Office of Research & Development

Overview of VA research on

Alzheimer's Disease

Introduction

Dementia is a general term for disorders involving a decline in memory, thinking, judgment, and learning ability.

Alzheimer's disease, first described by Alois Alzheimer in 1906, is one of the most common forms of dementia. It involves the deterioration of nerve cells in the brain, which in turn affects thoughts, memory, and language.

Those with Alzheimer's disease may, at first, notice mild confusion and difficulty remembering. Eventually, people with the disease may fail to even recognize important people in their lives and undergo dramatic personality changes. Alzheimer's is the sixth leading cause of death in the United States, with death usually coming as a result of secondary infections such as pneumonia and bladder infections, that which are common in incapacitated patients, as well as the inability to follow medical instructions

Existing Alzheimer's disease medications and management strategies may temporarily improve or ameliorate the symptoms of the disease, allowing people with the diagnosis to maximize their ability to function and maintain their independence for a while longer. At present, however, there is no cure for Alzheimer's disease.

VA provides care for Veterans with Alzheimer's or other forms of dementia throughout the full range of VA health care services. Among the services VA provides to eligible Veterans are home-based primary care, homemaker and home health aides, respite care, adult day health care, outpatient clinic services, inpatient hospital services, nursing home services, and hospice care. VA also provides support to caregivers as an essential part of all these services.

In 2004, VA began the nationwide Alzheimer's Disease Neuroimaging Initiative. This study, funded by VA, the National Institute on Aging, and other sources, is making it easier for clinicians to diagnose Alzheimer's disease in its early stages.

VA's Center for Imaging of Neurodegenerative Diseases, located in San Francisco and operated in partnership with the University of California, San Francisco, is devoted exclusively to magnetic resonance imaging of the human brain, and is homing in on clues regarding Alzheimer's disease and other diseases involving the progressive loss of brain function.

VA's 21 Geriatric Research Education and Clinical Centers (GRECCs) increase basic knowledge of aging and the diseases commonly associated with growing older.

Their research staffs publish hundreds of peer-reviewed articles on aging, and provide thousands of hours of geriatric education. Many of these articles are on diseases commonly related to aging, including Alzheimer's disease.

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Selected Major Accomplishments

  • 2004: Took on leadership of a nationwide study to identify brain changes linked to Alzheimer's disease
  • 2006: Established the Center for Imaging of Neurodegenerative Diseases at the San Francisco VA, in collaboration with the Department of Defense
  • 2011: Demonstrated the effectiveness of an insulin-based treatment, using a special nasal delivery system, to possibly help ward off Alzheimer's
  • 2014: Found that Vitamin E, an inexpensive treatment, can significantly delay functional decline among patients with mild to moderate Alzheimer's
  • 2015: Developed a simple blood test that can be used to predict the buildup of amyloid in the brain, an Alzheimer's biomarker, with modest accuracy

New, Ongoing, and Published Research

VA researchers have long been interested in Alzheimer's disease. Some are working on potential drug therapies for prevention and treatment of Alzheimer's. Others are exploring the genetic and environmental causes of the disease, or studying the best ways to provide long term care for patients with Alzheimer's. Still others are working to better understand the connection between Alzheimer's and other chronic diseases such as diabetes.

In addition to these avenues of research, VA investigators are looking at ways to delay and possibly prevent the onset of Alzheimer's disease. They are also developing new ways to detect the disease, to understand its connection to other illnesses and injuries, and to support those who have the difficult responsibility of caring for Veterans with Alzheimer's.

➤The Alzheimer's Disease Neuroimaging Initiative

Although physicians can almost always determine if a person has dementia, there is no single test that can show whether a person has Alzheimer's, or is at risk of developing Alzheimer's. VA researchers at the Center for Imaging of Neurodegenerative Diseases, located at the San Francisco VA Health Care System, are managing the nationwide Alzheimer's Disease Neuroimaging Initiative (ADNI) as part of efforts to find new ways to diagnose the disease, or even predict its onset.

Researchers associated with the initiative have found that a protein called beta-amyloid 42 collects in the brains of people with Alzheimer's disease, and that low levels of the protein in the blood or spinal fluid indicate high levels in the brain.

While dementia can result from any number of health problems, such as strokes and tumors, amyloid buildup happens only in patients with Alzheimer's.

At present, amyloid levels can be determined only through spinal taps or special imaging machines. Finding amyloid in the brains of otherwise healthy people indicates they are at risk of developing Alzheimer's in the future.

Once physicians know that someone is at risk of Alzheimer's, they may in the future be able to provide treatment or recommendations for lifestyle changes that can either delay the onset of Alzheimer's related dementia, or prevent it altogether.

