Alzheimer’s Disease

Last updated date: 17-Jul-2023

Originally Written in English

Alzheimer's disease

Dementia is a general term that refers to a decrease in cognitive abilities severe enough to impair daily activities. Alzheimer's disease is the most prevalent type of dementia, affecting at least two-thirds of dementia cases in older people.

Alzheimer's disease is a neurodegenerative condition that causes a gradual decline in behavioural and cognitive capabilities such as memory, comprehension, language, attention, reasoning, and judgment. In the United States, it is the sixth leading cause of mortality. Early-onset is rare and occurs in less than 10% of Alzheimer's patients. There is no cure for Alzheimer's disease, although there are treatments available that may alleviate specific symptoms.

Alzheimer's disease symptoms vary depending on the stage of the disease. Depending on the severity of cognitive impairment, Alzheimer's disease is categorized as preclinical or presymptomatic, mild, or dementia-stage. 

Executive functioning impairment can range from minor to severe in the early stages. Then there's a language issue and a loss of visuospatial abilities. Apathy, social isolation, disinhibition, agitation, psychosis, and wandering are prevalent neuropsychiatric symptoms in the mid to late phases. 

Alzheimer's disease is an illness that always progresses. A person diagnosed with Alzheimer's disease at the age of 65 has an average life expectancy of 4 to 8 years. Alzheimer's disease can affect people for 20 years after the first symptoms appear. In Alzheimer's disease, pneumonia is the most prevalent cause of mortality.


Alzheimer's disease Epidemiology

Alzheimer's disease Epidemiology

Alzheimer's disease can be divided into a familial type and a sporadic type and early-onset (before the age of 65) and late-onset (after the age of 65). The 6-month prevalence of Alzheimer's disease in the general population is estimated to be 5.5 % to 9 %.  

In the United States, around 4.5 million persons aged 65 and up have clinical Alzheimer's disease. After the age of 65, the incidence doubles every 5 years. The age-specific incidence rises considerably from less than 1% per year before the age of 65 to 6% per year beyond the age of 85. The prevalence rate increases from 10% at the age of 65 to 40% after the age of 85. Women have a somewhat greater incidence rate of Alzheimer's disease, significantly beyond the age of 85.


Alzheimer's disease Pathophysiology

Alzheimer's disease Pathophysiology

A buildup of aberrant neuritic plaques and neurofibrillary tangles is a hallmark of Alzheimer's disease.

Plaques are tiny lesions with a core of extracellular amyloid beta-peptide surrounded by larger axonal terminals that are spherical. A transmembrane protein known as an amyloid precursor protein is the source of beta-amyloid peptide (APP). Proteases known as alpha, beta, and gamma-secretase break the beta-amyloid peptide off the APP protein. 

APP is usually cleaved by alpha-secretase or beta-secretase, and the resulting small fragments are not harmful to neurons. However, cleavage by beta-secretase followed by gamma-secretase produces 42 amino acid peptides (beta-amyloid 42). The aggregation of amyloid caused by an increase in beta-amyloid 42 levels promotes neuronal damage. Beta-amyloid 42 enhances fibrillary amyloid protein production over normal APP breakdown. The APP gene is found on chromosome 21, which is connected to Alzheimer's disease in families.

In Alzheimer's disease, amyloid deposits around meningeal and cerebral arteries, as well as grey matter. Multifocal grey matter deposits consolidate to produce milliary structures known as plaques. However, brain scans have revealed amyloid plaques in some people without dementia, while brain scans have revealed no plaques in others with dementia.

A tau protein forms fibrillary intracytoplasmic aggregates in neurons called neurofibrillary tangles. The tau protein's main job is to keep axonal microtubules stable. Microtubules are vital for intracellular transport and run along neuronal axons. Tau protein is responsible for maintaining microtubules together. Hyperphosphorylation of tau occurs in Alzheimer's disease due to extracellular beta-amyloid accumulation, resulting in tau aggregate development. 

Tau aggregates generate neurofibrillary tangles, which are twisted paired helical filaments. They start in the hippocampus and spread to the rest of the cerebral cortex. Tangles have a more vital link to Alzheimer's disease than plaques.

Granulovacuolar degeneration of hippocampal pyramidal cells is another feature of Alzheimer's disease. The role of the vascular contribution in the neurodegenerative process of Alzheimer's disease is not entirely understood. Subcortical infarcts raise the chance of dementia fourfold. The cerebrovascular disease also exaggerates the severity of dementia and the rate at which it progresses.


Alzheimer's disease Causes

Alzheimer's disease Causes

Both genetic and environmental risk factors influence Alzheimer's disease. The most critical risk factor is age; at 65, the probability of developing Alzheimer's disease is approximately 3%, rising to more than 30% by 85. The occurrence in people under the age of 65 is less known, although estimates imply that this age group accounts for around 3% of all instances. Although total numbers are rising as the population ages, the age-specific incidence declines in some countries.

