Smell Test Could Track Alzheimer’s Progression

(McGill University) Promising finding suggests odour identification tests may help scientists track the evolution of the disease in persons at risk.

By the time you start losing your memory, it’s almost too late. That’s because the damage to your brain associated with Alzheimer’s disease (AD) may already have been going on for as long as twenty years. Which is why there is so much scientific interest in finding ways to detect the presence of the disease early on. Scientists now believe that simple odour identification tests may help track the progression of the disease before symptoms actually appear, particularly among those at risk.

“Despite all the research in the area, no effective treatment has yet been found for AD,” says Dr. John Breitner, the director of the Centre for Studies on Prevention of Alzheimer’s Disease at the Douglas Mental Health Research Centre of McGill University. He is one of the authors of the study on the subject that was recently published in the journal Neurology.

“But, if we can delay the onset of symptoms by just five years, we should be able to reduce the prevalence and severity of these symptoms by more than 50%.”

Bubble Gum or Gasoline?

Close to 300 people with an average age of 63 who are at risk of developing AD because they had a parent who had suffered from the disease, were asked to take multiple choice scratch-and-sniff tests to identify scents as varied as bubble gum, gasoline or the smell of a lemon. One hundred of them also volunteered to have regular lumbar punctures to measure the quantities of various AD-related proteins whose presence in the cerebrospinal fluid (CSF).

The researchers found that those with the most difficulty in identifying odours were those in whom other, purely biological indicators of AD, were most evident.

“This is the first time that anyone has been able to show clearly that the loss of the ability to identify smells is correlated with biological markers indicating the advance of the disease,” says Marie-Elyse Lafaille-Magnan, a doctoral student at McGill and the first author on the study.

“For more than 30 years, scientists have been exploring the connection between memory loss and the difficulty that patients may have in identifying different odours. This makes sense because it’s known that the olfactory bulb (involved with the sense of smell) and the entorhinal cortex (involved with memory and naming of odours) are among the first brain structures first to be affected by the disease.”

“This means that a simple smell test may potentially be able to give us information about the progression of the disease that is similar to the much more invasive and expensive tests of the cerebrospinal fluid that are currently being used,” the director of research program on Aging, Cognition and Alzheimer’s disease of the Douglas Institute and one of the authors on the study.

“However, problems identifying smells may be indicative of other medical conditions apart from AD and so should not be substituted for the current tests.”

The researchers caution more that far more work needs to be done to see how changes in a person’s ability to identify smells over time relates to the progression of the disease itself. For the time being, smell tests are simply one more avenue to explore as researchers look for ways to identify the disease before the symptoms actually begin to appear.


Original Research: Abstract for “Odor identification as a biomarker of preclinical AD in older adults at risk” by Marie-Elyse Lafaille-Magnan, BSc, MSc, Judes Poirier, PhD, CQ, Pierre Etienne, MD, Jennifer Tremblay-Mercier, MSc, Joanne Frenette, BSN, MN, Pedro Rosa-Neto, MD, PhD, John C.S. Breitner, MD, MPH; For the PREVENT-AD Research Group in Neurology. Published online July 25 2017 doi:10.​1212/​WNL.​0000000000004159

Copyright © 2017 McGill University


Women Have More Active Brains Than Men

(Journal of Alzheimer’s Disease) Largest functional brain imaging study to date identifies specific brain differences between women and men, according to a new report in the Journal of Alzheimer’s Disease

Amsterdam, NL – In the largest functional brain imaging study to date, the Amen Clinics (Newport Beach, CA) compared 46,034 brain SPECT (single photon emission computed tomography) imaging studies provided by nine clinics, quantifying differences between the brains of men and women. The study is published in the Journal of Alzheimer’s Disease.

Lead author, psychiatrist Daniel G. Amen, MD, founder of Amen Clinics, Inc., commented,

“This is a very important study to help understand gender-based brain differences. The quantifiable differences we identified between men and women are important for understanding gender-based risk for brain disorders such as Alzheimer’s disease. Using functional neuroimaging tools, such as SPECT, are essential to developing precision medicine brain treatments in the future.”

The brains of women in the study were significantly more active in many more areas of the brain than men, especially in the prefrontal cortex, involved with focus and impulse control, and the limbic or emotional areas of the brain, involved with mood and anxiety. The visual and coordination centers of the brain were more active in men. SPECT can measure blood perfusion in the brain. Images acquired from subjects at rest or while performing various cognitive tasks will show different blood flow in specific brain regions.

