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The Role of Genetics in Dementia
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The Role of Genetics in Dementia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 10411

Special Issue Editor

Dr. Ioannis Liampas

E-Mail Website
Guest Editor
Department of Neurology, Faculty of Medicine, University of Thessaly, Volos, Greece
Interests: dementia; Alzheimer’s disease; cognitive impairment; cognitive decline; neuropsychiatric manifestations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, neurogenetics have accumulated more and more attention and have revolutionized the understanding of multiple formerly enigmatic neurological disorders. With the increased availability and affordability of genetic testing, precision medicine has become a growingly popular concept. Among others, genetic testing and personalized medicine are expected to domineer the future of dementia care and upcoming advancements in pharmacological treatments. This collection aims to cover the most recent developments in the field of genetics in dementia and cognitive impairment. Studies on the genetic architecture of Alzheimer’s disease and other dementia entities, on the contribution of genetics to cognitive impairment and decline, on epigenetic variation and gene-environment interactions, are welcome. Any types of manuscripts supported by the Journal—original research articles, brief reports, communications, case reports, narrative reviews, systematic reviews, and meta-analyses—pertaining to these topic are welcome.

Dr. Ioannis Liampas
Guest Editor

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Keywords

  • dementia
  • Alzheimer’s disease
  • mild cognitive impairment
  • cognitive decline
  • cognition
  • neurogenetics
  • epigenetics
  • gene-environment interactions

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Published Papers (5 papers)

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Review

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27 pages, 707 KiB  
Review
Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer’s Disease
by Efthalia Angelopoulou, Christos Koros, Alexandros Hatzimanolis, Leonidas Stefanis, Nikolaos Scarmeas and Sokratis G. Papageorgiou
Int. J. Mol. Sci. 2024, 25(5), 2645; https://doi.org/10.3390/ijms25052645 - 24 Feb 2024
Cited by 4 | Viewed by 2595
Abstract
The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer’s disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents [...] Read more.
The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer’s disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline. Full article
(This article belongs to the Special Issue The Role of Genetics in Dementia)
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13 pages, 315 KiB  
Review
Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review
by Ioannis Liampas, Panagiota Kyriakoulopoulou, Vasileios Siokas, Eirini Tsiamaki, Polyxeni Stamati, Zinovia Kefalopoulou, Elisabeth Chroni and Efthimios Dardiotis
Int. J. Mol. Sci. 2024, 25(3), 1795; https://doi.org/10.3390/ijms25031795 - 1 Feb 2024
Cited by 3 | Viewed by 1923
Abstract
In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer’s disease—AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, [...] Read more.
In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer’s disease—AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD—APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive–neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research. Full article
(This article belongs to the Special Issue The Role of Genetics in Dementia)

Other

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11 pages, 809 KiB  
Brief Report
Mutational Landscape of Alzheimer’s Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy
by Claudia Saraceno, Lorenzo Pagano, Valentina Laganà, Andrea Geviti, Silvia Bagnoli, Assunta Ingannato, Salvatore Mazzeo, Antonio Longobardi, Silvia Fostinelli, Sonia Bellini, Alberto Montesanto, Giuliano Binetti, Raffaele Maletta, Benedetta Nacmias and Roberta Ghidoni
Int. J. Mol. Sci. 2024, 25(13), 7035; https://doi.org/10.3390/ijms25137035 - 27 Jun 2024
Viewed by 2071
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Role of Genetics in Dementia)
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10 pages, 2594 KiB  
Case Report
PSEN1 His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine–Tryptophan Interactions in TM-4 Stability
by Eva Bagyinszky, Minju Kim, Young Ho Park, Seong Soo A. An and SangYun Kim
Int. J. Mol. Sci. 2024, 25(1), 116; https://doi.org/10.3390/ijms25010116 - 21 Dec 2023
Cited by 1 | Viewed by 1086
Abstract
A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal [...] Read more.
A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer’s disease (EOAD). PSEN1 His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aβ) oligomerization tendency with blood. The PSEN1 His214 amino acid position plays a significant role in the gamma–secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid–extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma–secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aβ was reflected in the increased Aβ oligomerization tendency and the accumulations of Aβ in the brain from amyloid-PET, leading to EOAD. Full article
(This article belongs to the Special Issue The Role of Genetics in Dementia)
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14 pages, 2282 KiB  
Case Report
Patient with PSEN1 Glu318Gly and Other Possible Disease Risk Mutations, Diagnosed with Early Onset Alzheimer’s Disease
by YoungSoon Yang, Eva Bagyinszky and Seong Soo A. An
Int. J. Mol. Sci. 2023, 24(20), 15461; https://doi.org/10.3390/ijms242015461 - 23 Oct 2023
Cited by 2 | Viewed by 1903
Abstract
In this manuscript, we introduced a French EOAD patient in Korea who carried the presenilin-1 (PSEN1) Glu318Gly mutations with four possible risk variants, including sortilin-related receptor 1 (SORL1) Glu270Lys, ATP-binding cassette subfamily A member 7 (ABCA7) Val1946Met, [...] Read more.
In this manuscript, we introduced a French EOAD patient in Korea who carried the presenilin-1 (PSEN1) Glu318Gly mutations with four possible risk variants, including sortilin-related receptor 1 (SORL1) Glu270Lys, ATP-binding cassette subfamily A member 7 (ABCA7) Val1946Met, translocase of outer mitochondrial membrane 40 (TOMM40) Arg239Trp, and granulin (GRN) Ala505Gly. The patient started to present memory decline and behavioral dysfunction in his early 60s. His brain imaging presented amyloid deposits by positron emission tomography (PET-CT). The multimer detection system (MDS) screening test for plasma for amyloid oligomers was also positive, which supported the AD diagnosis. It was verified that PSEN1 Glu318Gly itself may not impact amyloid production. However, additional variants were found in other AD and non-AD risk genes, as follows: SORL1 Glu270Lys was suggested as a risk mutation for AD and could increase amyloid peptide production and impair endosome functions. ABCA7 Val1946Met was a novel variant that was predicted to be damaging. The GRN Ala505Gly was a variant with uncertain significance; however, it may reduce the granulin levels in the plasma of dementia patients. Pathway analysis revealed that PSEN1 Glu318Gly may work as a risk factor along with the SORL1 and ABCA7 variants since pathway analysis revealed that PSEN1 could directly interact with them through amyloid-related and lipid metabolism pathways. TOMM40 and PSEN1 could have common mechanisms through mitochondrial dysfunction. It may be possible that PSEN1 Glu318Gly and GRN Ala505Gly would impact disease by impairing immune-related pathways, including microglia and astrocyte development, or NFkB-related pathways. Taken together, the five risk factors may contribute to disease-related pathways, including amyloid and lipid metabolism, or impair immune mechanisms. Full article
(This article belongs to the Special Issue The Role of Genetics in Dementia)
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