Alzheimer’s disease,
the trademark of a generation. 

Alzheimer’s disease is commonly referred to a chronic degenerative disease with a slow beginning but worsening over time. This is the most common cause of Dementia with difficulty in remembering recent events. With a progression of the disease, disorientation and problems with language and mood swings with a loss of motivation can be seen. The early signs may be suspected when a pattern in forgetting recent events or conversations is repeated. Memory loss and cognitive problems are seen as the hallmarks of the disease. A continuous decline in thinking, behavior and social skills that disrupts one’s ability to function independently is soon observed. Often problems in managing self-care and behavior problems will surface while the person’s condition declines. They develop severe memory impairment until they lose the ability to carry out tasks. He / She will withdraw slowly from the society and soon bodily functions are lost, leading to death in a three to nine years’. Mainly. this progressive disease causes brain cells to degenerate and die. 

Much need to be understood about the disease. It is believed to be inherited from a parent genetic baggage. Depression, High blood pressure and history of head injury are directly implicated as risk factors. We discussed also head injuries encountered in professional soccer players as a risk factor for Chronic Traumatic Encephalopathy, in an article already published in the AMHE Newsletter (May 6, 2019 Issue  # 254). This time, the brain is found, covered with plaques and the history of the illness, the cognitive testing, the medical imaging and the blood tests can be suggestive. Often the initial symptoms of aging can mask the picture. No medications or supplements have been able to slow down the process. Some believes that mental and physical exercises can decrease the risk in developing the disease.

There is no known treatment to reverse or stop the progression. Patients with Alzheimer become increasingly dependent on others for assistance requiring a caregiver. It is encouraged to involve such patients in exercise program for beneficial effects on their social and physical needs with respect to their daily living activities. Antipsychotic medications can be recommended for psychosis or behavioral problems. There are around 30 million of people in the world affected by the disease which generally will start after the age of 65 years.

Let us review what impression such disease has made in the eyes of the one who has observed it before us. Egyptian vizier Ptahhotep (2500 B.C.) wrote that “the ageing, every night, becomes more and more childish”. Ancient Greek and Roman philosophers have associated dementia to old age. Plato (259 B.C.), in his “Timaeus” described an illness that lead to “all manners of rashness and cowardice and off forgetfulness as well as of stupidity”. The Roman satirist Juvenal (1st Century A.D.) wrote:” The failing mind which forget the names of slaves and cannot recognize the face of the old friend who dined with him last night nor those of the children whom he brought up”. Franciscan friar Roger Bacon (13th Century) published in “Methods of Preventing the appearance of Senility”, speculated that condition of the ventricular system in the brain may somehow be related to Dementia. American historians in the 1600’s have stipulated that some of the women prosecuted and burned in Salem trial may have been suffering from Dementia. British physician James Cowles Prichard (1835) used for the first time, the term of Senile Dementia in his “Treatise of Insanity”. Soon, in the 1880, it was “old timer’s disease”. In 1901, a 55-year-old German female patient of the name of Auguste Deiter, was hospitalized in a Frankfurt institution after she started losing her memory and acting erratically. She met a German physician, psychiatrist and pathologist, Alois Alzheimer who cared for her until her death in 1906. Dr Alzheimer requested her brain for a post mortem autopsy. At the conclusion of his analysis, he discovered a significant brain atrophy with “protein plaques and neural tangles” never described before. He died soon after his pathologic findings and this is Emil Kraepelin who reported the clinical (hallucinations and delusions) and pathologic (arteriosclerotic changes) features found in this first patient, coining it at first “Pre Senile Dementia”. He published his findings in a textbook of Psychiatry in 1910. Earlier, the diagnosis of Alzheimer was given to individual between the ages of 45 and 65 who developed Dementia but after 1977, the diagnosis of Alzheimer become independent of age. The term “Senile dementia of the Alzheimer type” was used for a while until eventually the nomenclature adopted the term “Alzheimer Disease”.

Four stages of the disease have been suggested with a pattern of cognitive and functional impairment:


In this stage of the disease, one can easily mimic the symptoms for Ageing with mild neuropsychological tests revealing cognitive difficulties in the daily living activities, short term memory loss and difficulty in remembering recent events. Abstract thinking, apathy, depression can be noted as a transitional phase before dementia. Memory loss appears to be the predominant symptom often called a mild cognitive impairment (MCI), a prodromal stage of the disease. 

Early stage

Early difficulties with language, perception (Agnosia), execution of movements (Apraxia) are more encountered than memory loss. Problems with memory is seen as “Episodic” when it deals with old memory, “Semantic” when it concerns learned facts and “Implicit” when the daily living activities like holding a fork to eat or hold on a glass to drink, are forgotten. You can expect difficulty in finding the proper words to talk, write or draw. Patient can still live at home but will require more assistance or supervision in performing tasks like dressing up or cooking which may still be possible. Remembering important information like special dates can become difficult. Mood and personality changes can be also expected at this stage.

