This document discusses the application of precision medicine to Alzheimer's disease. It begins with background on the history and concepts of precision medicine and Alzheimer's disease. Precision medicine aims to personalize treatment based on individual characteristics like genetics and biomarkers. For Alzheimer's, precision medicine could help identify at-risk groups, understand the disease process, and develop targeted treatments. The role of genetics in precision medicine for Alzheimer's is discussed. Future directions include incorporating precision medicine into clinical trials to further advance personalized prevention and treatment of Alzheimer's disease.

1. Nirmal kumar
Department of Biotechnology
MANIT BHOPAL
PRECISION MEDICINE - The Golden Gate for
Detection, Treatment and Prevention of
Alzheimer’s Disease

2.  Introduction
 History
 Precision medicine
 Precision Medicine Initiative: From Genes to Health
 Alzheimer Disease
 The systems biology paradigm for complex multifactorial diseases:
 The role of Genetics in precision medicine for AD
 Application of precision medicine to Alzheimer’s disease (AD)
 Future directions
 Conclusion
Contents

3.  The concept of precision medicine, also termed “personalized medicine” or
“individualized medicine”, is a rapidly advancing field in medical clinical and
research settings.
 In contrast to the “one-size-fits-all-approach”, it aims to optimize
effectiveness of disease prevention and treatment and minimize side effects
for persons less likely to respond to a particular therapeutic, by considering an
individual’s specific makeup of genetic, biomarker, phenotypic and
psychosocial characteristics.
 The measurement of molecular, environmental, and behavioral factors
contributing to a specific disease improves the understanding of disease onset
and progression as well as response to treatment.
 In addition, it allows a more accurate diagnosis and more effective disease
prevention and treatment strategies specifically personalized to the individual.
Introduction

4.  The ancient Greek and Roman philosophers and physicians associated old age with
increasing dementia. It was not until 1901 that German psychiatrist Alois
Alzheimer identified the first case of what became known as Alzheimer's disease, named
after him, in a fifty-year-old woman he called Auguste D. He followed her case until she
died in 1906, when he first reported publicly on it.
 During the next five years, eleven similar cases were reported in the medical literature, some
of them already using the term Alzheimer's disease.
 The disease was first described as a distinctive disease by Emil Kraepelin after suppressing
some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic
changes) contained in the original report of Auguste D.
 He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype
of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 15
July, 1910.
History

5.  Precision medicine is "an emerging approach for disease treatment and
prevention that takes into account individual variability in genes, environment,
and lifestyle for each person." This approach will allow doctors and researchers
to predict more accurately which treatment and prevention strategies for a
particular disease will work in which groups of people. It is in contrast to a
"one-size-fits-all" approach, in which disease treatment and prevention
strategies are developed for the average person, with less consideration for the
differences between individuals.
 In theory, the concept of precision medicine
in clinical practice has been applied since initial
efforts to classify disease and administer a specific
treatment on the basis of this diagnosis.
Precision medicine

6.  More recent examples include the testing for specific mutations in the BRCA1
and BRCA2 genes in breast cancer patients, or the treatment of cystic fibrosis
tailored to target the specific cause underlying the condition in a specific
individual.
 A dramatic recent change in the concept is, however, the vision of applying
precision medicine broadly across a vast number of disorders, which now
became feasible due to the implementations of large-scale biologic databases
(such as databases of human genetic variation), a variety of high throughput
methods for characterizing patient biomarkers of disease (i.e., proteomics,
metabolomics, genomics, transcriptomics), coupled with significant advances
in the computational tools needed for analyzing the massive amounts of data
generated by these technologies.
 Precision medicine became the focus of major governmental initiatives to
transform medical practice.
Continue…

8. Precision Medicine Initiative:
From Genes to Health

9.  Alzheimer’s is a progressive, degenerative and incurable
Neurological brain disease that cause deterioration of brain nerve
cells and ultimately death
 The deterioration is caused by:
a. A build up of abnormal substance called amyloid plaques
(an insoluble protein deposit );
b. And neurofibrillary tangles.
Alzheimer Disease

10. Comparison of a normal aged brain (left) and the brain of a person with
Alzheimer's (right). Characteristics that separate the two are pointed out.
Alzheimer Disease

12.  Next-generation molecular and high-throughput techniques are opening new
avenues of research towards the discovery of mechanisms and networks
underlying complex multifactorial diseases.
 These networks enhance progress towards new molecular signatures,
comprehensive risk classification and translational (directly applicable to
patient) targeted interventions leading to the conceptualization of the
precision medicine paradigm
 Next-generation sequencing (NGS) technologies are already delivering in
terms of both the detection and treatment of diseases with a basic genomic
component (e.g., Mendelian and, as yet, uncharacterized diseases) . However,
many complex diseases including diabetes, neurodegenerative diseases, and
most cancers will require a SB-based approach to identify effective
interventions.
The systems biology (SB) paradigm for complex
multifactorial diseases: from systems theory to
precision medicine

