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Curated Papers > Recent high-impact research on "Alzheimer's Disease" (IF≥30, last 5 years)

Genetic Insights into Alzheimer's Disease. ​

Literature Information ​

DOI10.1146/annurev-pathmechdis-012419-032551
PMID33497263
JournalAnnual review of pathology
Impact Factor34.5
JCR QuartileQ1
Publication Year2021
Times Cited10
KeywordsAlzheimer's disease, aging, amyloid, genetics, neurodegeneration
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Review
ISSN1553-4006
Pages351-376
Issue16()
AuthorsCaitlin S Latimer, Katherine L Lucot, C Dirk Keene, Brenna Cholerton, Thomas J Montine

TL;DR ​

This review examines the genetic underpinnings of Alzheimer's disease (AD), highlighting how advancements in understanding both hereditary and sporadic forms of the disorder have elucidated its pathophysiology and clinical manifestations. These insights not only enhance our comprehension of AD but also pave the way for developing innovative therapeutic strategies.

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Alzheimer's disease · aging · amyloid · genetics · neurodegeneration

Abstract ​

Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological manifestations. While a clinical diagnosis is often made on the basis of initial memory dysfunction that progresses to involve multiple cognitive domains, definitive diagnosis requires autopsy examination of the brain to identify amyloid plaques and neurofibrillary degeneration. Over the past 100 years, there has been remarkable progress in our understanding of the underlying pathophysiologic processes, pathologic changes, and clinical phenotypes of AD, largely because genetic pathways that include but expand beyond amyloid processing have been uncovered. This review discusses the current state of understanding of the genetics of AD with a focus on how these advances are both shaping our understanding of the disease and informing novel avenues and approaches for development of potential therapeutic targets.

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Primary Questions Addressed ​

  1. How do specific genetic variants influence the risk of developing sporadic Alzheimer's disease compared to hereditary forms?
  2. What role do non-amyloid genetic pathways play in the progression of Alzheimer's disease?
  3. How can advancements in genetic research inform the development of targeted therapies for Alzheimer's disease?
  4. In what ways do neuropsychological manifestations of Alzheimer's disease differ between genetically predisposed individuals and those with sporadic cases?
  5. What are the implications of genetic findings on early diagnosis and intervention strategies for Alzheimer's disease?

Key Findings ​

Research Background and Purpose ​

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline, affecting both hereditary and sporadic forms. The purpose of this review is to synthesize current knowledge regarding the genetic factors involved in AD and how these insights are influencing the development of new therapeutic strategies.

Main Methods/Materials/Experimental Design ​

The review employs a comprehensive literature analysis of genetic studies related to Alzheimer's disease. It emphasizes the role of genetic pathways in the pathology of AD and explores the implications of these findings for therapeutic development.

Mermaid diagram

Key Results and Findings ​

  • Advances in genetic research have revealed multiple pathways involved in AD beyond just amyloid processing.
  • Identification of specific genetic variants linked to increased risk of AD has been critical in understanding the disease's complexity.
  • The review highlights the potential for new therapeutic targets based on these genetic insights, suggesting a shift towards personalized medicine approaches in AD treatment.

Main Conclusions/Significance/Innovation ​

The review underscores the importance of genetics in shaping our understanding of Alzheimer's disease. By elucidating the genetic underpinnings, researchers can develop targeted therapies that address not only amyloid plaques but also other pathological mechanisms involved in AD. This represents a significant innovation in the approach to treatment, moving away from one-size-fits-all strategies.

Research Limitations and Future Directions ​

  • The review acknowledges the limitations of current genetic studies, including potential biases in sample selection and the need for more diverse genetic backgrounds.
  • Future research should focus on longitudinal studies that can better elucidate the role of genetic factors over time and in different populations.
  • There is a call for more integrative approaches that combine genetic data with other biomarkers to enhance the understanding and treatment of AD.
SectionSummary
Research BackgroundAD is a progressive neurodegenerative disorder; understanding genetics is crucial for therapeutic advancements.
Methods/DesignLiterature analysis of genetic studies; focus on genetic pathways related to amyloid and other mechanisms.
Key ResultsIdentification of genetic variants; potential for novel therapeutic targets; emphasis on personalized medicine.
ConclusionsGenetics significantly informs AD understanding and treatment; shift towards targeted therapies is essential.
LimitationsNeed for diverse genetic backgrounds; biases in sample selection; longitudinal studies required for deeper insights.
Future DirectionsFocus on integrative approaches combining genetic and biomarker data; further exploration of genetic influences over time.

References ​

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Literatures Citing This Work ​

  1. Sex-specific accelerated decay in time/activity-dependent plasticity and associative memory in an animal model of Alzheimer's disease. - Sheeja Navakkode;Jessica Ruth Gaunt;Maria Vazquez Pavon;Vibhavari Aysha Bansal;Riya Prasad Abraham;Yee Song Chong;Toh Hean Ch'ng;Sreedharan Sajikumar - Aging cell (2021)
  2. TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans. - Caitlin S Latimer;Jade G Stair;Joshua C Hincks;Heather N Currey;Thomas D Bird;C Dirk Keene;Brian C Kraemer;Nicole F Liachko - Disease models & mechanisms (2022)
  3. Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms. - Giulia Faravelli;Valentina Mondani;P Patrizia Mangione;Sara Raimondi;Loredana Marchese;Francesca Lavatelli;Monica Stoppini;Alessandra Corazza;Diana Canetti;Guglielmo Verona;Laura Obici;Graham W Taylor;Julian D Gillmore;Sofia Giorgetti;Vittorio Bellotti - Frontiers in molecular biosciences (2022)
  4. An Alzheimer's Disease Mechanism Based on Early Pathology, Anatomy, Vascular-Induced Flow, and Migration of Maximum Flow Stress Energy Location with Increasing Vascular Disease. - Conrad N Trumbore;Aditya Raghunandan - Journal of Alzheimer's disease : JAD (2022)
  5. Finding new and better treatments for psychiatric disorders. - Steven M Paul;William Z Potter - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2024)
  6. Retinal electrophysiology in central nervous system disorders. A review of human and mouse studies. - Paul A Constable;Jeremiah K H Lim;Dorothy A Thompson - Frontiers in neuroscience (2023)
  7. Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia. - Amalia Perna;Kathleen S Montine;Lon R White;Thomas J Montine;Brenna A Cholerton - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2023)
  8. Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia. - Ya-Ru Zhang;Bang-Sheng Wu;Shi-Dong Chen;Liu Yang;Yue-Ting Deng;Yu Guo;Xin-Rui Wu;Wei-Shi Liu;Ju-Jiao Kang;Jian-Feng Feng;Wei Cheng;Jin-Tai Yu - Alzheimer's & dementia : the journal of the Alzheimer's Association (2024)
  9. The Hippo signaling pathway as a therapeutic target in Alzheimer's disease. - Doris Chen;Stella Wigglesworth-Littlewood;Frank J Gunn-Moore - Molecular neurodegeneration (2025)
  10. Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease. - Xinyue Zhang;Shujia Huang;Hongfeng Xu;Yanan Hu;Ling Gao - Frontiers in pharmacology (2025)

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