Subjects included 119 healthy volunteers and 26,683 patients with a variety of psychiatric conditions such as brain trauma, bipolar disorders, mood disorders, schizophrenia/psychotic disorders, and attention deficit hyperactivity disorder (ADHD). A total of 128 brain regions were analyzed for subjects at baseline and while performing a concentration task.

Caption: Side view of the brain summarizing blood flow results from tens of thousands of study subjects shows increased blood flow in women compared to men, highlighted in the red colored areas of the brain: the cingulate gyrus and precuneus. Men in this image have higher blood flow in blue colored areas – the cerebellum.

Understanding these differences is important because brain disorders affect men and women differently. Women have significantly higher rates of Alzheimer’s disease, depression, which is itself is a risk factor for Alzheimer’s disease, and anxiety disorders, while men have higher rates of (ADHD), conduct-related problems, and incarceration (by 1,400%).

Editor-in-Chief of the Journal of Alzheimer’s Disease and Dean of the College of Sciences at The University of Texas at San Antonio, Dr. George Perry said, “Precisely defining the physiological and structural basis of gender differences in brain function will illuminate Alzheimer’s disease and understanding our partners.”

The study findings of increased prefrontal cortex blood flow in women compared to men may explain why women tend to exhibit greater strengths in the areas of empathy, intuition, collaboration, self-control, and appropriate concern. The study also found increased blood flow in limbic areas of the brains of women, which may also partially explain why women are more vulnerable to anxiety, depression, insomnia, and eating disorders.


Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2017


Antidepressant Use Increases Risk of Head Injuries Among Persons with Alzheimer’s Disease

(University of Eastern Finland) Antidepressant use is associated with an increased risk of head injuries and traumatic brain injuries among persons with Alzheimer’s disease, according to a new study from the University of Eastern Finland. Antidepressant use has previously been linked with an increased risk of falls and hip fractures, but the risk of head injuries has not been studied before. The results were published in Alzheimer’s Research & Therapy.

Antidepressant use was associated with a higher risk of head injuries especially at the beginning of use — during the first 30 days -, but the risk persisted even longer, up to two years. The association was also confirmed in a study design comparing time periods within the same person, thus eliminating selective factors. The association with traumatic brain injuries was not as clear as for head injuries, which may be due to a smaller number of these events in the study population. The use of other psychotropic drugs did not explain the observed associations.

Head injuries are more common among older people than younger ones, and they are usually caused by falling. As antidepressant use has previously been associated with an increased risk of falling, the researchers were not surprised that the use of antidepressants also increased the risk of head injuries.

“However, our findings give cause for concern because persons with Alzheimer’s disease frequently use antidepressants, which have been considered a safer alternative to, for example, benzodiazepines,” says Senior Researcher Heidi Taipale from the University of Eastern Finland.

“Our study population consisted of persons diagnosed with Alzheimer’s disease, but it is likely that the risk is similar also in other older persons without Alzheimer’s disease. This is something we will be studying in the future.”

The study constitutes part of the nationwide register-based MEDALZ study, which includes all community-dwelling persons diagnosed with Alzheimer’s disease in Finland during 2005-2011. The study included 10,910 antidepressant users and 21,820 nonusers, all of whom had Alzheimer’s disease.


Journal Reference:

Heidi Taipale, Marjaana Koponen, Antti Tanskanen, Piia Lavikainen, Reijo Sund, Jari Tiihonen, Sirpa Hartikainen, Anna-Maija Tolppanen. Risk of head and traumatic brain injuries associated with antidepressant use among community-dwelling persons with Alzheimer’s disease: a nationwide matched cohort studyAlzheimer’s Research & Therapy, 2017; 9 (1) DOI: 10.1186/s13195-017-0285-3


A Personalized Approach to Alzheimer’s Disease Prevention

(American Geriatrics Society) Alzheimer’s disease (AD) is a type of dementia that causes problems with memory, thinking, and behavior. It affects more than 5 million Americans. The Alzheimer’s Association estimates that some 16 million people will develop the disease by the year 2050 if an effective treatment is not discovered. Symptoms of AD usually develop slowly and worsen over time. They often become severe enough to interfere with daily tasks, and can eventually cause death.