ADNI has developed a simple blood test that can be used to predict the buildup of amyloid in the brain with modest accuracy. If the findings of a 2015 study by ADNI researchers can be turned into a non-invasive, inexpensive, and reliable test for diagnosing the disease, the test can be used to spare people with dementia and their families the anxieties associated with uncertainty, and improve their likelihood of benefiting from current and future advances in treatment.

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➤Predicting the risk of developing Alzheimer's disease

Gene variant effect on hippocampus size—The hippocampus is a small region of the brain that plays an important role in memory and spatial navigation. VA researchers and others have shown that the smaller a person's hippocampus is, the greater the chances of cognitive decline and Alzheimer's disease late in life.

In 2014, a team of researchers from VA's Geriatric Research, Education, and Clinical Center in Nashville and Vanderbilt and Duke universities found that variants in a gene responsible for regulating blood pressure that is often tied to cardiovascular problems in older people may also cause shrinking of the hippocampus.

The team found that three variants of the AGTR1 gene, part of a hormone system responsible for regulating blood pressure and fluid balance, were associated with greater change in hippocampal volume and memory problems. This shrinkage occurred only in the right side of the hippocampus, which is related more to navigation.

The study looked at gene variants in 138 adults older than age 60. The team hopes that the gene variant can serve as a biomarker for future risk of memory loss and depression, and possibly for other psychiatric illnesses. It may also provide clues to guide future treatments.

Dementia risk of former POWs—More than 142,000 Americans have been captured and interned as Prisoners of War (POWs) since the beginning of World War I. In February 2015, VA's Veterans Benefits Administration estimated that 22,641 were still living.

TBI's link to dementia—A 2014 study by researchers from the San Francisco VA Health Care System and the University of California, San Francisco, that included more than 180,000 Veterans over 55 found that those who had been POWs had about a 50 percent greater risk of developing dementia in later life. Those who had both been POWs and developed posttraumatic stress disorder (PTSD) had more than double the risk.

Among the 484 Veterans in the study who had been POWs, about 80 percent served during World War II. The rest served in either Korea or Vietnam.

Older Veterans with a diagnosis of a traumatic brain injury (TBI) had a 60 percent greater risk of developing dementia over a nine-year period, compared with Veterans of the same age who had not suffered a TBI.

A 2014 study by researchers from the San Francisco VA Medical Center and the University of California looked at the records of nearly 200,000 Veterans aged 55 years or older who had at least one inpatient or outpatient visit during both the years 2000-2003 and 2003-2012 and did not have a diagnosis of dementia on their first visit.

The results suggested that TBI in older Veterans may predispose them toward the development of dementia, and raised concern about the potential long-term consequences of TBI in younger Veterans and others.

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➤Preventing the onset of Alzheimer's disease

Benefits of exercise—Nearly all health care professionals believe that exercise has significant health benefit, regardless of age, sex, or physical activity. The health benefits of regular exercise and physical activity include weight control, improvements in mood, energy boosts, and better sleep.

Exercise can also combat health conditions and diseases, including cardiovascular disease, stroke, and depression. Two researchers from the VA Palo Alto Health Care System and Stanford University are conducting a study to determine just what it is about exercise that is so beneficial—in hopes that finding out this mystery factor might prevent common aging-related diseases such as Alzheimer's.

According to the researchers, during exercise muscles secrete molecules that are beneficial to the body and the brain. Within those molecules are hormones, growth factors, and small proteins called cytokines that are integral for cell signaling.

The study will be the first systematic attempt to tie these molecules to their effect on the body. Investigators will take blood from an exercised animal and inject it into an unexercised animal, in hopes of seeing positive effects. They will then analyze the blood to see what factors are responsible for the changes.

A previous 2014 study, which included one of the researchers, demonstrated that blood from young mice could reverse cognitive aging in older mice. The new study will focus on the specific factors in blood that have an effect on the brain.

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➤Living with Alzheimer's disease

In order to live at home, patients with memory and judgment problems such as those caused by Alzheimer's disease must be closely supervised. The level of vigilance required of caregivers, however, can be lessened if they take some simple measures to make their homes safer.

Home safety toolkit—Researchers at the Edith Nourse Rogers Memorial Veterans Hospital in Bedford, Massachusetts. and Boston University have created a safety toolkit that provides research-based recommendations for home safety. Their 25-page, illustrated, simple-language guide was tested on 108 pairs of patients and caregivers.

The study found that in families using the toolkit, versus those receiving usual care, there was less caregiver strain, better home safety, and fewer accidents and risky behaviors among those with Alzheimer's.

