajay | Li, Yi | Sabuncu, Mert R. | Feiz, Farnia | Nayak, Siddharth | Shteingart, Jacob | Ozoria, Sindy | Gholipour Picha, Saman | Stern, Yaakov | Luchsinger, José A. | Devanand, Davangere P. | Razlighi, Qolamreza R.

Article Type: Research Article

Abstract: Background: Histopathologic studies of Alzheimer’s disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition. Methods: Using multiple linear …regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant. Conclusions: The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, PET, remote association, tau

DOI: 10.3233/JAD-231362

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1467-1482, 2024

Authors: Galankin, Timofey L. | Bespalov, Anton Y. | Moebius, Hans Y.

Article Type: Research Article

Abstract: Background: The term Behavioral and Psychological Symptoms of Dementia (BPSD) covers a group of phenomenologically and medically distinct symptoms that rarely occur in isolation. Their therapy represents a major unmet medical need across dementias of different types, including Alzheimer’s disease. Understanding of the symptom occurrence and their clusterization can inform clinical drug development and use of existing and future BPSD treatments. Objective: The primary aim of the present study was to investigate the ability of a commonly used principal component analysis to identify BPSD patterns as assessed by Neuropsychiatric Inventory (NPI). Methods: NPI scores from the …Aging, Demographics, and Memory Study (ADAMS) were used to characterize reported occurrence of individual symptoms and their combinations. Based on this information, we have designed and conducted a simulation experiment to compare Principal Component analysis (PCA) and zero-inflated PCA (ZI PCA) by their ability to reveal true symptom associations. Results: Exploratory analysis of the ADAMS database revealed overlapping multivariate distributions of NPI symptom scores. Simulation experiments have indicated that PCA and ZI PCA cannot handle data with multiple overlapping patterns. Although the principal component analysis approach is commonly applied to NPI scores, it is at risk to reveal BPSD clusters that are a statistical phenomenon rather than symptom associations occurring in clinical practice. Conclusions: We recommend the thorough characterization of multivariate distributions before subjecting any dataset to Principal Component Analysis. Show more

Keywords: Alzheimer’s disease, dementia, neurobehavioral signs and symptoms, Neuropsychiatric inventory, principal component analysis

DOI: 10.3233/JAD-231008

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1483-1491, 2024

Authors: Wen, Jiaqi | Hao, Xiwa | Jia, Yanhong | Wang, Baojun | Pang, Jiangxia | Liang, Furu

Article Type: Research Article

Abstract: Background: Lipids have a significant impact on the development and functioning of the nervous system, but the sex differences between the association of LDL/HDL, which reflects lipid metabolic status, and cognitive impairment remains unclear. Objective: We aimed to determine if there were sex differences between the association of LDL/HDL and cognitive function in US older adults. Methods: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2011–2012 and 2013–2014 cycles. The main outcome was poor cognitive performance defined by the Digit Symbol Substitution Test (DSST) <  34 based …on published literature. Results: A total of 1,225 participants were included in the study, with a cognitive impairment incidence of 25.6% (314/1,225). Multivariate regression models demonstrated a significant association between cognitive decline and each 1-unit increase in LDL/HDL, after adjusting for all covariates (adjusted odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.11–1.67). Furthermore, subgroup analysis revealed an interaction between LDL/HDL and cognitive impairment in sex subgroups. Conclusions: LDL/HDL was associated with cognitive impairment in the US older adult population in adjusted models, although the significance of this association was not observed in females. Show more

Keywords: Alzheimer’s disease, cognition, LDL/HDL cholesterol ratio, National Health and Nutrition Examination Survey (NHANES), older adults, sex differences

DOI: 10.3233/JAD-231195

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1493-1502, 2024

Authors: Janbek, Janet | Laursen, Thomas Munk | Frimodt-Møller, Niels | Magyari, Melinda | Haas, Jürgen G. | Lathe, Richard | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype. Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms. Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016–2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were …those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC). Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20–1.27) and 1.70 for NMC cases (1.62–1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant. Conclusions: Cases with vascular dementia and not Alzheimer’s disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term. Show more

Keywords: Alzheimer’s disease, autoimmune disease, epidemiology, immunosenescence, infection, population-based, reverse causality, vascular dementia

DOI: 10.3233/JAD-231349

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1503-1514, 2024

Authors: Moreno-Rodriguez, Marta | Perez, Sylvia E. | Martinez-Gardeazabal, Jonatan | Manuel, Ivan | Malek-Ahmadi, Michael | Rodriguez-Puertas, Rafael | Mufson, Elliott J.

Article Type: Research Article

Abstract: Background: Although sporadic Alzheimer’s disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1 ), sphingosine 1-phosphate 1 …(S1P1 ), and muscarinic M2 /M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2 /M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia. Show more

Keywords: Alzheimer’s disease, autoradiography, cholinergic, lipidomic, MALDI-MSI, mild cognitive impairment, muscarinic receptor

DOI: 10.3233/JAD-231485

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1515-1532, 2024

Authors: Costa, Cinzia | Nardi Cesarini, Elena | Eusebi, Paolo | Franchini, David | Casucci, Paola | De Giorgi, Marcello F. | Calvello, Carmen | Paolini Paoletti, Federico | Romoli, Michele | Parnetti, Lucilla

Article Type: Research Article

Abstract: Background: Dementia is prevalent among the elderly, also representing a risk for seizures/epilepsy. Estimations of epilepsy risk in dementia patients are not widely available. Objective: Our research aims to ascertain the incidence of epilepsy and its associated risk factors in subjects with dementia in the Umbria region, based on data from healthcare databases. Methods: In this retrospective study based on the healthcare administrative database of Umbria, we identified all patients diagnosed with dementia from 2013 to 2017, based on ICD-9-CM codes. For epilepsy ascertainment, we used a validated algorithm that required an EEG …and the prescription of one or more anti-seizure medications post-dementia diagnosis. A case-control analysis was conducted, matching five non-dementia subjects by gender and age to each dementia patient. Cox proportional hazards models were then utilized in the analysis. Results: We identified 7,314 dementia cases, also including 35,280 age- and sex-matched control subjects. Out of patients with dementia, 148 individuals (2.02%) were diagnosed with epilepsy. We observed a progressive increase in the cumulative incidence of seizures over time, registering 1.45% in the first year following the diagnosis, and rising to 1.96% after three years. Analysis using Cox regression revealed a significant association between the development of epilepsy and dementia (HR = 4.58, 95% CI = 3.67–5.72). Additional risk factors were male gender (HR = 1.35, 95% CI = 1.07–1.69) and a younger age at dementia onset (HR = 1.03, 95% CI=1.02-1.04). Conclusions: Dementia increases epilepsy risk, especially with early onset and male gender. Clinicians should have a low threshold to suspect seizures in dementia cases. Show more

Keywords: Administrative databases, Alzheimer’s disease, antiseizure medications, dementia, epilepsy

DOI: 10.3233/JAD-231309

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1533-1542, 2024

Article Type: Correction

DOI: 10.3233/JAD-249007

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1543-1546, 2024