In a new study, published in the Journal of the American Geriatrics Society, James E. Galvin, MD, MPH, Professor of Integrated Medical Science and Associate Dean for Clinical Research, Charles E. Schmidt College of Medicine, Florida Atlantic University, examined potential AD prevention strategies.

Dr. Galvin notes that just four medications have been approved to treat AD symptoms. A major effort is underway to develop new treatments for the disease by the year 2025, and researchers have launched several new studies.

Another area of research interest focuses on AD prevention strategies. In studies of people with AD, researchers have discovered conditions that increase risk factors associated with the disease. When these conditions are combined, they account for more than 50 percent of the risk for AD. They include:

  • Diabetes
  • High blood pressure
  • Kidney problems
  • Alcohol and tobacco use
  • High cholesterol
  • Coronary heart disease
  • Depression
  • Low activity life style
  • Diet

Researchers looked at 19 studies about various brain-stimulating activities that may lower risks for AD, . They discovered that doing crossword puzzles, playing card games, using a computer, making arts or crafts, taking classes, having group discussions, and listening to music all had protective effects against AD.

Researchers have learned that physical activity helps reduce AD risk by up to 65 percent, depending on the type of exercise and its intensity. That’s because exercise reduces blood vessel disease risk, improves your breathing function, supports the survival of the cells that make up your body, and lessens inflammation.

Age remains the greatest risk factor for AD: by 82, the risk for developing the disease is 42 percent. The good news: 58 percent of older adults do not develop AD.

Presently, we don’t understand why some people develop the disease and others don’t. But addressing the risk factors we do know about could make a difference. For example, up to 30 percent of AD cases may be preventable by living a well-balanced, healthy life. That would include eating a healthy diet with plenty of fresh fruits and vegetables, whole grain foods, lean proteins, and few to no “fast” or processed foods. A healthy lifestyle also includes physical activity and social engagement.

The future of researching ways to prevent AD should probably focus on people at risk for developing the disease, said researchers, and should highlight how to improve management of chronic health conditions and education about living healthier.


Journal Reference:

James E. Galvin. Prevention of Alzheimer’s Disease: Lessons Learned and AppliedJournal of the American Geriatrics Society, 2017; DOI: 10.1111/jgs.14997

Copyright 2017 ScienceDaily or by third parties, where indicated


Blocking a Key Enzyme May Reverse Memory Loss

(Massachusetts Institute of Technology) In the brains of Alzheimer’s patients, many of the genes required to form new memories are shut down by a genetic blockade, contributing to the cognitive decline seen in those patients.

MIT researchers have now shown that they can reverse that memory loss in mice by interfering with the enzyme that forms the blockade. The enzyme, known as HDAC2, turns genes off by condensing them so tightly that they can’t be expressed.

For several years, scientists and pharmaceutical companies have been trying to develop drugs that block this enzyme, but most of these drugs also block other members of the HDAC family, which can lead to toxic side effects. The MIT team has now found a way to precisely target HDAC2, by blocking its interaction with a binding partner called Sp3.

“This is exciting because for the first time we have found a specific mechanism by which HDAC2 regulates synaptic gene expression,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the study’s senior author.

Blocking that mechanism could offer a new way to treat memory loss in Alzheimer’s patients. In this study, the researchers used a large protein fragment to interfere with HDAC-2, but they plan to seek smaller molecules that would be easier to deploy as drugs.

Picower Institute postdocs Hidekuni Yamakawa, Jemmie Cheng, and Jay Penney are the lead authors of the study, which appears in the Aug. 8 edition of Cell Reports.

Memorable Interactions

In 2007, Tsai first discovered that blocking HDAC activity could reverse memory loss in mice. There are several classes of HDACs, and their primary function is to modify histones — proteins around which DNA is spooled, forming a structure called chromatin. These modifications condense chromatin, making genes in that stretch of DNA less likely to be expressed.

Human cells have about a dozen forms of HDAC, and Tsai later found that HDAC2 is responsible for the blockade of memory-linked genes. She also discovered that HDAC2 is elevated in human Alzheimer’s patients and in several mouse models of the disease.

“We think that HDAC2 serves as a master regulator of memory gene expression, and during Alzheimer’s disease it’s elevated so it causes an epigenetic blockade of the expression of those memory genes,” she says.

“If we can remove the blockade by inhibiting HDAC2 activity or reducing HDAC2 levels, then we can remove the blockade and restore expression of all these genes necessary for learning and memory.”

