Archives for November 2017

Tips for Alzheimer’s Caregivers: Preparing for the Road Ahead and Getting the Help You Need

( Caring for someone with Alzheimer’s disease or another type of dementia impacts every aspect of your daily life. As an Alzheimer’s patient loses one ability after another, a caregiver faces tests of stamina, problem solving, and resiliency. Maintaining your emotional and physical fitness is crucial, not just for you but also for the person you’re caring for. Preparing yourself, understanding your loved one’s experience, and seeking support from others can help you succeed on the caregiving journey.

The Alzheimer’s and Dementia Care Journey

Caring for someone with Alzheimer’s disease or dementia can be a long, stressful, and intensely emotional journey. But you’re not alone. In the United States, there are about 15 million people caring for someone with dementia, and millions of others around the world. As there is currently no cure for Alzheimer’s disease—and only limited medical treatments available for the symptoms—it is your caregiving that can make the biggest difference to your loved one’s quality of life. That is a remarkable gift.

However, caregiving can also become all-consuming. As your loved one’s cognitive, physical, and functional abilities diminish over a period of years, it’s easy to become overwhelmed and neglect your own health and well-being. The burden of caregiving can put you at increased risk for significant health problems and an estimated 30 to 40 percent of dementia caregivers will experience depression, high levels of stress, or burnout. Nearly all Alzheimer’s or dementia caregivers will at some time experience sadness, anxiety, loneliness, and exhaustion. Seeking help and support along the way is not a luxury for caregivers; it’s a necessity.

Just as each individual with Alzheimer’s disease progresses differently, so too can the caregiving experience vary widely from person to person. However, there are strategies that can help make the caregiving journey as rewarding as it is challenging. Learning all you can about what is happening and what to expect on the Alzheimer’s journey will not only help your loved one, but is also the first step towards protecting your own mental and physical health.

The Challenges and Rewards of Alzheimer’s Care

Caring for a person with Alzheimer’s disease can often seem to be a series of grief experiences as you watch your loved one’s memories disappear and skills erode. The person with Alzheimer’s will change and behave in different, sometimes disturbing or upsetting ways. For both caretakers and their patients, these changes can produce an emotional wallop of confusion, anger, and sadness.

As the disease advances, your loved one’s needs will increase and your caregiving responsibilities will become more challenging. At the same time, the ability of your loved one to show appreciation for all your hard work will diminish. Caregiving can literally seem like a thankless task. For many, though, a caregiver’s long journey includes not only challenges, but also many rich, life-affirming rewards.

Challenges of Alzheimer’s care:

  • Overwhelming emotions as capabilities lessen
  • Fatigue and exhaustion as caregiving demands increase
  • Isolation and loneliness as independence disappears
  • Financial and work complications as costs rise and resources are challenged

Rewards of Alzheimer’s care:

  • Bonds deepen through care, companionship, and service
  • Problem solving and relationship skills grow through experience
  • New relationships form through education and support
  • Unexpected rewards develop through compassion and acceptance

Preparing for the Road Ahead

The more you learn about your loved one’s disease and how it will progress over the years, the better you’ll be able to prepare for future challenges, reduce your frustration, and foster reasonable expectations. In the early stages of Alzheimer’s, for example, you can support your loved one’s independence and self-care, but the person’s cognitive and physical regression means he or she will ultimately require 24-hour care.

Though it may be hard to contemplate such a difficult outlook, the sooner you put plans in place, the more your loved one can be involved in the decision-making process. Paying for long-term care can be a major source of stress, so it’s important to research all your options as early as possible. Consult with the patient’s medical team and other family members to make legal and financial arrangements and determine the long-term care options that are best suited to you and your loved one.

Developing Your Own Personal Support Plan Ahead of Time

Balancing the enormous task of caring for a cognitively-impaired adult with your other responsibilities requires skill, attention, and meticulous planning. By focusing so diligently on your loved one’s needs, it’s easy to fall into the trap of neglecting your own health. But that will not only hurt yourself, but also hurt the person you’re trying to care for. If you’re not getting the physical and emotional support you need, you won’t be able to provide the best level of care, and you face becoming overwhelmed.

Ask for help. It’s important to reach out to other family members, friends, or volunteer organizations to help with the daily burden of caregiving. Accepting help for mundane tasks such as grocery shopping and cleaning can free you up to spend more quality time with the patient. When someone offers to help, let them. You’re not being neglectful or disloyal to your loved one. Caregivers who take regular time away not only provide better care, they also find more satisfaction in their caretaking roles.  

Learn or update caregiving skills. Being thrust into the role of caregiver doesn’t come with an instruction manual, but there are books, workshops, and online training resources that can teach you the skills you need. Learn all you can about symptoms, treatment, and behavior management. As the disease progresses and challenges change, you’ll need to update your skillset and find new ways of coping.

Join a support group. You’ll find that you’re not alone and you’ll be able to learn from the experiences of others who have faced the same challenges. Connecting with others who know first-hand what you’re going through can also help reduce feelings of isolation, fear, and hopelessness.

Learn how to manage stress. Caregiving for a loved one with dementia can be one of the most stressful tasks you’ll undertake in life. To combat this stress, you need to activate your body’s natural relaxation response through techniques such as deep breathing, meditation, rhythmic exercise, or yoga. Fitting these activities into your life can help reduce the stress of caregiving and boost your mood and energy levels.

Make use of available resources. There are a wealth of community and online resources to help you prioritize your efforts and provide effective care. Start by finding the Alzheimer’s association in your country. These organizations offer practical support, helplines, advice, and training for caregivers and their families. They can also put you in touch with local support groups. See Resources and References section below for a directory of associations.

Plan for your own care. Visit your doctor for regular checkups and pay attention to the signs and symptoms of excessive stress. It’s easy to abandon the people and activities you love when you’re mired in caregiving, but you risk your health and peace of mind by doing so. Take time away from caregiving to maintain friendships, social contacts, and professional networks, and pursue the hobbies and interests that bring you joy.

Signs of Caregiver Stress and Burnout

No matter how strong and resilient you are, you’re still likely to have problems with certain aspects of Alzheimer’s or dementia care. The stress of day-to-day care, watching your loved one’s health deteriorate, and having to make difficult decisions about long-term care can leave anyone feeling overwhelmed and exhausted. Recognizing the signs of caregiver stress and burnout is the first step to dealing with the problem.

10 Signs of Caregiver Stress

If you experience any of these signs of stress on a regular basis, make time to talk to your doctor.

1. Denial about the disease and its effect on the person who has been diagnosed. “I know Mom is going to get better.”

2. Anger at the person with Alzheimer’s, anger that no cure exists, or anger that people don’t understand what’s happening. “If he asks me that one more time I’ll scream!”

3. Social withdrawal from friends and activities that once brought pleasure. “I don’t care about getting together with the neighbors anymore.”

4. Anxiety about the future. “What happens when he needs more care than I can provide?”

5. Depression that begins to break your spirit and affects your ability to cope. “I don’t care anymore.”

6. Exhaustion that makes it nearly impossible to complete necessary daily tasks. “I’m too tired for this.”

7. Sleeplessness caused by a never-ending list of concerns. “What if she wanders out of the house or falls and hurts herself?”

8. Irritability that leads to moodiness and triggers negative responses and actions. “Leave me alone!”

9. Lack of concentration that makes it difficult to perform familiar tasks. “I was so busy, I forgot we had an appointment.”