The team is currently working with VA primary care clinics and other VA organizations to provide the toolkit and some sample low-cost safety items to caregivers of Veterans throughout the nation.

VA also offers a program for caregivers called "REACH VA." The program provides caregivers for Veterans with Alzheimer's with 12 individual in-home and telephone counseling sessions, and five telephone support group sessions. Caregivers are also given a quick guide to help them learn more about the disease, and to cope with situations that may arise.

Dementia medications may cause weight loss—In 2015, researchers from the San Francisco VA Health Care System and the University of California, San Francisco found that a class of medications commonly used to treat dementia, called cholinesterase inhibitors, may contribute to clinically significant weight loss.

The medications, which include donepezil, galantimine, and rivastigmine, are marginally beneficial for most patients and may have serious side effects such as gastrointestinal symptoms. In a study group of 1,188 patients on cholinesterase inhibitors, one out of every 21 patients experienced at least a 10-pound weight loss over a 12-month period.

The team suggested that clinicians need to account for this risk when prescribing these drugs to older adults.

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➤Possible treatments for Alzheimer's disease

Insulin treatments—In 2011, a pilot study by VA researchers found that a nasal insulin treatment improved memory, thinking skills, and functional ability in people with Alzheimer's disease or mild cognitive impairment. The study built on previous studies that linked low brain levels of insulin to Alzheimer's and to brain aging in general.

The researchers found that insulin delivered through the nostrils, in the form of a spray, reached the brain within minutes and did not increase insulin levels throughout the whole body—and that the treatment improved patients' ability to recall a story after a delay.

In 2015, a study funded by VA and the National Institute of Aging found that a longer-lasting synthetic form of insulin, called insulin detemir, may provide even better results than naturally-occurring insulin.

Adults with a variation of the apoliprotein E (APOE) gene called APOE-ε4 who received 40 doses of insulin detemir for 21 days showed significant improvement in their short-term ability to retain and process verbal and visual information, and those who had a gene known to increase the risk of Alzheimer's had higher memory scores than other subjects. However, those who did not have the variation, which is associated with an increased risk of Alzheimer's disease, got worse in those areas.

Vitamin E delays cognitive function decline—In the Jan. 1, 2014, issue of the Journal of the American Medical Association, a VA research team reported that taking supplemental vitamin E significantly delayed the decline of cognitive functioning in patients with mild to moderate Alzheimer's disease. The five-year study showed that the vitamin added, on average, six months of better cognitive functioning for patients with this progressive disease.

Lab experiments target memory and Alzheimer's outcomes—Researchers at the James J. Peters VA Medical Center in the Bronx and the Icahn School of Medicine at Mount Sinai are testing a new drug that blocks plaque-forming amyloids and also spurs the creation of new brain cells in animals. The drug has already been shown to be safe in humans, at least on a limited basis.

The investigational drug, known as a BCI-838, blocks proteins in the brain known as Group II metabotropic glutamate receptors. These receptors, which normally help enable memory and other brain functions, also are central to the production of beta amyloid, one of the main signs of Alzheimer's.

In a study published in 2014, the research team found that mice with Alzheimer's that received daily doses of BCI-838 over three months showed improved learning and reduced anxiety. They also showed reductions in the levels of beta amyloid in the brain, and new brain cells, or neurons, formed in the hippocampus.

Besides looking at the possibility of using BCI-838 to help Veterans with Alzheimer's, the team is also looking at the possibility that the drug can help grow new brain cells in Veterans with TBI.

Researchers with the VA San Diego Health Care System, Scripps Research Institute, and University of California, San Diego, School of Medicine showed in 2015 that increasing a membrane protein called caveolin-1 (Cav-1) in neurons within the brain can improve learning and memory in aged mice.

The team delivered Cav-1 directly into the hippocampus of adult and aged mice, thereby bringing cholesterol back to cell membranes, and helping the brain to form new synaptic contacts (contacts that pass nerve impulses from cell to cell). The mice demonstrated improved neuron growth and better retrieval of contextual memories, by freezing in place—an indication of fear—when placed in a location where they'd once received small electric shocks.

The research team is now testing this therapy in mouse models of Alzheimer's disease, and hopes to expand it to possibly treat injuries such as spinal cord injury and traumatic brain injury.

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More on Our Website

 

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Selected Scientific Articles by Our Researchers

Translation of a dementia caregiver support program in a health care system—REACH VA. Nichols LO, Martindale-Adams J, Burns R, Graney MJ, Zuber J. Describes the National Institute on Aging's Resources for Enhancing Alzheimer's Caregiver Health (REACH) trial, and its translation at VA into REACH VA. Arch Intern Med, 2011 Feb 28;171(4):353-9

Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy may be useful for patients with amnestic mild cognitive impairment and Alzheimer's disease. Arch Neurol, 2012 Jan;69(1):29-38

Clinical trial of a home safety toolkit for Alzheimer's disease. Horvath KJ, Trudeau SA, Rudolph JL, Trudeau PA, Duffy ME, Berlowitz D. Results of the test of a new educational intervention to improve the competence of informal caregivers for persons with dementia living in the community. Int J Alzheimers Dis. 2013;913606.