Most of the existing HDAC inhibitors that block HDAC2 also affect HDAC-1, which can have toxic side effects because HDAC1 is necessary for cell proliferation, especially in the production of white and red blood cells.

To find a way to more specifically target HDAC2, Tsai set out to identify proteins that help the enzyme bind to genes required for memory formation. First, she analyzed gene expression data from postmortem brain samples taken from people who did not have Alzheimer’s disease, including 28 brains with high HDAC-2 levels and 35 with low levels. This search yielded more than 2,000 genes whose levels closely matched HDAC2 levels, suggesting that those genes might work in tandem with HDAC2.

Based on what they already knew about these genes’ functions and how they physically interact with HDAC2, the researchers then picked out three of those genes for further testing. Those tests revealed that a gene called Sp3 is necessary to recruit HDAC2 to chromatin to enact its blockade of memory-linked genes.

The researchers also examined gene expression data from postmortem brains of Alzheimer’s patients and found a nearly perfect correlation between levels of HDAC2 and sp3.

Specific Targets

The researchers then explored what would happen if they lowered Sp3 levels in a mouse model of Alzheimer’s disease. In these mice, the same type in which they previously studied the effects of blocking HDAC2, they found that deactivating Sp3 also restored the mice’s ability to form long-term memories.

The researchers used a type of short RNA strand to perform the genetic “knockdowns” in these experiments, but for this approach to be useful for potentially restoring memory function in human patients, scientists would likely need to develop a drug in the form of a small protein or chemical compound.

To that end, the researchers identified the section of the HDAC2 protein that binds to Sp3. When they engineered neurons to overproduce that HDAC2 fragment, the fragment sopped up most of the available Sp3, blocking it from binding HDAC2 and releasing the blockade of memory-linked genes. Furthermore, the fragment did not interfere with cell proliferation, suggesting that this more targeted approach would not have the adverse side effects of more general HDAC inhibitors.

The protein fragment that the researchers used to block the interaction in this study has about 90 amino acids, which would likely be too large to use as a drug, so the researchers hope to either identify a smaller segment that would still be effective, or find a chemical compound that would also disrupt the Sp3-HDAC2 interaction.

Tsai also hopes to further investigate some of the other genes that were found to correlate with HDAC2, in hopes of identifying other drug targets. She also plans to explore whether this approach could be useful in treating other disorders that involve elevated levels of HDAC2, such as posttraumatic stress disorder.


Journal Reference:

Hidekuni Yamakawa, Jemmie Cheng, Jay Penney, Fan Gao, Richard Rueda, Jun Wang, Satoko Yamakawa, Oleg Kritskiy, Elizabeta Gjoneska, Li-Huei Tsai. The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in NeuronsCell Reports, 2017; 20 (6): 1319 DOI: 10.1016/j.celrep.2017.07.044

Copyright Massachusetts Institute of Technology


High Blood Pressure Medication Shows Protective Effect for Brain Structure and Function

(Journal of Alzheimer’s Disease)  A new study from Sunnybrook researchers provides evidence that a specific type of treatment for hypertension, or high blood pressure, appears to protect against brain degeneration associated with Alzheimer’s disease, and preserve cognition when compared to other classes of anti-hypertensive medications.

“We know that hypertension is an important risk factor for Alzheimer’s Disease (AD) and small vessel disease in the brain, so we sought to investigate whether different treatments for hypertension, specifically angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-inhibitors), have different effects on cognition and the brain structures that affect and control it,” says Dr. Jodi Edwards, co-lead author of the study and Epidemiology Post-Doctoral fellow at Sunnybrook Health Sciences Centre.

The researchers identified a group of elderly adults both with and without mild cognitive impairment or AD who had exposure to blood pressure medications, from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a large AD neuroimaging study.

From MRI scans of the brain, they looked at total brain tissue volume, volume of the memory structures of the brain (ie. hippocampus) and volume of the white matter tissue of the brain. They also looked at participants’ cognitive performance on tests of memory, language, and executive function and examined whether both brain tissue volume and cognition were associated with different types of high blood pressure treatments.

“Individuals prior to AD who were treated with ARBs showed significantly larger overall brain volumes, larger volumes of tissue in the hippocampus – the area responsible for things like memory – and better performance on tests of memory, language, and executive function than those treated with ACE-inhibitors or other high blood pressure medications,” said Dr. Joel Ramirez, co-lead author and Imaging Research Associate at Sunnybrook.