10. Health problems that begin to take a mental and physical toll. “I can’t remember the last time I felt good.”

Source: Alzheimer’s Association

When prolonged and excessive stress from caring for a loved one with Alzheimer’s or dementia leaves you feeling emotionally, mentally, and physically exhausted, you may be facing burnout. Burnout reduces your productivity and saps your energy, leaving you feeling helpless, hopeless, angry, and resentful. Eventually, you may feel like you have nothing more to give.

The warning signs of caregiver burnout include:

  • Excessive stress and tension
  • Debilitating depression
  • Persistent anxiety, anger, or guilt
  • Extreme irritability or anger with the dementia patient
  • Decreased overall life satisfaction
  • Relationship conflicts and social isolation
  • Lower immunity and greater need for healthcare services
  • Excessive use of medications, drugs, or alcohol

Burnout can damage your health and the health of the person you’re caring for, so if you recognize the signs, it’s important to take action right away.

Coping with Stress and Burnout

No matter the day-to-day demands of caregiving for a patient with Alzheimer’s or dementia, it’s imperative that you carve out time for your own self-care. These tips can help:

Seek regular respite care. You cannot do it all alone. Ask other family members, friends, or members of your place of worship for help with respite care so you can get a much needed break. You can also seek help from volunteer organizations, support groups, day care programs, and residential respite care facilities. Schedule frequent breaks throughout the day, take time out to pursue hobbies and interests, and stay on top of your own health needs. Seek professional help if you recognize you’re exhibiting any warning signs of caregiver burnout.

Get moving.  Regular exercise not only keeps you fit, it releases endorphins that can really boost your mood. Aim for at least 30 minutes of exercise on most days. If it’s difficult to get away for that long at once, break the time up into 10 minute sessions sprinkled throughout the day. Take a walk or jog outside, dance to your favorite music, work out to an exercise DVD, or cycle to the store. Taking a group exercise class or working out with friends can give you a valuable social outlet as well.

Talk to someone. Talk to a trusted friend, family member, clergy member, or therapist, about how you feel and what you’re going through. The person you talk to doesn’t have to be able to solve your problems, he or she just has to be a good listener. The simple act of talking face-to-face with someone who cares can be extremely cathartic. Opening up won’t make you a burden to others. In fact, most friends will be flattered that you trust them enough to confide in them, and it will only strengthen your bond.

Take time to play. In the early stages of Alzheimer’s disease, include your loved one in short walks, board games, or jigsaw puzzles. Join an online scrabble tournament, practice your golf swing, or play with a pet. A daily dose of fun is good medicine, and doesn’t require money, a car, or huge blocks of time.

Try something new. Challenge yourself to learn a new skill while you are “on the job.” Order a self-paced foreign language program or try an exercise video game. From tennis to golf to pitching a strike, so-called “exergames” offer living room-friendly activities for every age and skill level. With just a few minutes of practice each day, you can flex mental muscle and relieve harmful stress.

See the funny side. Humor is a well-known antidote to stress, sadness, illness, and boredom. Give yourself permission to chuckle at the absurdities you and your loved one experience, and surround yourself with laughter. Instead of heavy dramas on TV or video, go for a hearty belly laugh by watching episodes of your favorite sitcom. Your infectious good mood can help replenish your inner resources and sooth your loved one.

Making Time for Reflection Can Help with Acceptance

One of the biggest challenges as a caretaker for someone with Alzheimer’s or dementia is to accept what is happening to your loved one. At each new stage of the disease, you have to alter your expectations about what your loved one is capable of. By accepting each new reality and taking time to reflect on these changes, you can better cope with the emotional loss, and deepen the feelings of satisfaction and love in your role as caretaker.

Keep a daily journal to record and reflect on your experiences. By journaling your thoughts, you can mourn losses, celebrate successes, and look for those thought patterns that keep you from acting in the present.

Count your blessings. A daily gratitude list can chase away the blues and let you focus on what your loved one is still capable of, rather than the abilities he or she has lost.

Celebrate what is possible. Your loved one still has many abilities. Structure activities to invite participation on whatever level is possible, and you will both find real enjoyment.

Try to envision your loved one’s world. Imagine not being able to remember and do life’s simple tasks. By valuing what your loved one is able to give, you can find satisfaction on even the toughest days.

Practice relaxation techniques. Meditation, deep breathing, visualization, mindfulness, yoga, or rhythmic exercise can calm, restore, and promote happiness. Experiment with different techniques to find the ones that work best for you.

Improve emotional awareness. Remaining engaged, focused, and calm in the midst of such tremendous responsibility can challenge even the most capable caregivers. By developing your emotional awareness skills, however, you can relieve stress, experience positive emotions, and bring new peace and clarity to your caretaking role.

Tap into the rewards of connecting with the person you’re caring for

Even when the person you’re caring for can no longer verbally express love or appreciation, you can find a deeper sense of reward in your role as caregiver by making time each day to really connect with the person. Avoid all distractions and focus fully on the person. Make eye contact (if that’s possible), hold the person’s hand or stroke his or her cheek, and talk in a calm, reassuring tone of voice. When you connect in this way, you’ll experience a process that boosts your mood, reduces stress, and supports your physical and emotional well-being. And it can also have the same effect on your loved one.

How to Help an Alzheimer’s or Dementia Caregiver

If a friend or family member is caring for someone with Alzheimer’s or dementia, it’s important to offer all the help and support you can.

Don’t wait to be asked to help. Many caregivers find it difficult to ask others for help, no matter how much they may need it, so make the offer. And when you do, be specific. As well as simply asking, “What can I do to help?” make suggestions like, “I’m free tomorrow afternoon, can I sit with the patient while you take a break?” or “What can I get you from the grocery store today?” Helping out with even the most simple or mundane chores can free the caregiver up to spend more quality time with the patient or take a break to recharge his or her batteries.

Be a friend. Caregivers are prone to withdrawing from family and friends but they still need regular contact with the outside world. Phone calls, texts, or emails are fine, but nothing beats a personal visit to lift a caregiver’s mood. Again, don’t wait to be asked; be the one to reach out.

Be a good listener. Venting frustrations about caregiving can be a great stress reliever. Listen to the caregiver’s fears and concerns without judging.

Show your gratitude. If the caregiver is a sibling looking after your parent, for example, it’s important to express your gratitude. The person with mid- or late-stage Alzheimer’s or dementia may not able to show appreciation to the caretaker so it’s important other family members recognize the caregiver’s hard work and sacrifice and regularly show their appreciation. While a card or a simple “Thank you” can go a long way, when accompanied by the offer of some respite, it can be a blessing.

Recognize the signs of caregiver stress and encourage the caregiver to focus more on his or her own health and well-being.