Vitamin E, Memantine, and Alzheimer Disease. Dysken MW, et al. Vitamin E can slow functional decline and decrease caregiver burden in patients with mild to moderate Alzheimer's disease. JAMA 2014 Jan 1;311(1):33-44

Prisoner of war status, posttraumatic stress disorder, and dementia in older veterans. Meziab O, Kirby KA, Williams B, Yaffe K, Byers AL, Barnes DE. POW status and PTSD increase risk of dementia in an independent, additive manner in older Veterans. Alzheimers Dement. 2014 Jun;10(3 Suppl):S236-41.

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabi R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function. Nat Med. 2014 Jun;20(6):659-63.

Traumatic brain injury and risk of dementia in older Veterans. Barnes DC, Kaup A, Kirby KA, Byers AL, Diaz-Arrastia R, Yaffe K. TBI in older veterans was associated with a 60 percent increase in the risk of developing dementia over 9 years. Neurology. 2014 Jul 22;83(4):312-9.

Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age. Zannas AS, McQuoid DR, Payne ME, MacFall JR, Ashley-Koch A, Steffens DC, Potter GG, Taylor WD. Genetic variants of the renin-angiotensin system may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Am J Psychiatry. 2014 Nov 1;171(11):1214-21.

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse. Kim SH, Steele JW, Lee SW, Clemenson GD, Carter TA, Treuner K, Gadient R, Wedel P, Glabe C, Barlow C, Ehrlich ME, Gage FH, Gandy S. In Alzheimer's mice, treatment with the drug BCI-838 was associated with the reversal of transgene-related amnestic behavior, reduction in anxiety, and stimulation of hippocampal growth. Mol Psychiatry. 2014 Nov;19(11):1234-42.

Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures. Apostolova LG, Hwang KS, Avila D, Elashoff D, Kohannim O, Teng E, Sokolow S, Jack CR, Jagust WJ, Shaw L, Trojanowski JQ, Weiner MW, Thompson PM: Alzheimer's Disease Neuroimaging Initiative. A classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy. Neurology, 2015 Feb 17;84(7):729-37.

Weight loss associated with cholinesterase inhibitors in individuals with dementia in a national healthcare system. Sheffrin M, Miao Y, Boscardin WJ, Steinman MA. Clinicians should consider the risk of weight loss when prescribing cholinesterase inhibitors. J Am Geriatr Soc. 2015 Aug;63(8):1512-8.

Blood-borne revitalization of the aged brain. Castellano JM, Kirby ED, Wyss-Coray T. A review of brain rejuvenation studies in the broader context of systemic rejuvenation research, discussing mechanisms for blood-borne brain rejuvenation and suggesting promising avenues for future research and development of therapies. JAMA Neurol. 2015 Oct;72(10):1191-4.

Neuron-targeted Caveolin-1 improves molecular signaling, plasticity, and behavior dependent on the hippocampus in adult and aged mice. Mandyam CD, Schilling JM, Cu1 W, Egawa J, Niesman IR, Kellerhals SE, Staples MC, Buslja AR, Risbrough VB, Posadas E, Grogman GC, Chang JW, Roth DM, Patel PM, Patel HH, Head BP. Caveolin-1 is a novel therapeutic strategy in disorders involving impaired hippocampal function. Biol Psychiatry. 2015 Oct 8. Pli: S0006-3223(15)00817-3.

Association between Alzheimer dementia mortality rate and altitude in California counties. Thielke S, Slatore CG, Banks WA. Individuals who live at higher altitudes may have a 50 percent lower risk of dying of Alzheimer's disease compared with their counterparts living at lower altitudes. JAMA Psychiatry, 2015 Dec 1;72(12):1253-4.

Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. Claxton A, Baker D Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S. Intranasal insulin detemir, which is longer lasting than regular insulin, improves cognition and daily functioning for adults with Alzheimer's disease or mild cognitive impairment. J Alzheimers Dis. 2015;44(3):897-906.

Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse. Peng Y, Kim MJ, Hullinger R, O'Riordan KJ, Burger C, Pehar M, Puglielli L. Compounds that inhibit two cellular proteins can help remove the toxic plaques found in the brain of mice with Alzheimer's disease. Brain 2016.

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