Introduction

Alzheimer Disease (also called Alzheimer’s Disease) is the leading cause of dementia worldwide at the moment. Not only is it the leading cause of dementia, Alzheimer’s rates are growing year on year. It is predicted that there will be over 13 million people with Alzheimer Disease in the USA by the year 2050.

Considering the fact that the cost of care for a patient with Alzheimer’s Disease is almost $100,000 over the course of the illness, this disease has significant financial implications (1). While the general public may not know the exact financial figure involved, the fact that Alzheimer’s Disease is expensive is not lost on the majority of people.

Of course, the cost is not just financial. Many people have a great fear of developing Alzheimer’s Disease which could mean being unable to work or look after themselves. This fear is so great that some people even try to future proof their life (financially and logistically) against this illness.

In this article, we review Alzheimer’s Disease and current treatment options.

Who gets Alzheimer Disease?

Age is a major factor in Alzheimer’s Disease. Alzheimer’s Disease is mostly a disease of older people. It is rarely seen in people under the age of 60 years of age. The risk of developing Alzheimer’s Disease increases significantly when people hit the age of 65. In fact, the risk of developing Alzheimer’s Disease doubles every 5 years after the age of 65.

The one thing we know for sure is that we are all getting older – is there a way to protect ourselves against Alzheimer Disease? We will discuss that later.

There are 3 variants of Alzheimer’s Disease which are worth mentioning.

  • Early Onset Alzheimer’s Disease

People who develop signs and symptoms of Alzheimer’s Disease before the age of 65 are said to have early onset Alzheimer’s Disease. These people also tend to have some unusual symptoms such as language difficulties, visual disturbance and/or mood changes.

It is essential that people with early onset Alzheimer’s Disease are carefully evaluated in order to rule out other (often treatable) medical or psychiatric conditions.

  • Inherited Alzheimer’s Disease

A subset of people develop symptoms of Alzheimer’s Disease before the age of 46 are considered to have inherited Alzheimer’s Disease. This is a rare disorder and is seen in less than 1% of all patients with Alzheimer’s Disease. However, when we think about how many people have Alzheimer’s Disease, even 1% of this number means that this does affect a significant number of people worldwide. These people usually have a genetic mutation which affects amyloid metabolism and this causes early onset Alzheimer’s Disease.

  • Down Syndrome

Adults with Down Syndrome can develop Alzheimer’s Disease up to 20 years earlier than the general population.

What is Alzheimer Disease?

Alzheimer’s Disease is classified as a neurological disease (a disease of the nervous system). It is a form of dementia. Dementia is a progressive, irreversible deterioration in brain function. The rate at which Alzheimer ‘s Disease progresses varies from person to person.

What are the key symptoms?

The key symptom of Alzheimer’s Disease is memory impairment. Memory is a very complex thing. There are so many different forms of memory. We use different parts of our brains for different things. Recent memories and old memories are stored separately.

The change in memory in Alzheimer’s Disease tends to follow a specific pattern. It all starts with difficult remembering events. This is followed by problems with language and learning. In the very early stages, sometimes family, friends or colleagues notice the memory deficits before the patient themselves recognises the problem.

Judgement impairment and problem solving skills also occur and can present in many ways eg disorganisation, loss of insight or problems with multitasking.

Behavioural problems can present with agitation, aggression and social disengagement.

A common presenting feature is dyspraxia which is difficulty with physical activities that we have learned how to do. As an example, a doctor might ask a patient to show them how to tie shoe laces and the patient struggles to complete this task (a task which they may well have done daily for the previous fifty years).

A poor sense of smell is considered by many people to be diagnostic of Alzheimer’s Disease

The key issue here is that other causes of loss of smell (eg seasonal allergies) needs to be excluded before loss of smell can be considered as a possible red flag for Alzheimer’s Disease. Can you guess why it is hard to use smell as a diagnostic tool in clinical practice? Because patients with Alzheimer’s Diseases rarely report it and family members can’t report it on behalf of the patient.

People with Alzheimer’s Disease often have sleep disturbances. They tend to spend more time awake in bed and wake up frequently.

Practically speaking, probably the key issue with Alzheimer’s Disease is the fact that it affects ADLs or Activities of Daily Living. What are ADLs? Ask anyone who is caring for someone with Alzheimer’s Disease and they will tell you exactly what ADLs are. This means cooking, dressing, shopping, paying bills, washing, assisting with going to the toilet etc etc. It can be exhausting for a caregiver.