Related Articles

Caregiver Stress and Burnout: Tips for Regaining Your Energy, Optimism, and Hope

Family Caregiving: Tips for Making Family Caregiving Easier and More Rewarding

Living with Dementia: Coping Tips & Strategies for Both You and Your Family

Care for the Caregiver: Part 1 (Video)

Care for the Caregiver: Part 2 (Video)

Dementia care specialist Teepa Snow discusses the fear of dementia and dealing with the challenges of caring for a loved one. (YouTube/Senior Helpers National)

Caregiver Support

Alzheimer’s Associations – A worldwide directory of Alzheimer’s associations that offer information, advice, and support for caregivers. (Alzheimer’s Disease International)

Family Care Navigator – For caregivers in the U.S., a state-by-state resource to help you locate services and other resources. (Family Caregiver Alliance)

Caregiver Action Plan – Create a personalized action plan for caregiving and link to information, support, and local resources. (Alzheimer’s Association)

Alzheimer’s Caregiving: How to Ask for Help – Suggestions on how to engage family and friends in helping out with patient care. (Mayo Clinic)

Caregiver’s Stress Check – Tests your stress and provides recommendations for addressing common caregiver’s issues. (Alzheimer’s Association)

Caregivers and Mental Health

Depression and Caregiving – Describes the symptoms of caregiver depression and offers suggestions on what to do for yourself if you are depressed as a result of caregiving. (Family Caregiver Alliance)

Dementia, Caregiving and Controlling Frustration – Discusses causes of frustration, warning signs that frustration is occurring, and several methods caregivers can use to help control or alleviate their frustrations. (Family Caregiver Alliance)

Changes to Your Relationship – Information about how the caregiver’s relationships may change: intimacy with the patient, and closeness to family and friends, with tips for resolving family conflicts. (Alzheimer’s Association)

Preventing Caregiver Burnout

Preventing Caregiver Burnout – Caregiver burnout is something you may not notice, but people you know may notice changes in you and express their concern. (Area Agency on Aging)

 PDF version


Authors: Lawrence Robinson, Melissa S. Wayne, M.A. and Jeanne Segal, Ph.D. Last updated: October 2017.

© All rights reserved.


Alzheimer’s Disease Prevention: From Risk Factors to Early Intervention

 2017 Sep 12;9(1):71. doi: 10.1186/s13195-017-0297-z.

Alzheimer’s disease prevention: from risk factors to early intervention.

Crous-Bou M1Minguillón C1Gramunt N1,2Molinuevo JL3,4.


Due to the progressive aging of the population, Alzheimer’s disease (AD) is becoming a healthcare burden of epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in mild-moderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD is allowing the development of intervention studies and secondary preventionprogrammes on asymptomatic at-risk individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as highly relevant.In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the pathophysiological hallmarks and intervention at the preclinical stage of the disease.

Firstly, we summarize the evidence on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as revising current primary prevention strategies.

Secondly, we review the development of public-private partnerships for disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention trials.

Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for the onset of AD-related cognitive impairment.The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD prevention programmes that, by delaying the onset of Alzheimer’s dementia for only a few years, would have a huge impact on public health.


The prevalence of dementia worldwide is estimated to be over 45 million people [1] and is predicted to triple by 2050 as a consequence of increased life expectancy, establishing dementia as one of the biggest global public health challenges. Alzheimer’s disease (AD) is the most common form of dementia and accounts for 60–80% of cases [1]. AD is a progressive neurodegenerative disease, irreversible and disabling, causing a large socioeconomic burden [2].

The criteria for AD diagnosis have been revised extensively, and experts agree that the hallmark pathological criteria include increased levels of amyloid-beta (Aβ) peptide, which is deposited extracellularly in diffuse and neuritic plaques, and hyperphosphorylated tau (p-tau), a microtubule assembly protein that accumulates intracellularly as neurofibrillary tangles [3]. Initial diagnostic efforts focused on patients at the dementia stage of the disease and, only recently, the importance of a long pre-dementia stage, preceding the clinical onset of the disease symptoms, has been recognized. As the disease progresses, the subject’s cognition changes from an initial phase where it is fully preserved to a final stage characterized by dementia [4]. The initial silent and asymptomatic stage, referred to as preclinical AD, is characterized by a sequence of pathophysiological hallmarks that start to appear about 20 years before the onset of symptoms [5].

Unfortunately, none of the drugs tested to date in clinical trials in order to change the course of the disease have shown effective results in AD dementia [6]. Therefore, many interventional studies are currently moving their focus to cognitively healthy individuals at risk of developing AD (before substantial irreversible neuronal network dysfunction and loss, associated with overt clinical symptoms, have occurred) as the best strategy to reduce AD incidence and prevalence.

In this review, we will summarize current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention based on early detection of the pathophysiological hallmarks and intervention at the preclinical stage. Furthermore, we will discuss a number of selected environmental risk factors for AD, and we will describe currently ongoing interventional initiatives focused on primary prevention of AD, as well as some of the public–private partnerships (PPPs) for disease prevention that are setting up a framework to identify and select individuals for clinical trials focused on preclinical stages.

Primary Prevention

Modifiable Risk Factors for AD

Since AD develops over a long preclinical stage that can last for several decades, the extent to which risk factors assessed in late life or shortly before the onset of clinical symptoms are a result of pathological changes rather than having a causal relationship has been discussed intensively. Longitudinal studies that include participants in early mid-life have been crucial to assess the relationship between early or mid-life exposures and cognitive decline or AD later in life [7].

Observational studies have identified several modifiable risk factors for AD. Based on a comprehensive systematic review of the evidence related to risk factors for cognitive decline and AD, the US National Institutes of Health highlighted diabetes mellitus, smoking, depression, mental inactivity, physical inactivity and poor diet as being associated with increased risk of cognitive decline, AD, or both [8].

Later on, this list was further extended to include hypertension, obesity and low educational attainment [9]. Recently, an association was demonstrated between the presence of vascular risk factors in mid-life and amyloid deposition later in life [10], even though some of these factors are still under debate. It has been estimated that up to a third of AD cases are potentially attributed to these factors and, consequently, could be prevented [11].

Modifiable risk factors for AD are mostly related to either cardiovascular risk factors (diabetes, hypertension and obesity) or lifestyle habits (e.g. smoking, physical activity, diet, mental and social activity). Diabetes has been associated with an increased risk of AD (RR = 1.39). It has been suggested that diabetes could increase the risk by directly affecting Aβ accumulation in the brain since hyperinsulinemia disrupts brain Aβ clearance by competing for the insulin-degrading enzyme [1213].

In contrast, other studies suggest that diabetes might increase the risk of cerebrovascular but not AD pathology, and that at least part of the relationship between diabetes and cognitive impairment may be modified by neuropathology [14]. Even though the association between high blood pressure and AD risk is complex and age related, evidence suggest that mid-life, and not late-life, hypertension is associated with a 50% increased risk of AD and dementia in later life.

Elevated blood pressure might increase the risk of AD by decreasing the vascular integrity of the blood–brain barrier, resulting in protein extravasation into brain tissue, which can consequently lead to cell damage, apoptosis and an increase in Aβ accumulation [15]. However, the direction of a possible causal relationship between hypertension and subsequent cognitive decline is under debate since there is also increasing evidence that hypertension may be a protective response to cerebral hypoperfusion, which is demonstrable 10 years prior to AD onset [1617].

Observational studies have shown a U-shaped relationship between weight and cognitive performance: both low and high body weight have been associated with increased risk of AD and cognitive impairment. This association might also have an age-dependent component. Data also exist for reverse causation in the years preceding disease onset; that is, loss of body weight might be caused by cognitive impairment during the pre-dementia phase of AD. Consequently, the relationship between body weight and AD seems to be a consequence of mid-life obesity, which could increase the risk of AD by 60%. Even though the underlying mechanisms of this association remain unknown, studies suggest that insulin resistance and co-incidence with diabetes mellitus may play a role [18].