Alzheimer's disease is categorized based on when it manifests and if it is hereditary. Early-onset Alzheimer's disease appears before the age of 65, but late-onset Alzheimer's disease accounts for more than 95 % and appears beyond the age of 65. Mendelian (typically dominant) inheritance characterizes familial Alzheimer's disease, whereas sporadic Alzheimer's disease has no simple familial link. Because of genetic mutations, nearly all cases of early-onset Alzheimer's disease are familial, whereas the vast majority of late-onset Alzheimer's disease is due to sporadic causes. 

Up to 80% of individuals with Down syndrome develop dementia by the age of 65. Down syndrome is caused by a trisomy of chromosome 21, which contains the APP gene, and having three copies of this gene is enough to elevate A levels. However, the higher chance of getting the condition may be related in part to the triplication of other genes on chromosome 21.

Sporadic Alzheimer's disease is frequently caused by a combination of genetic and environmental risk factors, the most prevalent of which are cerebral hypoperfusion and inflammation. Trauma, sepsis, and infection-related inflammation has been associated with both short- and long-term cognitive impairment. Traumatic brain damage and bone fractures in the elderly have been linked to an increased risk of dementia. 

Vascular disease and dementia have a close relationship. Cardiovascular disease, such as hypertension and heart attack, and cerebrovascular disease, such as ischemia, are linked to an increased risk of Alzheimer's disease. Poor diet, obesity, high cholesterol, and a sedentary lifestyle are risk factors for developing vascular diseases and dementia. A poor diet and high cholesterol levels can cause metabolic disorders both systemically and in the brain, as well as alterations in oxygen levels. Furthermore, type 2 diabetes nearly doubles the incidence of dementia. 


Alzheimer's disease Genetic

Alzheimer's disease Genetic

Alzheimer's disease is an autosomal dominant condition with nearly complete penetrance. Mutations in three genes are connected to the autosomal dominant type of the disease: the AAP gene on chromosome 21, Presenilin 1 (PSEN1) on chromosome 14, and Presenilin 2 (PSEN2) on chromosome 1. Increased production and aggregation of the beta-amyloid peptide may result from APP mutations. PSEN1 and PSEN2 mutations cause beta-amyloid accumulation by interfering with gamma-secretase processing. The bulk of early-onset Alzheimer's disease is caused by mutations in these three genes, which account for around 5% to 10% of all cases.


Clinical manifestations of Alzheimer's disease

Clinical manifestations of Alzheimer's disease

The initial symptoms are frequently misattributed to age or stress. Extensive neuropsychological testing can identify modest cognitive impairments up to eight years before a person meets the clinical criteria for Alzheimer's disease diagnosis. These early signs can impact even the most complex everyday tasks. The most evident deficit is short-term memory loss, which manifests as difficulties recalling previously learned knowledge and failure to learn new material.

Subtle issues with executive skills such as attentiveness, planning, flexibility, and abstract thinking, as well as deficits in semantic memory (memory of meanings and concept relations), can potentially be symptoms of Alzheimer's disease in its early stages. At this stage, apathy and despair can be observed, with apathy remaining the most persistent symptom throughout the disease. 

The disease's preclinical stage is also known as mild cognitive impairment. This is frequently identified as a transitional period between normal ageing and dementia. Mild cognitive impairment can appear with several symptoms. When memory loss is the most prominent, it is referred to as amnestic mild cognitive impairment, and it is commonly considered a prodromal stage of Alzheimer's disease. Amnestic mild cognitive impairment is more than 90% likely related to Alzheimer's disease.


How many stages for Alzheimer's disease?

Alzheimer's disease stages

Alzheimer's disease progresses in three stages, with a progressive cognitive and functional impairment pattern. Early or mild, middle or moderate, and late or severe are the three stages. The disease is known to affect the hippocampus, which is related to memory and is responsible for the initial symptoms of memory impairment. The degree of memory impairment increases as the disease advances.


The progressive deterioration of learning and memory in patients with Alzheimer's disease finally leads to a conclusive diagnosis. More common than memory problems are language, executive function, perception (agnosia), and movement execution (apraxia) impairments. Alzheimer's disease affects not all memory skills in the same way. Older memories of a person's life (episodic memory), facts learned (semantic memory), and implicit memory (the body's knowledge of how to perform tasks, such as eating with a fork or drinking from a glass) are influenced less than newer facts or memories.

Language issues are characterized primarily by a decline in vocabulary and decreased word fluency, resulting in a general impoverishment of spoken and written language. At this stage, the Alzheimer's patient is typically capable of articulating fundamental thoughts properly. 

