One of the major causative genes involved in Frontotemporal dementia (FTD) is Granulin (GRN), encoding for Progranulin (PGRN). GRN mutation carriers show a substantial heterogeneity with high variability in age at onset and pathological presentation, even within the same family or identical mutations, suggesting the presence of additional genetic factors. Single nucleotide polymorphisms in the Transmembrane protein 106B (TMEM106B) locus were identified as a genetic risk-associated factor for FTD. The top variant identified was the non-coding rs1990622, with the major allele (T) associated with an increased risk to develop FTD, while subjects with the minor allele (C) were less likely to develop disease, suggesting a protective effect. In this study, we investigate in a large Italian cohort of GRN mutation carriers, how the coding variant TMEM106B-rs3173615, in linkage disequilibrium with rs1990622, modulates age at onset, survival, and PGRN levels, including, up to date, the highest sample size of homozygous protective allele carriers. Genetic screening for TMEM106B-rs3173615 was performed on a total of 187 GRN mutation carriers, comprising 131 FTD patients and 56 pre-symptomatic subjects. Individuals with the protective genotype (GG) had a risk of FTD onset reduced by 80%, with a median age at onset of 77 years compared to a median age at onset of 63 years for individuals without the protective genotype. TMEM106B-rs3173615 acts as a genetic modifier of age at onset in the presence of GRN mutations and could be considered in clinical practice to optimize risk stratification for FTD.

Monogenic forms of Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) represent the two principal neurodegenerative disorders leading to early-onset dementia, primarily linked to mutations in key AD- and FTD-associated genes. The marked heterogeneity in age at onset and penetrance among carriers of pathogenic mutations suggests that monogenic variants act within a broader polygenic background. The combined impact of AD- and FTD-related genetic variation on disease incidence in monogenic forms remains largely unexplored. Herein, we investigate gene-gene interaction patterns in monogenic AD and FTD, with a focus on genetic variability in key AD (APP, PSEN1, PSEN2) and FTD (MAPT, GRN, C9orf72)-associated genes and their association with cumulative disease incidence. Within the GARDENIA Consortium, we studied 426 individuals from Italian pedigrees, including patients (n = 319) and presymptomatic (n = 107) carriers of causative variants in APP (n = 39), PSEN1 (n = 71), PSEN2 (n = 13), MAPT (n = 29), GRN (n = 188), and C9orf72 (n = 86). Age at symptoms onset, age at last follow-up and sex were recorded. Whole exome sequencing was performed, focusing on non-causative variants (n = 64) in the key AD (APP, PSEN1, PSEN2) and FTD genes (MAPT, GRN, C9orf72). Weighted genetic burden scores were derived using Fine-Gray competing risk models to estimate variant-specific effects on cumulative AD and FTD incidence, accounting for mutually exclusive outcomes and family clustering. Model fit was evaluated using Akaike Information Criterion. Higher AD-risk-weighted burden scores in AD-related genes were associated with a significantly increased cumulative incidence of AD, while higher FTD-risk-weighted scores in FTD-related genes showed a trend toward association with increased cumulative incidence of FTD. A significant interaction between burden scores was observed. AD and FTD burden scores showed a negative interaction for AD (~79% attenuation) but a modest synergistic effect for FTD (~6% increase). These findings could imply context-dependent pleiotropy rather than simple additive genetic effects. Our study suggests that even in carriers oh highly penetrant AD or FTD causative variants, genetic background could substantially modulate cumulative disease incidence. Integrating polygenic information with monogenic status may improve prognostic stratification and inform precision approaches in dementia research and clinical trials.

Recent studies have highlighted the significant role of ADAM17/TACE (encoded by ADAM17/TACE) in the pathogenesis of Alzheimer's disease (AD). Yet, the relationship between ADAM17/TACE gene polymorphisms and AD was less studied. This study aims to analyse the relationship of ADAM17/TACE gene polymorphism with the risk, age of onset, neuropsychiatric manifestations, cognitive impairment, and medial temporal lobe atrophy in sporadic AD (sAD). This case-control association study was conducted in an Italian cohort consisting of 297 sAD patients and 316 controls. Seven tag-SNPs were selected and genotyped. Linear and logistic regression analyses were used to assess the association between parameters of interest and the genetic variability of ADAM17/TACE. After Bonferroni correction, our findings underscore the complexity of genetic influences of ADAM17/TACE on sAD, particularly the roles of rs12692385 in modulating sAD risk and the performance on the Rey Auditory Verbal Learning Test - delayed recall. In addition, rs13008101 significantly affected the performance on the Clock Drawing Test. Moreover, rs10179642 and rs35280016 were associated with a higher frequency and severity of hallucinations and agitation/aggression, respectively. These results contribute to a deeper understanding of the genetic underpinnings of sAD and may be useful for examining the risk of developing sAD, assessing cognitive deficits, neuropsychiatric symptoms, and informing new therapeutic strategies and future research targeting ADAM17/TACE.

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.

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.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR=2.16, P=0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

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.

Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., proNGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. In addition to pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

When treating structured health-system-related knowledge, the establishment of an over-dimension to guide the separation of entities becomes essential. This is consistent with the information retrieval processes aimed at defining a coherent and dynamic way – meaning by that the multilevel integration of medical textual inputs and computational interpretation – to replicate the flow of data inserted in the clinical records. This study presents a strategic technique to categorize the clinical entities related to patients affected by neurodegenerative diseases. After a pre-processing range of tasks over paper-based and handwritten medical records, and through subsequent machine learning and, more specifically, natural language processing operations over the digitized clinical records, the research activity provides a semantic support system to detect the main symptoms and locate them in the appropriate clusters. Finally, the supervision of the experts proved to be essential in the correspondence sequence configuration aimed at providing an automatic reading of the clinical records according to the clinical data that is needed to predict the detection of neurodegenerative disease symptoms.