With regards to lifestyle-related factors, the association between smoking and AD risk has been controversial and remains unclear. Most observational studies show an association between current smoking and increased risk of dementia, AD and cognitive decline. Even though relative risks for AD are relatively small (RR = 1.20–1.60), nearly 14% of AD cases are estimated to be potentially attributable to smoking due to its high prevalence [9]. Smoking may increase AD risk through several mechanisms, mostly related to oxidative stress and inflammatory responses [19].

Epidemiological studies have shown that physical activity has a beneficial effect on brain health, which could be explained through multiple mechanisms including activation of brain plasticity, promotion of brain vascularization, stimulation of neurogenesis, reduction of inflammation levels or even by decreasing the rate of amyloid plaque formation. In comparison with sedentary behaviours, individuals with high levels of physical activity have been shown to reduce their AD risk by half (RR = 0.72 for all causes of dementia; RR = 0.55 for AD) [2021]. Involvement in exercise programmes has been shown to significantly improve cognitive function in healthy older people. In contrast, physical inactivity has been associated with an increased risk of cognitive impairment in most longitudinal studies.

However, whilst there is convincing evidence of an association between physical activity and subsequent cognitive decline, the direction of a possible causal relationship is still debatable. In their recent study, Sabia et al. [22] did not find evidence of a neuroprotective effect of physical activity and suggest that previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation (i.e. due to a decline in physical activity levels in the preclinical phase of dementia).

The Mediterranean diet (MD) [23] may also protect against cognitive decline, AD and all-cause dementia [2425]. Observational studies have shown that higher adherence to a MD is associated with slower rates of cognitive decline, reduced progression to AD and improvements in cognitive function. Specifically, it has been shown that adherence to a MD might have a beneficial effect on memory, executive function and visual constructs [25]. A recent intervention study, PREDIMED, has shown that a MD supplemented with olive oil or nuts is associated with improved cognitive function [26].

Cognitive, social and intellectual activity jointly with higher education and occupational attainment have been shown to decrease risk of cognitive decline and dementia by increasing cognitive reserve, the capacity of the brain to resist the effects of neuropathological damage [27]. Observational studies consistently show that people who engage in mentally stimulating activities are less likely to develop AD (RR = 0.54). About 19% of AD cases worldwide are potentially attributable to low education attainment, making it the risk factor that contributes to the largest proportion of AD cases [9].

Helping to build a cognitive reserve that enables individuals to continue functioning at a normal level despite experiencing neurodegenerative changes seems to have a high impact on disease onset. The beneficial impact of bilingualism on brain reserve and consequently on AD risk and cognition has been highlighted recently [2829]. Studies suggest that lifelong bilingualism may delay the onset of dementia by about 4.5 years by contributing to cognitive reserve and, consequently, protecting against neurodegeneration.

The fact that a third of AD cases are potentially attributable to modifiable risk factors highlights the potential of risk factor reduction for disease prevention. However, the need for therapeutic strategies for the remaining two-thirds of cases is still urgent.

Primary Prevention Strategies

Intervention strategies focused on modifiable risk factors for the disease are becoming a realistic and relevant therapeutic strategy for disease prevention. Interestingly, large epidemiological cohort studies suggest that the incidence of age-specific dementia is decreasing, probably due to a better control of cardiovascular risk factors [3031].

As an example, several intervention studies focused on primary prevention of dementias are currently ongoing, mainly in Europe, with the aim of reducing disease incidence. It is worth mentioning the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study [32] which aimed to investigate whether a multidomain intervention could prevent cognitive decline among older people. Additionally, investigators aimed to assess the effect of this multidomain intervention on disability, quality of life, depressive symptoms, the use of health care services and vascular risk factors. The 1200 participants of the FINGER study had an increased risk of cognitive decline. To date, results from this large, long-term, randomized controlled trial (RCT) have demonstrated that a multidomain intervention including diet, exercise, cognitive training and monitoring vascular risk can improve or maintain cognitive functioning in older people (60–77 years old) from the general population at risk of dementia [33].

The Prevention of Vascular Dementia by Intensive Care (PreDIVA) trial aimed to determine whether the control of cardiovascular risk factors could reduce dementia incidence. PreDIVA tested whether a multicomponent intervention targeting vascular risk factors could prevent new cases of dementia [34]. Researchers conducted a 6-year, open cluster RCT in primary care with over 3500 cognitively healthy participants aged 70–78. Results showed that this multidomain intervention focused on vascular care did not result in a reduced incidence of all-cause dementia in an unselected population of older people and did not have an effect on mortality, cardiovascular disease or disability, despite a greater improvement in systolic blood pressure in the intervention group compared with the control. Investigators suggested that the absence of effect might have been caused by modest baseline cardiovascular risks and high standards of usual care received by the control group. Hence, these results do not rule out the potential benefit of a better management of cardiovascular risk factors on brain health [35].

Another relevant study is the Multidomain Alzheimer Preventive Trial (MAPT) which aimed to evaluate the efficacy of a single multidomain intervention including nutritional counselling, physical exercise and cognitive training, the efficacy of an isolated omega 3 fatty acid supplementation and the efficacy of a combination of the two previously mentioned interventions on the prevention of cognitive decline in frail older participants aged 70 years or older [36]. A total of 1680 participants were followed for a period of 3 years; the study also collected imaging and biological data to be potentially used in future AD prevention and treatment trials. Both the multidomain intervention and polyunsaturated fatty acids, either individually or in combination, had no significant effects on cognitive decline over 3 years in older people with memory complaints. Particularly, the fact that participants had subjective memory complaints at enrolment, their mean age was 75 years and that almost half of participants showed a clinical dementia rating of 0.5 might have been important methodological limitations of the study. It might have been too late for the preventive intervention to show its potential efficacy. However, a post-hoc analysis performed on those participants with a positive amyloid scan showed a significant benefit in favour of the intervention [37].

Recently, a new study based on an eHealth intervention has been presented. Healthy Ageing Through Internet Counselling in the Elderly (HATICE) aims to investigate whether a multidomain intervention to optimize self-management of lifestyle-related risk factors for cardiovascular disease in older individuals, delivered through a coach-supported interactive platform, can improve the cardiovascular risk profile and reduce the risk of cardiovascular disease and cognitive decline [38]. The study has recruited 2600 people older than 65 years at increased risk of cardiovascular disease. Investigators developed an intuitive, easy-to-use platform, allowing for widespread use among older adults with only limited computer skills. Results from this study are expected in 2017.