“In elderly hypertensive adults without AD, ARBs appear to have a greater protective effect on multiple MRI markers of neurodegeneration in the brain – brain structures vulnerable to AD,” says Dr. Sandra Black, senior author of the study and Brill Chair of Neurology at Sunnybrook and University of Toronto.

“We suspect this may be because different classes of blood pressure medications have different effects on brain energy metabolism and on how the brain processes amyloid, the toxic protein that builds up in the brain to form amyloid plaques, a hallmark of AD.”

“These findings provide new evidence to suggest that the type of medication used to manage high blood pressure may have important effects on the brain, particularly in elderly adults at risk of cognitive decline and AD. As ACEIs are generally more commonly used in clinical practice, choosing a medication, such as ARBs, that have the same benefits for blood pressure control, but may also have benefits for the brain would be desirable in clinical practice when treating patients with hypertension.”


Published in the August 1, 2017 issue of the Journal of Alzheimer’s Disease, this is one of the first studies to compare the use of anti-hypertensive medications for MRI-derived markers of neurodegeneration or SVD and cognition in elderly adults at risk of dementia. This study was funded by a Catalyst Grant from the Canadian Institutes for Health Research (CIHR) and data was obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Edwards JD, Ramirez J, Callahan BL, Tobe SW, Oh P, Berezuk C, Lanctôt K, Swardfager W, Nestor S, Kiss A, Strother S, Black SE; Alzheimer’s Disease Neuroimaging Initiative. Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study. J Alzheimers Dis, doi: 10.3233/JAD-170238.

Journal of Alzheimer’s Disease is published by IOS Press

Copyright © 2017


Meet the World’s First Alzheimer’s Patient

(Wikipedia) Auguste Deter (German pronunciation: [aʊ̯ˈɡʊstə ˈdeːtɐ]; 16 May 1850 – 8 April 1906) is a German woman notable for being the first person to diagnosed with Alzheimer’s disease. Her maiden name is unknown. She married Karl Deter in the 1880s and together they had one daughter. Auguste had a normal life. However, during the late 1890s, she started showing symptoms of dementia, such as: loss of memory, delusions, and even temporary vegetative states. She would have trouble sleeping, would drag sheets across the house, and scream for hours in the middle of the night.

Auguste D aus Marktbreit.jpg
Born 16 May 1850
Kassel, Germany
Died 8 April 1906 (aged 55)
Frankfurt, Germany
Nationality German
Known for First diagnosis of “Alzheimer’s
Spouse(s) Karl Deter

As a railway worker, Karl was unable to provide adequate care for his wife. He had her admitted to a mental institution, the Institution for the Mentally Ill and for Epileptics (Irrenschloss) in Frankfurt, Germany on 25 November 1901. There, she was examined by Dr. Alois Alzheimer.

Dr. Alzheimer asked her many questions, and later asked again to see if she remembered. He told her to write her name. She tried to, but would forget the rest and repeat: “I have lost myself.” (German: “Ich hab mich verloren.”) He later put her in an isolation room for a while. When he released her, she would run out screaming, “I will not be cut. I do not cut myself.”

After many years, she became completely demented, muttering to herself. She died on 8 April 1906. More than a century later, her case was re-examined with modern medical technologies, where a genetic cause was found for her disease by scientists from Gießen and Sydney.

The results were published in the journal The Lancet Neurology. According to this paper, a mutation in the PSEN1 gene was found, which alters the function of gamma secretase, and is a known cause of early-onset Alzheimer’s disease.

Medical Record Rediscovery

In 1996, Dr. Konrad Maurer and his colleagues, Drs. Volk and Gerbaldo, rediscovered the medical records of Auguste Deter. In these documents, Dr. Alzheimer had recorded his examination of his patient, including her answers to his questions:

“What is your name?”
“Family name?”
“What is your husband’s name?” – she hesitates, finally answers:
“I believe … Auguste.”
“Your husband?”
“Oh, so!”
“How old are you?”
“Where do you live?”
“Oh, you have been to our place.”
“Are you married?”
“Oh, I am so confused.”
“Where are you right now?”
“Here and everywhere, here and now, you must not think badly of me.”
“Where are you at the moment?”
“We will live there.”
“Where is your bed?”
“Where should it be?”

Around midday, Frau Auguste D. ate pork and cauliflower.