Moderate stage

The more the disease progresses, the more the patient lose his/her independence. They are unable to recall words in the vocabulary which lead to word substitutions (Paraphasia), unable to read or write. They fail to recognize their close relatives and start to lose the long term memory, rendering the patient to present behavioral and neuropsychiatric changes. They become irritable, delusional aggressive and refuse to perform tasks if they are not medicated. At this stage some will start to develop urinary incontinence. It may be time to think about transferring the patient to a home care or a long term facility.

 Advanced stage

In this final stage, the patient becomes completely dependent upon the caregivers who will use single words or short sentences to communicate. Often patients will understand and return emotional signals, or will fall in a deep apathy or even express aggressiveness. Soon, they will be unable to perform any simple task such as walking or taking a bath They become unable to recognize family members or close friends. They will exhibit signs of long term memory loss. They become bedridden and lose their muscle mass. More they will be unable to feed themselves and may die from infected pressure sores or pneumonia or malnutrition, but not from the Alzheimer disease itself. Sporadic cases with early onset of  Alzheimer’s disease may reach this stage faster and may experience difficulties in processing visual information. They may see only what centers on their visual field and they lose the awareness of anything else.

The cause of Alzheimer is unknown. Scientists are learning more about the genetics of the disease, the precise places where it strikes in the brain and the rampant proteins that empowers it with the cascade of breakdown that make it irreversible. Less than 5% of cases (200.000) have shown genetic differences which are being studied in twins and family. Others have postulated that an autosomal dominant inheritance with mutations of one to three genes encoding a specific protein like Amyloid Precursor Protein (APP) or Presenillin or Ab42 mainly found in senile plaques, can be traced. More genes like ABCA7 and SORL1 are also under investigation. Recently, genomes have been found in genes affecting late onset of Alzheimer disease like CASS4, FERMT2 etc.

.Some agrees that the disease is caused by the reduced synthesis of the neurotransmitter acetylcholine while others postulated that the extracellular amyloid beta is the fundamental cause of the disease due to the gene location for the amyloid precursor protein (APP), on the chromosome 21. It is believed that people with trisomy 21 (Down Syndrome) almost universally exhibit the earliest symptoms of Alzheimer’s disease by age 40. Individual developing such early signs of the disease are sporadic in nature. In facts, there is no such thing like a gene for Alzheimer’s disease. In 1994, the “BRCA” gene was discovered to contribute to a higher risk for breast and ovarian diseases but that same gene is now playing a role in the nerve death itself, responsible of Alzheimer’s disease. The BRCA gene not only affects the way cells can grow but also influence the nerve cells ability to repair their DNA. Deficit in the DNA repair seems to contribute to the cognitive decline encountered in the disease.

In Fact, while everybody makes “amyloid”. Authorities are still debating whether Alzheimer’s disease results from an over production of the protein in the brain or its inability to clear away the amyloid properly. In 2009, it was discovered that an amyloid-related mechanism that prunes neuronal connections in the brain, may trigger an ageing process later in life. A new generation of drugs that might be able to control the disease have been developed., This decade has bought two new medications: “Verabecestat” was used in a trial to inhibit the beta-secretase, responsible of the creation of the beta amyloid and “Aducanumab” responsible for it reduction. Both have failed, leaving scientists still questioning the validity of the amyloid hypothesis. A new “Tau Protein” is now proposed to explain the disease. It is also postulated that the tau protein forms neurofibrillary tangles inside the nerve cell bodies, destroying their structure. Finally, a neurovascular hypothesis through the blood-brain barrier has been proposed especially as encountered in Syphilis with the passage of the spirochetes into the brain, explaining the syphilitic dementia. Barry Reisberg proposed a medical hypothesis called “Retrogenesis”, initiated at the fetus neurodevelopment stage of neurulation” to the end at the myelination, a kind of reverse “neurogeneration” process starting with demyelination and death of the axon (white matter) to the death of the gray mater..

An experimental vaccine was also perfected in an attempt to clear the amyloid plaques, in the earlier human trials but unfortunately, did not trigger any effects on the dementia. Scientists have been led to suspect a non-plaque A2, oligomer as the primary pathogenic form. That same misfolded protein, called differently, “Prions”, can be traced in “Mad Cow Disease” and “Creutzteldt-Jacob diseases”, classifying those two diseases as well as neurodegenerative disorders. Researchers have developed biochemical tests to enable early detection. The cerebrospinal fluid has been analyzed for beta amyloid and total tau protein and phosphorylated tau protein concentration. A blood test is being developed to look for circulatory and inflammatory markers.