Of course, there is a spectrum of Alzheimer Disease and many people with Alzheimer may have some memory impairment but manage fine. Sadly, that is not always the case. I have a deep respect for family and friends who struggle to support people with Alzheimer Disease in their activities of daily living.

How is Alzheimer Disease Diagnosed?

Diagnosis of Alzheimer’s Disease rests on careful history taking from the patient and family members, physical examination, formal memory assessment and brain imaging (CT or MRI).

There are a number of different tests used to test memory.

A popular test for Alzheimer’s Disease used in hospitals is called the MoCA (Montreal Cognitive Assessment) (2). The score takes just ten minutes to do. It covers a range of mental skills eg people are asked to name as many objects as they can beginning with a certain letter, serial subtraction of 7 from 100, or remembering words or objects ten minutes after they were given them. It scores people from 0 to 30 and a core above 26 is considered normal.

A Special Mention – Pre-Clinical Alzheimer Disease

Some people with no signs or symptoms of Alzheimer’s Disease have changes noted on a brain scan when a brain scan is done for some other reason eg road traffic accident – this is called pre-clinical Alzheimer’s Disease.

Is There Any Research?

Yes, there is lots of research on Alzheimer’s Disease. There are over 100,000 publications which includes 10,000 clinical trials. So often when researching topics for Healthy But Smart, I find a few handful of publications and one handful of clinical trials. Not so in this case.

How is Alzheimer Disease Treated?

Unfortunately there is no magic cure or vaccine that can treat Alzheimer’s Disease. Here are the options.

Supportive Care

The treatment of Alzheimer Disease is mainly supportive. This means that we aim to manage the key symptoms and support people to live as full a life as possible for as long as possible.

The cornerstones of treatment are lifestyle interventions :

Managing mood, sleep and behavioural disturbances

Occupational therapy and environmental modification to support people to live safely and as independently as possible.

Nutritional Support

Wine is a rich source of phenols (resveratrol) andoften promoted for its health benefits. Now before you buy out the wine section in your local store, it is worth remembering that a large 2018 study in 30 million people in France showed that people with a history of alcohol use disorders (aka drinking too much) had a 3 fold greater risk of dementia (3).

Medications

Three main types of medications are used in the treatment of Alzheimer’s Disease:

  • Cholinesterase Inhibitors
  • NMDA (N-Methyl-D-Aspartate) blockers and
  • Antioxidants.

Cholinesterase Inhibitors

Patients with Alzheimer’s Disease have reduced activity of the brain chemical or neurotransmitter called acetylcholine.  Acetylcholine is mission critical for normal functioning of the brain. Nature has designed us to continuously produce and degrade acetylcholine which keeps body levels of acetylcholine stable ie homeostasis.

Degradation of acetylcholine occurs via an enzyme called acetylcholine esterase. Acetylcholine esterase inhibitors block the activity of acetylcholine esterase and raise the level of acetylcholine in the brain

Examples of cholinesterase inhibitors are:

  • Donepezil
  • Rivastigmine
  • Galantamine

NMDA Blockers

Glutamate is another key neurotransmitter in the brain. It binds to a number of receptors in the brain including NMDA ‍(N-Methyl-D-Aspartate) which controls learning and memory. NMDA hyperstimulation is believed to play a role in Alzheimer’s Disease. Agents that block NMDA hyperstimulation are used in Alzheimer Disease and include memantine.

In patients who need medication, cholinesterase inhibitors are usually prescribed.

NMDA blockers are reserved as add-on therapy to cholinesterase inhibitors in people with moderate to severe Alzheimer Disease but  not mild disease.

A 2008 comprehensive review published in the Annals of Internal Medicine evaluated the effectiveness of 4 cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and the NMDA blocker (memantine) in achieving clinically relevant improvements in cognition, global function, behavior, and quality of life, for patients with dementia. They pulled data from 96 publications representing 59 unique studies for this review.

The majority of these studies were of less than 6 months duration which limited their usefulness in a condition that can last decades. Overall, they concluded that all 5 drugs improved cognition and dementia but the effects were small. The authors admitted that it was unclear if these small changes were clinically significant and if they actually made a difference to patients and their families (4).