Specific movement coordination and planning difficulties (apraxia) may be present while executing fine motor tasks such as writing, sketching, or dressing, although they are frequently undetected. People with Alzheimer's disease can often continue to perform many activities separately as the condition develops, although they may require assistance or supervision with the most cognitively demanding activities.

Middle stage:

Progressive deterioration finally impedes independence, with patients unable to do most everyday tasks. Speech issues emerge due to difficulty retaining the language, resulting in frequent incorrect word replacements (paraphasias). Reading and writing abilities are also deteriorating. As time passes and Alzheimer's disease worsens, complex motor sequences become less coordinated, increasing the risk of falling. Memory issues intensify throughout this stage, and the person may fail to recognize close relatives. Long-term memory, which was previously intact, begins to deteriorate.

Changes in behaviour and neuropsychiatry become increasingly common. Wandering, irritation and emotional lability are common symptoms, which can lead to sobbing, episodes of unpremeditated aggressiveness or resistance to caregiving with sundowning is another possibility. 

Around 30% of individuals with Alzheimer's disease have illusionary misidentifications and other delusional symptoms. Subjects lose sight of their illness progress and restrictions as well (anosognosia). Urinary incontinence can occur. These symptoms cause stress for families and caregivers, which can be alleviated by transferring the individual from home care to another long-term care facility.

Final stage:

The patient is entirely dependent on caregivers during this stage, termed as the late-stage or severe stage. Language is limited to basic sentences or even single words, eventually leading to total aphasia. People may often comprehend and reciprocate emotional cues despite their loss of spoken language abilities. Although aggression may persist, excessive apathy and tiredness are more prevalent symptoms. 

People who have Alzheimer's disease will eventually be unable to execute even the most fundamental duties independently; their muscle mass and movement will decline to the point where they will be bedridden and unable to feed themselves. The cause of mortality is frequently an external issue, such as pressure ulcer infection or pneumonia, rather than the disease itself.


Diagnosis for Alzheimer's disease

Diagnosis for Alzheimer's disease

The essentials to diagnosis include a comprehensive history and physical examination. It is also critical to obtain a history from the patient's family and caregivers, as some patients may be unaware of their condition. To distinguish from other varieties of dementia, it is critical to identify the onset and early symptoms. It is essential to acquire an accurate assessment of functional skills such as fundamental and individual daily living tasks.

A comprehensive physical examination, including a complete neurological exam and mental status assessment, is required to assess the disease stage and rule out other disorders. In most cases, a thorough clinical examination can yield reasonable diagnostic accuracy. 

To rule out other disorders, a thorough neurological evaluation is required. The neurological exam is frequently normal in Alzheimer's disease.   Patients with Parkinson's disease, dementia with Lewy bodies, and TBI with or without dementia all have anosmia. Patients with severe Alzheimer's disease do not exhibit lateralized symptoms. 

They eventually become mute, fail to respond to verbal requests, remain confined to bed, and frequently slip into a persistent vegetative state. A mental status examination should assess concentration, attention, recent and remote memory, language, visuospatial functioning, praxis, and executive functioning.

Other diagnostic tools can aid in the diagnosis process, such as:

  • Routine laboratory tests: Complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), B12 are usually checked to rule out other causes.
  • Brain CT: May show cerebral atrophy and widened third ventricle. 
  • Cerebrospinal fluid (CSF) analysis: Can show low levels of beta-amyloid and elevated tau proteins which are helpful in the diagnosis of the preclinical stage. 
  • Electroencephalography (EEG): Typically shows a generalized slowing with no focal features. It is diagnostically helpful but still nonspecific. 
  • Volumetric MRI: Is utilized to quantify volumetric brain changes properly and reveals shrinkage in the medial temporal lobe in Alzheimer's disease. However, because hippocampal shrinkage is also associated with normal age-related memory impairment, the efficacy of volumetric MRI for early diagnosis of Alzheimer's disease is questionable. Volumetric MRI has yet to be shown as a valuable tool in diagnosing Alzheimer's disease.
  • Genetic testing: Is generally not advised for Alzheimer's disease. It is occasionally used in families with rare early-onset Alzheimer's disease.


Treatment for Alzheimer's disease

Treatment for Alzheimer's disease

Alzheimer's disease has no known cure. There is just symptomatic therapy available. Two categories of drugs are approved for treating Alzheimer's disease: cholinesterase inhibitors and partial N-methyl D-aspartate (NMDA) antagonists.


Cholinesterase Inhibitors:

Cholinesterase inhibitors work by raising the amount of acetylcholine in the body, which is a neurotransmitter utilized by nerve cells to communicate with one another and is essential for learning, memory, and cognitive functioning. Three medications in this category are FDA-approved for treating Alzheimer's disease: donepezil, rivastigmine, and galantamine.