Alzheimer’s disease is associated with the loss of neurons and synapses in the cerebral cortex resulting in a gross atrophy of the affected regions especially in the frontal, temporal and parietal lobes. This process appears to start in the medial temporal lobe, at the hippocampus (center of Memory and Learning) and spreads outward. Degeneration is also present in the brainstem nuclei as demonstrated on MRI and Pet scans. In 1984, proteins known a “Beta protein” were discovered as the principal components of the plaques. It is a disease of misfolding proteins (proteopathy) where plaques are being produced to host the deposits of beta-amyloid protein.  Sometimes, “Lewy bodies” can be seen in the brain of people suffering from Alzheimer disease but their accumulation is more often seen in another type of dementia with striking signs of typical memory loss, visual disturbances and sleep disorders. Enzymes fragment the APP (Amyloid Precursor Protein) and deposit it on the senile plaques. Similarly, another Tau protein is present in the brain tissue and by it aggregation (Taupathy), chemical changes are generated, forcing a disintegration of the neuron transport system and its death by disrupting the cell’s calcium ion homeostasis. It is believed that various inflammatory mechanisms with cytokines participate in this process, bringing tissue damage locally. Infrequently, Herpes virus simplex (HSV-1) has been also found on amyloid plaques suggesting that Alzheimer’s could be treated or prevented with an antiviral medication. Finally, Fungal infection has been described by Carrasco, a microbiologist in different brain regions on the plaques, suggesting perhaps an immune system response,

Alzheimer’s disease is diagnosed through the patient’s medical history, behavioral observations, relative’s history or confirmed with characteristic neurological and neuropsychological features supporting the condition. Physicians may look for tests pointing at thyroid dysfunction, vitamin deficiency, a tumor and even a stroke, prior to bring the diagnosis of Alzheimer. Patients or family may opt for a spinal tap to confirm the presence or the absence of the amyloid proteins.  Advanced scanning with CT, MRI, PET, SPECT have been used to exclude other cerebral pathologies. The SPECT (single proton emission computed tomography) appears to be superior in differentiating Alzheimer’s disease from other type of Dementia. PET remains investigational but has promising hope in locating the offending protein in the brain. The accumulation of proteins has been detected in selective patients more than 10 years prior to the beginning of their symptoms. MRI can detect better the size of a brain lesion. Many have looked for diagnostic criteria to facilitate the practitioner in recognizing the symptoms. Other have used assessment of intellectual functioning memory test. A “functional assessment staging tool” (FAST) has allowed people caring for these patients to stage the disease progression.

Unfortunately, the diagnosis can be only confirmed with accuracy in a post mortem examination of the brain material. The Alzheimer’s Association has established diagnostic criteria since 1984 and updated them in 2007, requiring the presence of cognitive impairment, a suspected dementia syndrome to be confirmed by neuropsychological testing, a histopathologic study of the brain tissue. Memory, Language, Perceptual skills, Attention, Problem solving and Executive functional abilities are looked for as well. The American Psychiatric Association published a manual: “Diagnostic and Statistical Manual Mental Disorders” to list the criteria. Intellectual activities like playing chess are linked to a reduced risk of Alzheimer’s disease. Reading, or playing board games activities or crossword puzzles. playing a musical instrument or any regular social activities have reduced the risk for developing the disease. Education has a tendency of delaying the symptoms as well as physical activities.

Many believe that a strict diet like the “Mediteranean” diet and /or food low in saturated fat and complex carbohydrates may decrease the risks. Hormones replacement therapy in menopause women may contribute to the disease while anti-inflammatory medications were found to have a protective effect in reducing the inflammation process around the amyloid plaques. It has been stated that red wine, coffee, cocoa and tea may decrease the risk of having dementia. High cholesterol, High blood pressure, Obesity, Diabetes and Cigarette Smoking, Air pollution are associated with higher risk. A questionable relation with celiac disease and Alzheimer’s disease was found doubtful recently. 