Based on experiences and data from the intervention studies on AD prevention described (summarized in Table 1), investigators from the European Dementia Prevention Initiative (EPDI) have recently launched the Multimodal Preventive Trials for AD (MIND-AD) project. While all trials described previously are testing the effects of multimodal interventions targeting vascular, dietary and lifestyle-related risk factors in older adults not suffering with dementia, the aim of the MIND-AD project is to identify effective prevention strategies for AD and dementia tailored to different “at-risk” groups. The novel approach of this project consists of multidomain interventions, inclusion of novel models of delivery (e.g. computer-based cognitive training, medical food), critical feedback from trial participants and synergistic use of data from several European countries with over 10,000 participants. Furthermore, a pilot study in which a multimodal preventive intervention will be tested for the first time in prodromal AD will be conducted (

Table 1 Description of randomized controlled trials of multidomain interventions for prevention of cognitive impairment, dementia or AD





Study population

1260 community dwellers from previous population-based non-intervention studies

3526 community dwellers

1680 community dwellers

2600 community dwellers

Main inclusion criteria

CAIDE Dementia Risk Score ≥ i6 and cognitive performance at the mean level or slightly lower than expected for age assessed with the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery

All community-dwelling older people without dementia registered with a participating general practice

Frail older people: spontaneous memory complaint, limitation in one instrumental activity of daily living and slow walking speed (i.e. lower than 0.8 m/s)

Older adults without dementia at increased risk of cardiovascular disease

Age at enrolment

60–77 years

70–78 years

≥70 years

≥65 years

Study design

Multicentre, randomized controlled trial

Multicentre, cluster randomized controlled trial

Multicentre, randomized controlled trial

Multicentre, randomized controlled trial


Multidomain: (1) nutritional guidance; (2) physical exercise; (3) cognitive training and social activity; and (4) intensive monitoring and management of metabolic and vascular risk factors

Multidomain: (1) nutritional advice; (2) physical activity advice; and (3) vascular care including medical treatment of risk factors

Multidomain: (1) nutritional advice; (2) physical activity advice; (3) cognitive training; and (4) vascular care, and/or 800 mg docosahexaenoic acid per day

e-health: multidomain interactive Internet platform, stimulating self-management of vascular risk factors, with remote support

Control group

General health advice

Usual care

Placebo alone

Static Internet platform with basic health information


2 years plus 5-year follow-up

6 years

3 years plus 2-year follow-up

18 months


Primary: change in cognitive performance. Secondary: dementia; disability; depression; vascular risk factors and outcomes; quality of life; utilization of health resources; and neuroimaging biomarkers.

Primary: cumulative incidence of dementia and disability score (ALDS) at 6 years of follow-up. Secondary: incident cardiovascular disease and cardiovascular and all-cause mortality. Other secondary: cognitive decline, depression, blood pressure, body mass index, blood lipid concentrations, and glucose concentration.

Primary: change in memory function. Secondary: cognitive performance, functional status, depression, cost-effectiveness

Primary: outcome is a composite score based on the average z-score of the difference between baseline and 18-month follow-up values of systolic blood pressure, low-density-lipoprotein and body mass index. Secondary: include the effect on the individual components of the primary outcome, the effect on lifestyle-related risk factors, incident cardiovascular disease, mortality, cognitive functioning, mood and cost-effectiveness


Completed in 2014

Completed in 2015

Completed in 2014

Due to finish in 2017

Findings (if available)

The multidomain intervention could improve or maintain cognitive functioning [24]

The intervention did not result in a reduced incidence of all-cause dementia and did not have an effect on mortality, cardiovascular disease or disability [26]

The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline. Post-hoc data showed that the combination of polyunsaturated fatty acids and multidomain intervention had potential beneficial effects in participants with CAIDE scores ≥ 6 or higher or evidence of brain amyloid pathology, suggesting that people with increased risk of dementia might benefit most from the intervention [28]








AD Alzheimer’s disease, ALDS Academic Medical Center Linear Disability Score, CAIDE Cardiovascular Risk Factors, Aging, and Incidence of Dementia, FINGER Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, HATICEHealthy Ageing Through Internet Counselling in the Elderly, MAPT Multidomain Alzheimer Preventive Trial, PreDIVAPrevention of Vascular Dementia by Intensive Care

In the USA, an example of a cognitive-related intervention is the ACTIVE study, the biggest RCT on cognitive training in healthy older adults [39]. The ACTIVE study included over 2800 cognitively healthy participants older than 65 years who attended 10 group sessions during a 6-week period where, according to the intervention arm, they received specific training in either memory, reasoning or speed of processing. A subgroup of participants in each arm received a few booster sessions just before the first and third years post intervention. The intervention groups were compared among them, and with a non-intervention control group. Results confirmed that domain-specific training was beneficial for maintaining cognition in the targeted domain. Two years later, the intervention showed modest benefits for cognitive training in cognitive performance, which were maintained at the 5-year follow-up [40], and slight benefits in self-reported function in daily living activities [41]. After the 10-year follow-up investigators concluded that those who received any intervention showed less functional decline in daily living activities, and those trained in reasoning and speed of processing also showed better performance in the targeted abilities [42]. Dementia rates at 10 years were significantly lower in participants in the speed of processing intervention group [43].

Results from intervention studies highlight the methodological limitations underlying the design and implementation of effective preventive strategies. Studies should take into account that AD is multifactorial and, consequently, interventions should be specific to risk profiles. Small long-term effects on cognition, as those shown by FINGER, are of high relevance for public health, since they may significantly contribute to the reduction of the overall burden of AD. An effective strategy for AD prevention could start with recommendations addressed to the general population (particularly to cognitively healthy subjects older than 50 years) on how to manage lifestyle and cardiovascular risk factors. In parallel, a multidomain long-term intervention could be offered to individuals identified as being at increased risk of developing AD (e.g. subjects with subjective memory concerns or a family history of dementia).

Secondary Prevention

New consensus diagnostic criteria for preclinical AD, together with the identification of at-risk individuals through the use of biomarkers that are altered before clinical decline (i.e. amyloid deposition in the brain), are key for identifying at-risk asymptomatic individuals who are ideal candidates to participate in secondary prevention trials. Cerebral Aβ deposition is considered a necessary, but not sufficient, step on the path towards AD development [44].

Furthermore, results from most trials focused on Aβ-centric approaches at the dementia stage of AD have been disappointing, suggesting that those participants have already surpassed the optimal therapeutic window for intervention [6]. The preclinical stage might offer the optimal window for therapeutic success and the opportunity to intervene at earlier stages of the continuum, arresting or delaying the onset of cognitive decline and ultimately dementia.

This approach is also supported by studies showing that biomarker abnormality in preclinical AD occurs in a temporal manner: low Aβ42 in cerebrospinal fluid (CSF) and cerebral amyloid deposits precede elevated CSF tau, topographical cerebral injury and cognitive decline [4546]. These pathologic changes may start decades before the onset of symptoms: in pre-symptomatic PSEN mutation carriers, CSF Aβ42 decline has been observed 25 years before clinical symptoms, whilst brain Aβ deposition and elevated CSF tau have been detected 15 years before symptom onset [47]. Observational studies have shown that cognitively normal individuals with abnormal levels of AD biomarkers exhibit longitudinal cognitive decline [4849], suggesting that they are at increased risk of progressing to cognitive impairment and, consequently, to dementia.

Several PPPs for disease prevention are currently ongoing, setting up a framework to identify and select individuals to be included in trials focused on the AD preclinical stage. These initiatives also aim to maximize efficiency to obtain a clinical signal and develop sensitive outcomes for detecting early decline, through new trial designs.

The Dominantly Inherited Alzheimer Network (DIAN) is an international PPP determined to understand a rare form of AD that is dominantly inherited, caused by a genetic mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) [50]. The DIAN pioneers observational studies in pre-symptomatic individuals based on the hypothesis that understanding this form of AD may provide insight into the more common form of the disease. DIAN is enrolling participants who are adult children of a parent with a mutated gene known to cause dominantly inherited AD. Participants may or may not carry the gene, and may or may not have disease symptoms. The DIAN is developing an expanded registry to enable trials for research-neglected individuals such as familial early-onset AD, to increase the power for successful trials and to test more drugs. Moreover, the project supports studies related to autosomal dominant AD to increase the chance of success of treatment trials. The ultimate objective of DIAN is a successful prevention trial that yields the approval of the first disease-modifying drug, bolsters interest in developing improved drugs and demonstrates a clear pathway to prevent AD in the general population.