Donepezil is effective at all stages of Alzheimer's disease. Galantamine and rivastigmine are licensed for use in the treatment of dementia. Donepezil and galantamine are acetylcholinesterase inhibitors that act quickly and are reversible. Rivastigmine is a slow, reversible acetylcholinesterase and butyrylcholinesterase inhibitor. Because of its once-daily dose, donepezil is frequently favoured above the others. Galantamine comes in the form of a twice-daily pill or a once-daily extended-release capsule. It is not appropriate for patients with end-stage renal disease or severe liver impairment. 

The most common side effects of these drugs are gastrointestinal manifestations. Sleep disturbances are more prevalent with donepezil. Because of the elevated vagal tone, bradycardia, cardiac conduction problems, and syncope can develop, and these drugs are contraindicated in individuals with severe cardiac conduction abnormalities.


Partial N-Methyl D-Aspartate (NMDA): Memantine

Memantine inhibits NMDA receptors and decreases calcium buildup in the cell. The FDA has approved it to treat moderate to severe Alzheimer's disease. Common adverse effects include dizziness, body pains, headaches, and constipation. It can be combined with cholinesterase inhibitors.

It is also necessary to treat anxiety, depression, and psychosis, which are common in the middle to late stages of Alzheimer's disease. Because of their anticholinergic action, tricyclic antidepressants should be avoided. Antipsychotics are only used for acute agitation if the patient or caregiver has exhausted all other options. However, their limited advantages should be balanced against the slight risk of stroke and mortality.


Differential diagnosis of Alzheimer dementia 

Differential diagnosis of Alzheimer dementia 

Differential diagnosis of Alzheimer dementia includes pseudo-dementia, Lewy body dementia, Vascular dementia, and frontotemporal lobar degeneration. Other disorders to consider and rule out when evaluating for Alzheimer's disease include age-associated memory impairment, alcohol or drug abuse, vitamin-B12 deficiency, patients on dialysis, thyroid problems, and polypharmacy.

  • Lewy Body Dementia: Approximately 15% of cases of dementia can be attributed to Lewy Body dementia. Cortical Lewy bodies are the histologic abnormalities found in these patients. Patients with Lewy Body dementia have core clinical features (fluctuating cognition, visual hallucinations, one or more symptoms of Parkinson with onset subsequent to the development of cognitive decline), suggestive clinical features (REM sleep behaviour disorder and severe antipsychotic sensitivity).


  • Frontotemporal Dementia: It accounts for 5% to 10% of all dementia cases, with a mean age of onset of 53, and is more frequent in men than in women. Frontotemporal Dementia is classified into two types: behavioural variation and language variant. Disinhibition, Apathy, Loss of compassion, Stereotyped or obsessive actions, Hyperorality, and decrease in social cognition and executive capacities are required for a possible diagnosis of behavioural variant. The language variant has a decline in language ability. In addition to these symptoms, proof of genetic mutation or frontal and temporal lobe involvement on CT/MRI is necessary for a likely diagnosis. 


  • Dialysis Dementia: Dialysis dementia is a neurologic consequence of long-term dialysis. It might be related to vascular issues (dialysis patients are more likely to have a stroke), metabolic problems, or dialysis itself. It was once associated with aluminium toxicity. However, this is no longer the case due to replacements to aluminium-containing substances. 


Prognosis of Alzheimer's disease

Prognosis of Alzheimer's disease

Alzheimer's disease is almost always progressive. A person diagnosed with Alzheimer's disease at the age of 65 has an average life expectancy of 4 to 8 years. Some people with Alzheimer's disease might live for up to 20 years after the first symptoms appear. Pneumonia is the leading cause of mortality in Alzheimer's disease.



Alzheimer’s Disease

Alzheimer's disease is the most common cause of dementia and a chronic neurodegenerative disorder. Although certain causal gene defects (e.g., amyloid precursor protein gene mutations) and risk factors (e.g., age) have been found, the actual process that causes Alzheimer disease remains unclear. 

The major histological hallmarks of Alzheimer's disease are senile plaques formed by the extracellular deposition of beta-amyloid protein in the brain's grey matter and neurofibrillary tangles caused by intracellular tau protein accumulation. 

The most prevalent sign of Alzheimer's disease is short-term memory loss. During the course of the disease, several cognitive skills, such as attention control, reasoning, orientation, and language, are affected. Individuals with Alzheimer's disease can usually maintain a social façade as the condition develops. 

The clinical examination is utilized to make the diagnosis, although neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and imaging are occasionally employed as well. There is currently no curative treatment. Cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists can be used to treat symptoms. The development of Alzheimer's disease is exceedingly variable. The average survival period after diagnosis ranges between 3 and 10 years.