There is no cure for Alzheimer’s disease and the treatment remains palliative in nature with medications, psychosocial help and care giving. There is no treatment that can make it a long-term manageable disease like Diabetes, HIV or Hepatitis. A professor of Neurology at Harvard University, Reisa Sperling MD, Director of the Research Center for Alzheimer and Treatment at Boston’s Brigham and Women’s Hospital, states that we are facing an epidemic disease. On a pharmaceutical point of view, five medications are being used to treat the cognitive problems: Acetylcholinesterase inhibitors: (Lacrine, Rivastigmine, Galantamine and Donezil) and the other medication is Memantine, an NMDA receptor antagonist with small benefits. No medication has resulted in slowing down the progression of the disease. The first group of medications increase the concentration of acetylcholine into the brain and with it, the most common side effects of nausea and vomiting and less common side effects of muscle cramps, bradycardia, loss of appetite and gastric acid production. Glutamate is an excitatory neurotransmitter of the nervous system and as such, it can lead to cell death by overstimulation. This process is called “excitotoxicity” and can occur in disease like Alzheimer, Parkinson and Multiple Sclerosis. Memantine was used first as an anti-influenza agent and act also the same way than glutamate but produce other side effects like hallucinations, confusions, fatigue, dizziness.

Researchers have also investigated some kind of immunotherapy or vaccination for the amyloid protein. Antipsychotics maybe used to reduce aggression and psychosis but can generate serious side effects like cognitive decline and stroke. Huperzine has recently been used but will take a while to check on it efficacy in the treatment of Alzheimer Disease. The statins have been ineffective in improving the disease. The use of Vitamins A, C, B12, E and Folic acid and Omega 3 have all failed to show evidences in reducing symptoms associated with Alzheimer disease. Curcumin has not shown any benefit but recently, an interest in the Cannabinoids to improve the symptoms of Dementia, appears to be promising

Psychological interventions are used as an adjunct to pharmacological treatment to control behavior and emotion. Art, music, pet therapies with recreational activities have been used to change the patient’s routine, but the effects on brain stimulation still remain uncertain. Late in the disease, one will be incapable for tending his own care, so modifications in the living environment and lifestyle need to be done for safety. It will certainly reduce the care giver burden. Safety locks, Food in little pieces or in puree, feeding tubes in patient with swallowing difficulties etc. can be necessary. As the disease progresses other medical issues may surface with dental care or pressure sores, but in the final stages, the treatment will center on relieving pain. Hospice can become the last choice. Alzheimer’s disease may be difficult to diagnose in the early stages but once the patient starts showing cognitive impairment in his/her daily living activities with memory loss, there will be no more doubt.  He/she may still remain independent but until the symptoms progress, then, the life expectancy is reduced to a seven to twelve years. Two-third of these patients are women mainly because they tend to live longer than men and the risk of Alzheimer increase with age. Men have a more favorable survival prognosis than women. Pneumonia, Malnutrition and Dehydration are more common causes of death compared to cancer in the general population.

Epidemiologic studies have tried to estimate a rate of 10-15 per thousand person-years for all dementia while 5-8 per thousand person-years for Alzheimer’s disease. Advancing age, older than 85 especially in women, is a risk factor in the United States. About one in ten adults over the age of 65, suffers of Alzheimer’s disease, an estimated 6 million American. This is the sixth leading cause of death in the country. The World Health Organization in 2005 stated that .379% of people worldwide have dementia, around 25 million but the prevalence rate would triple or quadruple by 2050. Taking care of patients with dementia can become costly in USA, Europe and other industrialized countries. The cost of living in Nursing Home, home daycare and long-term care facilities, may reach more than 100 billions of dollars per year. The role of the caregiver is often played by a spouse or a close relative but it brings a burden on many points of view: social, psychological, physical and economical aspects. They have also a higher rate of suffering from a mental disorder as well. 2/3 of Nursing Home residents have dementia. Rare cases of possible transmission of the disease are also being studied.

In conclusion, Alzheimer is a progressive neurocognitive disease that slowly erodes memory, judgement, learning capability and ability to function in adults older than 85 years of age, although it can be encountered in younger individuals (5 %) presenting genetic or familial particularities. It may appear that little progress in the treatment has been made since 1906, when Alois Alzheimer MD discovered the offending proteins responsible for the symptoms, but we have to remember that to date, medications used in the treatment, were destined to treat only symptomatic patients. It is not like treating a heart condition and wishing that the statins will work eventually at removing atherosclerotic plaques on the vessel’s walls. Researchers may have identified the responsible beta proteins and Tau proteins with their derivatives, so, it will take time to find a solution. Can Science succeed in repairing the damaged DNA in the brain cell to reverse the disease process? Can we look at more effective methods to get rid of these offending proteins? So many questions that will require concrete answers to implement a cure for such disease affecting so many millions of human beings. As we always wish to say, “help in on the way”.

As part of the generation of the baby-boomers, we have in hand a challenge for years to come. It hurts to see an ageing parent or a friend struggle with Dementia knowing that we are unable to change their condition.  If we believe that genetics have an important role to play in the effects of the disease, we will have to face the facts that their suffering may be ours, soon. I wish to dedicate this article to all my friends suffering from the disease. May they be able to understand that we do care for them.

Maxime Coles MD



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