The Alzheimer’s Prevention Initiative (API) is an international collaborative initiative established to provide an innovative approach to Alzheimer’s prevention research by evaluating the most promising therapies in cognitively normal people who, based on their age and genetic background, are at the highest imminent risk of developing AD symptoms [51]. The API is focused on prevention and treatment trials, biomarker studies and registries, with the ultimate goal being to delay, reduce the risk or prevent AD clinical onset. The API has set up a robust registry where members receive regular informational materials including new trials.

A major European PPP, the European Prevention of Alzheimer’s Dementia (EPAD) project, funded by the Innovative Medicines Initiative, is designed to increase the likelihood of the successful development of new treatments for the secondary prevention of Alzheimer’s dementia by creating a novel environment for testing numerous interventions [52]. EPAD aims to create the necessary infrastructure, including a registry and a longitudinal cohort study, for delivering an adaptive trial for secondary prevention of AD. EPAD will test different agents in pre-dementia AD participants through an infrastructure providing: improvement of access to existing cohorts and registries; development of a registry of approximately 24,000 individuals who might be at increased risk of developing AD; establishment of a longitudinal cohort study of 6000 subjects; and establishment of an adaptive, proof-of-concept trial including 1500 participants at any given time.

In the USA, the Global Alzheimer’s Platform (GAP) has already been launched, while Canada and Japan are about to promote similar sister initiatives. There are several projects under the GAP umbrella: GAP-track is establishing a global standing, trial-ready platform to reduce clinical testing cycle times by 2 years or more and achieve greater efficiency and uniformity in trial populations through large, well-characterized trial-ready cohorts, certified clinical trial sites and an adaptive proof-of-concept trial mechanism. This will enable the delivery of efficient and effective proof-of-concept and confirmatory trials and ultimately a more rapid delivery of effective therapies to patients or persons at risk. GAP-net is creating a trial-ready network of sites all over the USA for the prevention and treatment of AD [53].

Secondary prevention trials in asymptomatic participants with preclinical AD who are amyloid positive are already ongoing. Some of these trials are summarized in Table 2. In the context of the dominantly inherited form of AD, the DIAN-TU trial targets cognitively normal individuals, participants with mild cognitive impairment or mild dementia who are either known to have an AD-causing mutation or at risk for such a mutation. The aim is to assess the efficacy of gantenerumab and solanezumab by determining whether treatment improves cognitive outcomes and disease-related biomarkers. The API-ADAD (for Autosomal Dominant AD) trial will recruit preclinical members of the PSEN1 E280A mutation carrier kindred. It will evaluate the efficacy of crenezumab in 200 cognitively normal individuals who carry the PSEN1 E280Amutation. The study will also include 100 PSEN1 E280A mutation non-carriers who will receive placebo only.

Table 2 Description of currently ongoing AD prevention clinical trials







Estimated enrollment







Target population/specific characteristics

Autosomal dominant Alzheimer’s disease (ADAD) mutation carriers or persons that have a 50% chance of carrying an ADAD mutation

Membership in PSEN1 E280A mutation carrier kindred

Cognitively normal, positive brain amyloid PET

Cognitively normal with genetic risk (TOMM40 and APOEgenotype)

Cognitively normal APOE-ε4homozygous

Cognitively normal positive amyloid


18–80 years

30–60 years

65–85 years

65–83 years

60–75 years

60–85 years


Phase II/III

Phase II

Phase III

Phase III

Phase II/III

Phase II/III











Anti-Aβ antibodies

Anti-Aβ antibody

Anti-Aβ antibody

PPAR-γ agonist

Aβ vaccine

BACE inhibitor

BACE inhibitor


Ongoing, not recruiting

Active, not recruiting


Active, not recruiting



Primary outcome

Composite Cognitive Test Score

Composite Cognitive Test Score

Composite Cognitive Test Score

Time to diagnosis of mild cognitive impairment (MCI) due to AD

Time to diagnosis of MCI or dementia due to AD

Composite Cognitive Test Score

Composite Cognitive Test Score

Study duration

4 years

5 years

3 years

5 years

5 years

4.5 years

Trial identifier







Expected completion

December 2019

September 2020

October 2020

July 2019

August 2023

May 2023


Source: (accessed May 2017) [45]

A4 Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study, Aβ amyloid beta, AD Alzheimer’s disease, API-ADADAlzheimer’s Prevention Initiative for Autosomal Dominant Alzheimer’s Disease, API-GENERATION A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer’s Disease, BACE Beta-secretase, DIAN Dominantly Inherited Alzheimer Network, EARLY An Efficacy and Safety Study of JNJ-54861911 in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia, PET Positron Emission Tomography, PPAR Peroxisome proliferator activated receptor, PSEN1 presenilin 1, TOMMORROW Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer’s Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset

Regarding sporadic AD, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study aims to test whether an anti-amyloid antibody, solanezumab, can slow cognitive loss caused by AD. The overall goal is to test whether solanezumab can help slow the cognitive loss associated with amyloid build-up. The study plans to enrol 1150 cognitively healthy adults with a positive amyloid scan who are randomly assigned to receive the investigational drug or placebo. New studies with a similar approach, such as the EARLY study, are currently ongoing. The purpose of EARLY is to evaluate whether treatment with the BACE inhibitor JNJ-54861911 slows cognitive decline, as measured by a composite cognitive measure, the Preclinical Alzheimer Cognitive Composite (PACC), in cognitively healthy amyloid-positive participants.

Other studies employ a different approach, selecting participants through a genetic risk profile. The TOMMORROW study will use a genetic risk assignment algorithm (BRAA) to determine the 5-year risk of developing MCI due to AD. The efficacy of low-dose pioglitazone to delay the onset of MCI due to AD will be tested in cognitively normal, high-risk individuals, as identified by the BRAA. The study uses TOMM40 and APOE genotype and age to identify individuals who may be at a high or low risk of developing MCI in the following 5 years. High-risk individuals will be randomly assigned to the active or placebo arms. A small group of low-risk individuals will receive placebo. The API-GENERATION study, a randomized, double-blind, placebo-controlled, two-cohort parallel group study, aims to evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of AD symptoms. The purpose is to determine the effects of each of the two therapies given separately, on cognition, global clinical status and underlying pathology. Cognitively unimpaired individuals, homozygotes for APOE-ε4 aged 60–75 years, were selected as a high-risk population for progression to MCI due to AD and/or dementia.


Epidemiological evidence of AD risk factors is contributing and encouraging the development of primary prevention initiatives. Current trials and strategies are necessary steps whose results are helping to improve future designs, bringing some post-hoc analysis on the potential benefits of risk factor reduction on disease incidence. Identifying individuals at risk of developing the disease might be the key to success of intervention studies.

Ongoing clinical trials in asymptomatic participants with either a positive amyloid biomarker or at increased genetic risk of AD will help ascertain whether secondary prevention initiatives are valid strategies and whether clinical trials of 3–5 years are sufficient for delaying cognitive decline, and consequently the onset of Alzheimer’s dementia.