Older adults with dementia present an increased risk of mortality due to seasonal influenza. Despite concerning evidence, the influenza vaccination program has been unsuccessful, with low rates of uptake in Italian people ≥65 years. In addition, being vaccinated does not eliminate the risk of contracting a virus, especially by coming into close contact with other possibly unvaccinated people, such as family caregivers in the home environment. Therefore, the refusal of family caregivers to get vaccinated for seasonal influenza could have dire consequences for their relatives with dementia. The aims of this study were to investigate the predictive role of the Theory of Planned Behavior model (TPB) and past vaccination behavior on the intention to receive a seasonal influenza vaccine among family caregivers of people with dementia. Data were collected from seventy-one respondents during July–September 2021 using a cross-sectional web-based survey design. Results of hierarchical binary logistic regression showed that TPB (i.e., attitudes towards vaccination, subjective norms, and perceived behavioral control) explained 51.6% of the variance in intention to receive a seasonal influenza vaccine; past vaccination behavior increased this to 58.8%. In conclusion, past vaccination behavior and the theory of planned behavior variables effectively predict influenza vaccine willingness of family caregivers of people with dementia and should be targeted in vaccination campaigns.

Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., pro-NGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. Besides pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. Two major forms of the disease exist: sporadic - the causes of which have not yet been fully understood - and familial - inherited within families from generation to generation, with a clear autosomal dominant transmission of mutations in Presenilin 1 (PSEN1), 2 (PSEN2) or Amyloid Precursors Protein (APP) genes. The main hallmark of AD consists of extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein. An ever-growing body of research supports the viral infectious hypothesis of sporadic forms of AD. In particular, it has been shown that several herpes viruses (i.e., HHV-1, HHV-2, HHV-3 or varicella zoster virus, HHV-4 or Epstein Barr virus, HHV-5 or cytomegalovirus, HHV-6A and B, HHV-7), flaviviruses (i.e., Zika virus, Dengue fever virus, Japanese encephalitis virus) as well as Human Immunodeficiency Virus (HIV), hepatitis viruses (HAV, HBV, HCV, HDV, HEV), SARS-CoV2, Ljungan virus (LV), Influenza A virus and Borna disease virus, could increase the risk of AD. Here, we summarized and discussed these results. Based on these findings, significant issues for future studies are also put forward.

Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer's disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.

BACKGROUND:Immunosenescence is a complex process characterized by an age-related remodelling of immune system. The prominent effects of the immunosenescence process is the thymic involution and, consequently, the decreased numbers and functions of T cells. Since thymic involution results in a collapse of the T-cell receptor (TCR) repertoire, a reliable biomarker of its activity is represented by the quantification of signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels. Although it is reasonable to think that thymic function could play a crucial role on elderly survival, only a few studies investigated the relationship between an accurate measurement of human thymic function and survival at old ages.METHODS AND FINDINGS:By quantifying the amount sjTRECs by real-time polymerase chain reaction (PCR), the decrease in thymic output in 241 nursing home residents from Calabria (Southern Italy) was evaluated to investigate the relationship between thymic function and survival at old ages. We found that low sjTREC levels were associated with a significant increased risk of mortality at older ages. Nursing home residents with lower sjTREC exhibit a near 2-fold increase in mortality risk compared to those with sjTREC levels in a normal range.CONCLUSION:Thymic function failure is an independent predictor of mortality among elderly nursing home residents. sjTREC represents a biomarker of effective ageing as its blood levels could anticipate individuals at high risk of negative health outcomes. The identification of these subjects is crucial to manage older people's immune function and resilience, such as, for instance, to plan more efficient vaccinal campaigns in older populations.

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important "red flag" in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

People with dementia have an increased risk of contracting severe forms of COVID-19. Although in worldwide vaccination programs priority has been given to older people, having taken the vaccine does not totally eliminate the risk of contracting COVID-19 when one is in close contact with unvaccinated people. Thus, family caregivers’ choices to remain unvaccinated against COVID-19 could have potentially lethal consequences for their relatives. To our knowledge, this study represents the first attempt within the international literature to analyze COVID-19 vaccine uptake among family caregivers of people with dementia and to identify some of the psychological factors, related to COVID-19 and vaccination behavior, that could facilitate or hinder vaccine uptake. Contact information for family caregivers was obtained from five different centers and associations throughout the Italian territory. Data were collected from 179 respondents during July-September 2021 using a cross-sectional web-based survey design. More than 75% of the respondents indicated that had been vaccinated against COVID-19 and reported receiving vaccine information mainly from print or electronic newspapers (86%), followed by TV (81%) and families (64.2%). In multivariable logistic regression analyses, worries about unforeseen future effects was significantly related to COVID-19 vaccine uptake, indicating that family caregivers concerned about potential side effects of vaccines were less likely to have been vaccinated against COVID-19 (OR = 0.60, CI = 0.40-0.89). Openness to experience was also related to COVID-19 vaccine uptake, with family caregivers higher on this trait being less likely to have been vaccinated against COVID-19 (OR = 0.83, CI = 0.71-0.98). Implications for targeting of vaccine-related messages are discussed.