Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.

Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research.

Background and purpose:  Mitochondrial DNA (mtDNA) inherited variability (haplogroup/sub‐haplogroup) is currently emerging as not being neutral with respect to several complex traits like neurodegenerative diseases. Here we investigated the association of European mtDNA haplogroups/sub‐haplogroups with frontotemporal dementia (FTD).Method and Results:  A case‐control study was carried out on 114 patients with FTD (68 sporadic and 46 familial) and 180 controls, matched for age, gender and ethnicity. No association was found.Conclusions:  European mtDNA haplogroups/sub‐haplogroups are unlikely to play a major role in the risk of developing the disease.

DNA methylation is a critical epigenetic mechanism involved in numerous physiological processes. Alterations in DNA methylation patterns are associated with various brain disorders, including dementias such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Investigating these alterations is essential for understanding the pathogenesis and progression of these disorders. Among the various methods for detecting DNA methylation, DNA sequencing is one of the most widely employed. Specifically, two main sequencing approaches are commonly used for DNA methylation analysis: bisulfite sequencing and single-molecule long-read sequencing. In this review, we compared the performances of CpG methylation detection obtained using two popular sequencing platforms, Illumina for bisulfite sequencing and Oxford Nanopore (ON) for long-read sequencing. Our comparison considers several factors, including accuracy, efficiency, genomic regions, costs, wet-lab protocols, and bioinformatics pipelines. We provide insights into the strengths and limitations of both methods with a particular focus on their application in research on AD and FTD.

Nowadays, scientists are making efforts to elucidate the mechanisms involved in the phenotypic changes underlying the aging process in order to develop favorable therapeutical interventions. Epigenetic modifications, in particular DNA methylation, play a crucial role in the aging process, and this parameter has been used to set epigenetic clocks, algorithms that predict an individual’s biological age based on a defined set of CpGs. In this review, we focus on the most recent literature to discuss the use of epigenetic clocks in the context of cognitive decline and dysregulation of Alzheimer’s disease (AD)-related gene expression. We have summarized all published scientific papers in which epigenetic clocks have been applied to measure age acceleration in blood and brain specimens from patients affected with AD. Progressive age acceleration, consistent with a specific DNA methylation signature, was observed in patients affected by AD, and it was correlated with the onset of complex diseases, mitochondrial alterations, dementia and cognitive decline, even in the early stages of these conditions. The use of epigenetic clocks might be a valuable biomarker to enable an earlier identification of ideal measures to reverse modifications caused by aging and to mitigate multiple aspects of disease/aging mechanisms.