“What are you eating?”
“Spinach.” (She was chewing meat.)
“What are you eating now?”
“First I eat potatoes and then horseradish.”
“Write a ‘5’.”
She writes: “A woman”
“Write an ‘8’.”
She writes: “Auguste” (While she is writing she repeatedly says, “I have lost myself, so to say.”)

Alzheimer concluded that she had no sense of time or place. She could barely remember details of her life and frequently gave answers that had nothing to do with the question and were incoherent. Her moods changed rapidly between anxiety, mistrust, withdrawal and ‘whininess’. They could not let her wander around the wards because she would accost other patients who would then assault her. It was not the first time that Dr. Alzheimer had seen a complete degeneration of the psyche in patients, but previously the patients had been in their seventies. Ms. Deter piqued his curiosity because she was much younger. In the weeks following, he continued to question her and record her responses. She frequently responded, “Oh, God!”, and, “I have lost myself, so to say”. She seemed to be consciously aware of her helplessness. Alzheimer called it the “Disease of Forgetfulness”.

In 1902, Alzheimer left the “Irrenschloss” (Castle of the Insane), as the Institution was known colloquially, to take up a position in Munich but he made frequent calls to Frankfurt inquiring about Deter’s condition. On 9 April 1906, Alzheimer received a call from Frankfurt that Auguste Deter had died. He requested that her medical records and brain be sent to him. Her chart recorded that in the last years of her life, her condition had deteriorated considerably. Her death was the result of sepsis caused by an infected bedsore. On examining her brain, he found senile plaques and neurofibrillary tangles. These would be the hallmark of Alzheimer’s Disease as scientists know it today. Auguste would have been diagnosed with early-onset Alzheimer’s disease if seen by a current-day doctor.

Read the Medical Record: Auguste D and Alzheimer’s Disease



Why are Scientists Redefining Alzheimer’s Disease?

(MedicalNewsToday) Alzheimer’s disease is a progressive neurodegenerative disorder, thought to be caused by buildup of proteins in the brain. But there is increasing evidence that different biological processes are at the heart of the disease, providing scientists with a different approach to possible therapies.

In a plenary session delivered at the Alzheimer’s Association International Conference (AAIC) 2017, held in London, United Kingdom, Julie Williams, Ph.D. – a professor in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the U.K. – challenged the traditional views of Alzheimer’s disease by saying that “immunity is playing a significant role” in the disease.

Alzheimer’s disease is the sixth leading cause of death in the United States, affecting more than 5 million adults in the country.

The traditional view is that proteins accumulate in the brains of patients, leading to neuronal death. The culprits are the amyloid beta peptide and the tau protein.

Amyloid beta is produced when a short section of the amyloid precursor protein (APP) is severed. The function of the peptide in normal brain function is not known, but some evidence points toward a role in neurons. In Alzheimer’s disease, amyloid beta accumulates in plaques in the spaces between neurons.

Tau is a structural protein, important for neuronal function. But in Alzheimer’s, tau does not function properly and accumulates in tangles in neurons. How this contributes to cell death is unknown, but there is new evidence that shows that abnormal tau processing can lead to toxic effects.

How are scientists challenging the traditional view that abnormal protein buildup in the brain is to blame for the neurodegeneration seen in Alzheimer’s disease?

Joint Efforts to Identify New Genetic Variants

Until 2009, only four genes were known to be associated with Alzheimer’s disease. Mutations in three of these – APP, presenilin 1, and presenilin 2 – cause the inherited form of Alzheimer’s. This typically develops early in life, between the ages of 30 and 50. It is also known as early-onset Alzheimer’s disease.

Less than 1 percent of Alzheimer’s disease patients have this inherited form of the condition, in which an overproduction or abnormal folding of amyloid beta in the brain can be observed.

The majority of patients have the sporadic form of Alzheimer’s. Despite the fact that mutations in the apolipoprotein E gene (APOE) were known to be involved in susceptibility and earlier age of onset, only a subset of patients have the variant associated with the disease.

Predicting an individual’s risk of developing the disease with accuracy is, therefore, a challenge. For many years, there was a serious lack of progress in research looking to establish the underlying causes of susceptibility.

Today, we know that sporadic Alzheimer’s disease has a large genetic component, with its heritability being in the range of 58 to 79 percent. This means that other genetic variants must be involved.

Advances in genetics and technology led to a breakthrough, in 2009, that saw Prof. Williams and other researchers identify three new genes associated with Alzheimer’s disease using genome-wide association studies (GWAS).