13. A comprehensive understanding of the full pathophysiological spectrum of
dimensional (not categorical) neurodegenerative diseases (proteinopathies), such
as AD in precision medicine will require several advancements:
i) Understanding of the multifactorial nature of the disease (i.e., involving a
combination of genomic, epigenomic, interactomic, and environmental factors);
ii) Resolution of the “altered networks”, affecting essential modules and
interactomes;
iii) Realization of the nonlinear dynamic aspect of the disease translated through
its array of independent and interrelated mechanisms, with a fine balance,
interplay with and between impaired complex networks and homeostatic defense
mechanisms

14.  It is well-known that AD is a multi-factorial genetically complex multi-factorial disease with
heritability estimates between 58–79%. Given the increase in average life expectancy and the
subsequent rise of AD prevalence, the identification of subjects at high risk of developing AD
is key for prognosis and early intervention.
 Thus, genetics can provide a valuable starting point for advancement. AD is a heterogeneous
disease caused by a combination of environmental and genetic factors. Early-onset (AD
EOAD) is caused by highly penetrant variants, the majority of which are attributable to
mutations in one of three genes, amyloid precursor protein, presenilin 1, and presenilin 2.
 However, late-onset AD (LOAD) accounts for more than 95% of AD cases and is caused by a
more complex underlying genetic architecture. To date, along with the polymorphism in the
apolipo protein E gene, a number of common and moderately rare genome-wide significant
(GWS) susceptibility loci are associated with LOAD. Despite enormous efforts across the
research community and the successful identification of those loci, the understanding of the
aetiology of nonMendelian forms of neurodegenerative diseases remains limited and the
pressure to identify subjects at high risk of AD increases.
The role of Genetics in precision medicine for AD From
genomic medicine to precision medicine personal genomics
profiles:

15.  The aim of precision medicine, which is applicable to any disease including
AD, is specifically targeting the issue of underlying molecular and clinical
heterogeneity by identifying a person’s specific pattern of risk factors.
Application of precision medicine to Alzheimer’s
disease (AD)

16. The ultimate aim of precision medicine is to enable clinicians to accurately and efficiently identify the
most effective preventive or therapeutic intervention for a specific patient. For this, clinicians apply
tools (i.e., clinical tests and information-technology) that are implemented in the routine clinical
practice, are economically feasible, and help to disentangle the biological complexity underlying
human disease.
In addition, to advance the development of therapeutic targets, precision medicine is now beginning to
be incorporated into clinical trials: the Alzheimer’s Prevention Initiative, the Dominantly Inherited
Alzheimer Network Trial, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease trial
all are focusing on subgroups of individuals with known genetic risk for AD and biofluid biomarkers
or neuroimaging to detect onset of disease.
Although successful application of precision medicine to AD will demand extensive additional work
to identify risk groups, the underlying pathological processes and develop new interventions, and will
continue to require significant involvement of biologists, physicians, technology developers, data
scientists, patient groups and others, it is anticipated that this is only the beginning of a broad
precision medicine approach targeting the clinical and biological complexity of AD and building the
evidence base needed to guide clinical practice.
Future directions

17. The goal of precision medicine is to provide each patient with optimally timed
treatments that target the specific reasons he or she is experiencing the disease
(see our coverage on precision medicine on pages. This approach is widely
accepted in cancer care and in some diseases caused by single-gene mutations,
such as cystic fibrosis. It has also been endorsed by the White House Office of
Science and Technology for more widespread application in other areas of
medicine. This manuscript explains how precision medicine can bring greater
clarity to the clinical and biological complexity of the two most common
neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease.
Comprehensive risk assessment, detection of processes that change the brain,
and molecularly tailored treatments embody a precision medicine approach and
provide a strategy for optimal targeting and timing of efforts to prevent, stop, or
slow the progression of these diseases.
Conclusion

18. References
 J Prev Alzheimers Dis. 2016 December; 3(4): 243–259
doi:10.14283/jpad.2016.112.
 Jan 13, 2016. Accepted for publication Jan 25, 2016.
doi: 10.21037/atm.2016.03.05
 Association, American Psychiatric. Diagnostic and Statistical Manual of
Mental Disorders : DSM-5. (5th ed.).
 American Psychiatric Association. Washington DC, USA (2013).
 The Newsletter of the University of Washington Alzheimer?s Disease
Research Center FALL 2015206.764.2069800.317.5382 www.uwadrc.org