The implementation of effective prevention strategies is not free from challenges since they require the identification, characterization and participation of asymptomatic individuals, developing new primary endpoints, implementing the use of AD biomarkers in cognitively healthy people, disclosing these results and performing long trials, whose optimal length is yet to be determined. The incorporation of biomarkers to identify individuals at risk of developing AD dementia is a key step for the identification of ideal candidates to participate in trials and secondary prevention initiatives.

Clinical trials focused on the preclinical stage of AD might help to maximize the possibility of obtaining a clinical signal as well as developing sensitive methods for detecting early decline through new trial designs.


Copyright”© The Author(s). 2017

Investigating Patterns of Degeneration in Alzheimer’s Disease

(Brigham and Women’s Hospital) Alzheimer’s disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. In a paper to be published in Stem Cell Reports, researchers from Brigham and Women’s Hospital have found that factors encoded in the DNA of brain cells contribute to the patterns of degeneration, or vulnerability, in AD.

AD is characterized by plaques composed of amyloid β-protein (Aβ) and tangles composed of Tau protein; accumulation of Aβ protein leads to disruption of Tau and, eventually, neurodegeneration which affects brain regions in a variety of ways. The front, rostral, portion of the brain is generally more damaged by plaque build-up while the back, caudal, portion is generally spared.

Though there are several mechanisms that could cause these differences, the team focused on the potential contributions of cell-autonomous factors among neuronal subtypes that could affect both the generation of and the responses to Aβ. In a novel application of human induced-pluripotent stem cell (iPSC) technology, the team generated powerful culture systems that represent different areas of the brain.

The systems were developed by taking skin cells from patients with a familial Alzheimer’s disease mutation and turning these skin cells into stem cells. Stem cells divide to make more stem cells, providing an unlimited supply of cells. Stem cells also can be turned into any type of cell in the body, including brain cells. In this study, the authors showed that vulnerable brain cells made more toxic Aβ protein compared to brain cells from more protected regions of the brain.

In addition, the researchers found that brain cells in the protected, caudal portion of the brain have a less toxic response to Aβ than their rostral counterparts. Though early-onset, familial Alzheimer’s disease (fAD) accounts for a small number of AD cases, the study of fAD patients, or samples in this case, can reveal important aspects of the cell and molecular mechanisms underlying all types of AD. The team is currently using this information to investigate exactly why caudal neurons are protected and what differences in cell type cause neurons to be protected from AD.

“These findings illuminate our understanding of why some neurons are spared and why others are not spared in AD,” said Christina Muratore, PhD, of the Department of Neurology.

“If we can find out more information about why these subtypes of cells are protected, we may be able to use this information to tailor therapies to protect the vulnerable cells.”


What’s New in Research – November 2017

Journal Reference:

Christina R. Muratore, Constance Zhou, Meichen Liao, Marty A. Fernandez, Walter M. Taylor, Valentina N. Lagomarsino, Richard V. Pearse, Heather C. Rice, Joseph M. Negri, Amy He, Priya Srikanth, Dana G. Callahan, Taehwan Shin, Monica Zhou, David A. Bennett, Scott Noggle, J. Christopher Love, Dennis J. Selkoe, Tracy L. Young-Pearse. Cell-type Dependent Alzheimer’s Disease Phenotypes: Probing the Biology of Selective Neuronal VulnerabilityStem Cell Reports, 2017; DOI: 10.1016/j.stemcr.2017.10.015

© Brigham and Women’s Hospital 2017


Preliminary Stages of Dementia Reduce Human Face Memorization Ability

(Kumamoto University) A Japanese research group has revealed that elderly people with mild cognitive impairment (MCI) have a particularly weakened ability to memorize human faces in the short term when compared to healthy elderly people. MCI patients also had a different gaze behavior when trying to memorize a face. This research may lead to the early detection of dementia.

Alzheimer’s disease is considered to be the most common type of dementia, and early detection of preliminary stages is important to halt its progression into a more serious form of the disease. MCI, which is thought to be a preliminary stage of Alzheimer’s, is a state in which cognitive functions, such as memory or thinking ability, decrease at a level that do not affect daily life.

Brain imaging studies show that areas of the brain for memory and visually processing human faces in people with MCI are structurally and functionally transformed. To investigate these specific and yet unstudied areas, a research group from Kumamoto University in Japan conducted comparative experiments with normal elderly subjects and MCI patients (18 each) using a delayed-matching task with face and house stimuli in independent blocks. In each block, they asked subjects to remember a single image and then, after a short delay, select a memorized image from a set new of images. The researchers also recorded subject gaze trends during the image memorization process.

Their experiments revealed that the memorization performance of MCI patients was lower for facial images than for house images, but found no performance difference in normal subjects. The research also showed that, during the memorization process, MCI patient gaze concentration on the eyes of an image decreased but the time spent looking at the mouth increased in comparison to normal subjects. In essence, MCI patients had reduced short-term memorization ability and a different gaze pattern for faces when compared to normal people.

“Looking at the eyes is important for remembering the entirety of the face,” said Emeritus Professor Kaoru Sekiyama.

“MCI patients probably have an abnormality in the cognitive processing of faces due to the deterioration of brain function. It is possible that the distributed gaze pattern is compensation for this decreased function. We hope to shed some light on this possibility in future work.”

This research result was posted online in the journal Scientific Reports on 30 October 2017.


Journal Reference:

Toshikazu Kawagoe, Masateru Matsushita, Mamoru Hashimoto, Manabu Ikeda, Kaoru Sekiyama. Face-specific memory deficits and changes in eye scanning patterns among patients with amnestic mild cognitive impairmentScientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-14585-5

Copyright © 2017 by the American Association for the Advancement of Science (AAAS)


New Research Suggests High-intensity Exercise Boosts Memory

(McMaster University)The health advantages of high-intensity exercise are widely known but new research from McMaster University points to another major benefit: better memory.

The findings could have implications for an aging population which is grappling with the growing problem of catastrophic diseases such as dementia and Alzheimer’s.

Scientists have found that six weeks of intense exercise — short bouts of interval training over the course of 20 minutes — showed significant improvements in what is known as high-interference memory, which, for example, allows us to distinguish our car from another of the same make and model.

The study is published in the Journal of Cognitive Neuroscience.

The findings are important because memory performance of the study participants, who were all healthy young adults, increased over a relatively short period of time, say researchers.

They also found that participants who experienced greater fitness gains also experienced greater increases in brain-derived neurotrophic factor (BDNF), a protein that supports the growth, function and survival of brain cells.

“Improvements in this type of memory from exercise might help to explain the previously established link between aerobic exercise and better academic performance,” says Jennifer Heisz, an assistant professor in the Department of Kinesiology at McMaster and lead author of the study.

“At the other end of our lifespan, as we reach our senior years, we might expect to see even greater benefits in individuals with memory impairment brought on by conditions such as dementia,” she says.

For the study, 95 participants completed six weeks of exercise training, combined exercise and cognitive training or no training (the control group which did neither and remained sedentary). Both the exercise and combined training groups improved performance on a high-interference memory task, while the control group did not.

Researchers measured changes in aerobic fitness, memory and neurotrophic factor, before and after the study protocol.

The results reveal a potential mechanism for how exercise and cognitive training may be changing the brain to support cognition, suggesting that the two work together through complementary pathways of the brain to improve high-interference memory.