A total of 322 patients with moderate to severe Alzheimer’sDisease who were already receiving donepezil were randomized to the addition of either memantine or placebo. The combination arm of the study had significantly better outcomes in terms of cognition and activities of daily living (5).

Another study compared a cholinesterase inhibitor plus memantine versus a cholinesterase inhibitor plus placebo in 433 patients over 24 weeks. They showed no benefits of memantine over placebo (6).

What does all this mean? Clinical practice guidelines from the American Academy for Physicians (published in the same edition of the Annals of Internal Medicine as the medication meta-analysis) recommended that the use of cholinesterase inhibitors or memantine should be tailored to each patient based on the severity of their disease and should consider other relevant factors such as tolerability, adverse effect profile, ease of use, and cost of medication (7). That seems practical to me.

Antioxidants

  • Vitamin E
  • Selegiline

There is a comprehensive Cohcrane meta-analysis of 15 trials on selegiline in Alzheimer’s Disease (8). The meta-analysis revealed benefits on memory function and pooling the data for all cognitive tests suggested significant benefits in those subjects treated with selegiline as compared to controls. The authors of the study concluded that ‘Although the evidence for a beneficial effect of selegiline on patients with Alzheimer’s disease is promising there is not yet enough evidence to recommend its use routinely in practice’.

The Department of Veterans Affairs carried out a double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate Alzheimer’s Disease and compared vitamin E versus memantine versus the combination of vitamin E plus memantine versus placebo (9).

The patients were all followed up for 2 years. At the end of the study, the vitamin E arm of the study had   a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Usually in Alzheimer’s Disease, the need for caregiver assistance increases over time. In this study, the rate of increased need for extra caregiver time was less in the vitamin E arm.

Physicians in Colombia University  carried out a double-blind, placebo-controlled, randomized, multicenter trial in 341 patients with Alzheimer’s disease of moderate severity (10). This study compared selegiline (10 mg a day), vitamin E, (2000 IU a day), both selegiline and vitamin E, or placebo for two years. The end-point of the study was delay in progression of Alzheimer’s Disease.

Fast forward two years to the results of the study and this is where things get interesting. The whole idea behind randomization is to optimize the chance that the patients in each group are similar at baseline. This avoids bias in the study design. As an example, if doctors were allowed to allocate people to treatment or placebo, there is a chance that they might put the sickest people on treatment.

As we know in life, nothing is perfect and in this study, the randomization did not work well. At baseline, the people in the placebo group had a higher mental test score (ie had less dementia) than the people on treatment. When standard statistical analysis was done, there was no difference between the groups. But as we know, the placebo group had an advantage.

On re-analysis, the baseline mental test score was factored into the analysis and, abrakedabra, this time significant delays in disease progression for the patients treated with selegiline, vitamin E or combination therapy, were noted as compared to the placebo group. Realistically, it is probably valid to adjust for the differences between the mental test score at baseline. However, it is a bit dodgy. Let’s just say we will reserve judgement on this study.

Another trial found compared an antioxidant blend of vitamin E  plus vitamin C plus α-lipoic acid (ALA) with either coenzyme Q  or placebo for 16 weeks (11). A total of 78 people took part in the study. Monitoring involved mental test scores and analysis of spinal fluid markers of disease such as amyloid (Aβ42), tau, and P-tau(181) and F2-isoprostane levels (these are research tools at this stage and are not used in routine clinical practice).

Treatment had no effect on amyloid or tau levels. The antioxidant blend did have a significant beneficial effect on F2-isoprostane levels (a marker of oxidative stress).

But (and it’s a big but), the antioxidant blend group were noted to have a faster decline in their mental test score as compared to the coenzyme Q or placebo arm of the study. How can we reconcile the facts that the antioxidant blend improved a marker in the spinal fluid but not the actual disease?

Something is wrong here. Maybe this is a spurious result? Maybe the marker is not valid for the disease? Maybe the people doing the mental test scores messed up? Who cares about research markers if the clinical condition is getting worse?

Bottom line here is that based on these studies many physicians recommend vitamin E therapy (but not selegiline) in Alzheimer’s Disease.

Does Exercise Help?

Canadian investigators reviewed 17 trials with 1067 participants and found that exercise had no benefits in terms of cognition, neuropsychiatric symptoms, or depression, mortality, caregiver burden, caregiver quality of life in people with dementia (12). They found ‘promising evidence’ that exercise my help with activities of daily living.