Prof. Williams told the audience at the AAIC that it very quickly became clear that future discoveries using this type of genetic analysis would be dependent on data from large numbers of patients being available. To her, the only way to achieve this would be to collaborate with other teams around the world.

At the AAIC in 2010, held in Hawaii, the International Genomics of Alzheimer’s Project (IGAP) was born. IGAP is a collaboration of four large research consortia, led by Prof. Williams and other scientists across the U.S. and Europe.

IGAP researchers and other scientists have now identified 30 genes and genetic locations across the human genome that are involved a person’s susceptibility to Alzheimer’s. But what can scientists do with this new genetic information?

Identifying Individuals at Risk

In a study published in the journal Neurobiology of Aging in 2017, Prof. William’s team used their knowledge of susceptibility genes to test how accurately they could predict an individual’s risk of Alzheimer’s disease.

Using data from 17,000 Alzheimer’s patients and 37,000 controls, and looking at 87,583 mutations, they were able to identify the condition with an accuracy of 74.5 percent.

Prof. Williams explained that they were “now able to predict quite a lot of the risk of AD [Alzheimer’s disease] and it’s better than looking at APOE.”

“We have other genes that are protective and risk variants,” she added. Her team can use these to generate risk prediction scores. Knowing an individual’s risk level could help to identify who would benefit the most from early interventions.

But scientists still do not fully understand what causes the disease. Can these new genetic findings help?

From Susceptibility to Disease Mechanism

Rather than looking at each of the susceptibility genes in isolation, Prof. Williams and her team are interested in the pathways that these genes are involved in.

The strongest association that they have been able to identify has been the immune pathway. Other cellular processes are also implicated to some extent, including cholesterol transport and protein folding.

“We find very little evidence of amyloid beta production affecting common AD,” Prof. Williams said, adding that they did find variants that affect amyloid beta processing and clearance.

So might the amyloid buildup seen in Alzheimer’s patients be less of a problem with excess production and more to do with other processes?

Prof. Williams challenged the audience to imagine a scenario wherein there was no historic knowledge of the genes implicated in amyloid processing being involved in Alzheimer’s disease.

“Alzheimer’s disease is more of an autoinflammatory disease, than anything else,” Prof. Williams said.

“What we are seeing with immunity is happening quite early in the disease and maybe a primary event that is happening alongside amyloid [accumulation],” she added. “What we need to do is to understand mechanisms.”

The team’s latest discovery was published this week in Nature Genetics, and it supports this theory.

This study, performed by the IGAP group, identified two new genetic variants that confer Alzheimer’s disease risk. The genes – phospholipase C gamma and B-3-domain-containing transcription factor ABI3 – are highly expressed in microglial cells in the brain, which are part of the immune system.

Prof. Williams told the audience that scientists around the world are now studying genetic models to better understand how the immune system is involved in the neurodegeneration seen in Alzheimer’s.

What is really important is how researchers are putting this new knowledge and redefinition of the condition to use.

Pathways and Drug Targets

Prof. Williams explained that scientists can now take a more global view of the pathways involved in the disease.

“We might find drugable targets, that might not be directly related to the genes,” she added.

Sir Simon Lovestone, a psychiatrist and professor of translational neuroscience at the University of Oxford in the U.K., echoed this sentiment in the plenary session at the AAIC that immediately followed Prof. Williams’s talk.

Prof. Lovestone’s team used datasets from patients across the U.K. and Europe to look at neurodegenerative diseases.

“I want to make a case, that we can use this data, real world data, electronic health record data, that we can accelerate the search for drugs in Alzheimer’s research,” he told the audience.

To illustrate his approach, he explained that by looking at large numbers of patients and performing GWAS studies, his team can identify “pathways associated with all diseases”.

This led them to identify shared immune pathways associated with Alzheimer’s disease, age-related macular degeneration, and diabetes.

Crucially, it allowed them to look at pathways, rather than individual genes, to identify points along those pathways in laboratory studies that can be targeted with drugs.

Advances in technology are arming scientists with an improved knowledge of the genetics that underpin Alzheimer’s disease and which molecular pathways are involved in the disease pathology.

How this knowledge will help patients remains to be seen, but new ideas are certainly pushing the frontiers of Alzheimer’s research and drug development.


Healthline Media UK Ltd, Brighton, UK.

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