Researchers have begun to examine older adults to determine if they will experience the same positive results with the combination of exercise and cognitive training.

“One hypothesis is that we will see greater benefits for older adults given that this type of memory declines with age,” says Heisz. “However, the availability of neurotrophic factors also declines with age and this may mean that we do not get the synergistic effects.”

This research was also covered by the New York Times: Exercise May Enhance the Effects of Brain Training.

Citation workouts-to-remember-new-research-suggests-high-intensity-exercise-boosts-memory/

By Michelle Donovan, November 22, 2017

Journal Reference:

Jennifer J. Heisz, Ilana B. Clark, Katija Bonin, Emily M. Paolucci, Bernadeta Michalski, Suzanna Becker, Margaret Fahnestock. The Effects of Physical Exercise and Cognitive Training on Memory and Neurotrophic FactorsJournal of Cognitive Neuroscience, 2017; 29 (11): 1895 DOI: 10.1162/jocn_a_01164


Imaging Technique Shows Progress Alzheimer’s Disease

(University of Twente) Using ‘Raman’ optical technology, scientists of the University of Twente in The Netherlands, can now produce images of brain tissue that is affected by Alzheimer’s disease. The images include the surrounding areas, already showing changes.

Alzheimer’s disease is associated with areas of high protein concentration in brain tissue: plaques and tangles. Raman imaging is now used to get sharp images of these affected areas. It is an attractive technique, because it shows more than the specific proteins involved. The presence of water and lipids, influenced by protein presence, can also be detected. Using this technique, the researchers have studied brain tissue of four brain donors, three of them with Alzheimer’s disease.

Raman image of Alzheimer brain tissue. Red is the core of the affected area. Light grey is healthy tissue, darker grey already shows a transition.
Credit: Image courtesy of University of Twente


The affected area can, in this way, be shown in a sharp and clear way. After image processing, even an area appears that is in transition between healthy and affected tissue: this may give an indication how the disease is spreading in the brain. Even in the brain tissue of the healthy person, a small area is detected with protein activity. This can be a first sign of a neurodegenerative disease.

Raman microscopy uses a laser beam for the detection of chemical substances. The energy of the reflected and scattered light gives an indication of the substances present in a sample. In each of the four brain samples, 4096 spectra were examined in this way. A major advantage of Raman is that the chemicals don’t need a pretreatment, it is ‘label free’. In chemical analysis, Raman has proven to be a powerful technique.

Cell Level and Smaller

In this case, Raman was used to examine brain tissue outside the body, but it could even be used ‘in vivo’ for detecting specific areas during surgery. Compared to MRI, PET and CT imaging, Raman is able to detect areas, smaller than cells, with very high precision. In this way, it can be a very valuable extra technique. The Raman images now show protein activity at neural cell level, but the sensitivity is high enough for detecting areas that are even smaller — as is the case with the brain sample of the healthy person.

Cees Otto, of the Medical Cell Biophysics group of UT, published his work in Scientific Reports, together with colleagues from Leiden University and from Spain and Austria.


Journal Reference:

Ralph Michael, Aufried Lenferink, Gijs F. J. M. Vrensen, Ellen Gelpi, Rafael I. Barraquer, Cees Otto. Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patientsScientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-16002-3

Copyright 2017 University of Twente


Smell Test Challenge Suggests Clinical Benefit for Some Before Development of Alzheimer’s

(Columbia University Medical Center) Researchers at Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI) may have discovered a way to use a patient’s sense of smell to treat Alzheimer’s disease before it ever develops. Having an impaired sense of smell is recognized as one of the early signs of cognitive decline, before the clinical onset of Alzheimer’s disease. The researchers at CUMC and NYSPI have found a way to use that effect to determine if patients with mild cognitive impairment may respond to cholinesterase inhibitor drugs to treat Alzheimer’s disease.

The findings were published online this week in the Journal of Alzheimer’s Disease.

Cholinesterase inhibitors, such as donepezil, enhance cholinergic function by increasing the transmission of the neurotransmitter acetylcholine in the brain. Cholinergic function is impaired in individuals with Alzheimer’s disease.

Cholinesterase inhibitors, which block an enzyme that breaks down acetylcholine, have shown some effectiveness in improving the cognitive symptoms of Alzheimer’s disease. However, they have not been proven effective as a treatment for individuals with mild cognitive impairment (MCI), a condition that markedly increases the risk of Alzheimer’s disease.

“We know that cholinesterase inhibitors can make a difference for Alzheimer’s patients, so we wanted to find out if we could identify patients at risk for Alzheimer’s who might also benefit from this treatment,” said D.P. Devanand, MBBS, MD, professor of psychiatry, scientist in the Gertrude H. Sergievsky Center at CUMC, and co-director of the Memory Disorders Clinic and the Late Life Depression Clinic at NYSPI.

“Since odor identification tests have been shown to predict progression to Alzheimer’s, we hypothesized that these tests would also allow us to discover which patients with MCI would be more likely to improve with donepezil treatment.”

In this year-long study, 37 participants with MCI underwent odor identification testing with the University of Pennsylvania Smell Identification Test (UPSIT). The test was administered before and after using an atropine nasal spray that blocks cholinergic transmission.

The patients were then treated with donepezil for 52 weeks, and were periodically reevaluated with the UPSIT and with memory and cognitive function tests. Those who had a greater decline in UPSIT scores, indicating greater cholinergic deficits in the brain, after using the anticholinergic nasal spray test saw greater cognitive improvement with donepezil.

In addition, short-term improvement in odor identification from baseline to eight weeks tended to predict longer-term cognitive improvement with donepezil treatment over one year.

“These results, particularly if replicated in larger populations, suggest that these simple inexpensive strategies have the potential to improve the selection of patients with mild cognitive impairment who are likely to benefit from treatment with cholinesterase inhibitors like donepezil,” said Dr. Devanand.


Journal Reference:

D.P. Devanand, Cody Lentz, Richard E. Chunga, Adam Ciarleglio, Jennifer M. Scodes, Howard Andrews, Peter W. Schofield, Yaakov Stern, Edward D. Huey, Karen Bell, Gregory H. Pelton. Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. Journal of Alzheimer’s Disease, 2017; 60 (4): 1525 DOI: 10.3233/JAD-170497

© 2017 Columbia University


Physical Exercise as a Preventive or Disease-Modifying Treatment of Dementia and Brain Aging

Mayo Clin Proc. 2011 Sep;86(9):876-84. doi: 10.4065/mcp.2011.0252.

Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging.

Ahlskog JE1, Geda YE, Graff-Radford NR, Petersen RC.


A rapidly growing literature strongly suggests that exercise, specifically aerobic exercise, may attenuate cognitive impairment and reduce dementia risk. We used PubMed (keywords exercise and cognition) and manuscript bibliographies to examine the published evidence of a cognitive neuroprotective effect of exercise.

Meta-analyses of prospective studies documented a significantly reduced risk of dementia associated with midlife exercise; similarly, midlife exercise significantly reduced later risks of mild cognitive impairment in several studies.

Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls.

Meta-analyses of RCTs of aerobic exercise in healthy adults were also associated with significantly improved cognitive scores.

One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise.

Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors.

Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise. Animal studies indicate thatexercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors byexercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans.

Besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. 

Exercise should not be overlooked as an important therapeutic strategy.