Does Omega-3 Help?

Omega-3 is essential for brain health and has anti-oxidant activity which raises the theoretical possibility that it may help with Alzheimer’s Disease. Studies showed no benefit of omega-3 or DHA (docosahexanoic acid) supplementation in Alzheimer’s Disease (13,14).

Does Gingko Help?

Ginkgo biloba (extract of the leaves of the maidenhair tree) is used in Traditional Chinese Medicine and is widely recommended for enhancing brain function. A systematic review of 36 trials concluded that ‘the evidence that Ginkgo biloba has predictable and clinically significant  benefit for people with dementia or cognitive impairment is inconsistent and unreliable’ (15). A complicated way to say no to gingko.

Can Alzheimer’s Disease Be Prevented?

I think that people reading this article can probably be divided into two main groups:

  • people who have/may have  Alzheimer Disease and their families and
  • people who want to protect themselves against Alzheimer Disease.

An interesting meta-analysis from researchers in China and UCSF saved us hours (or maybe days or even months) of reading original research on prevention strategies in Alzheimer’s Disease (16). They initially identified 16,906 articles and selected out 323 articles which covered 93 risk-factors for the meta-analysis.

The results are mind-boggling.

They found evidence that folate, vitamin E, vitamin C and coffee could protect against Alzheimer Disease.

Depression significantly increased risk of developing Alzheimer Disease.

Pre-existing disease eg hypertension, increased the risk of Alzheimer Disease whereas a history of arthritis, heart disease, metabolic syndrome and cancer decreased the risk of Alzheimer’s Disease.

In terms of lifestyle (low education, high body mass index (BMI) in mid-life increased the risk of Alzheimer’s Disease whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high BMI in late-life decreased the risk.

I am not sure how to use this information or even how to make sense of it all.

And it goes on.

The study found that cholesterol lowering medication, antihypertensive medications and non-steroidal anti-inflammatory drugs therapy protected against Alzheimer Disease.

People with history of arthritis are likely to have exposure to non-steroidal anti-inflammatory drugs. Both arthritis and non steroidal anti-inflammatory drugs have been shown to be protective against Alzheimer Disease.

Is there a connection? Could this mean that people with arthritis take these medications for arthritis and that these medications have an intrinsic anti-Alzheimer effect? Is it just a coincidence? Did the statistics really account for possible associations like this?

Luckily, a panel of investigators from my alma mater, Northwestern University, published a consensus statement on the prevention of Alzheimer ‘sDisease (17). They concluded that ‘evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease’.

Goals & Reality

Researchers from Nova Scotia published some interesting research findings relating to Alzheimer’s Disease (18). They were studying donepezil in 108 patients with Alzheimer Disease. The physicians, the caregivers and the patients all set treatment goals. The researchers observed that physicians, patients and care-givers had different goals, expectations and impressions of treatment effects.

Physicians set fewer goals in terms of social interaction and leisure. Physicians noted statistically significant improvements at six months whereas patients/carers took 9 months to notice improvements. This is a really interesting finding. This really reminds us of the importance of including patients/caregivers in research trial design.

Building on this theme, a primary care physician from Virginia reviewed the treatment guidelines for Alzheimer ‘s Disease and made another interesting point (19). He pointed out the fact that the majority of the studies done for Alzheimer’s treatment were done to satisfy the requirements of regulatory authorities in order to get approval for the drug more than to help patients.

The author also points out the fact that some studies in Alzheimer’s Disease are flawed as they are designed to look for improvements. Treatment studies in Alzheimer’s Disease need to reflect the reality of treatment which is slowing disease progression and not actual improvements.

Conclusion

Alzheimer’s Disease is a significant and growing problem worldwide. Despite over 100,000 publications, there is relatively little solid data and very limited in terms of effective treatment options. Two parting observations on this condition.

Firstly, not everyone with memory lapses has Alzheimer’s Disease. We live in a fast paced world and we are inundated with information. Some people who worry that their memory is not as good as it used to be, fail to factor in the fact that their memory is being asked to handle way more data than ever before. Many of us have simply overloaded our operating system.

Secondly, studies have shown that when it comes to Alzheimer’s research, clinical researchers and caregivers have different goals and assessments of treatments. This gives a very clear message to clinicians and researchers like us that we need to re-focus our work to honor what really matters to the people who matter.