The cause of Alzheimer's Disease is not fully known.1

The causes probably include a combination of age-related changes( like what?)in the brain, along with genetic, environmental, and lifestyle factors.



Aging and Alzheimer's Risk

Older age does not cause Alzheimer’s, but it is the most important known risk factor for the disease. The number of people with Alzheimer’s disease doubles about every 5 years beyond age 65. About one-third of all people age 85 and older may have Alzheimer's disease.

Scientists are learning how age-related changes in the brain may harm neurons and affect other types of brain cells to contribute to Alzheimer’s damage. These age-related changes include atrophy (shrinking) of certain parts of the brain, inflammation, vascular damage, production of unstable molecules called free radicals, and breakdown of energy production within cells.

However, age is only one risk factor for Alzheimer’s disease. Many people live into their 90s and beyond without ever developing dementia.

Genetics of Alzheimer's Disease

Many people worry about developing Alzheimer’s disease, especially if a family member has had it. Having a family history of the disease does not mean for sure that you’ll have it, too. But it may mean you are more likely to develop it.

People’s genes, which are inherited from their biological parents, can affect how likely they are to develop Alzheimer’s disease. Genetic risk factors are changes or differences in genes that can influence the chance of getting a disease. These risk factors are the reason some diseases run in families.

There are two types of Alzheimer's—early-onset and late-onset. Both types have a genetic component.

Some Differences Between Late-Onset and Early-Onset Alzheimer's Disease


Alzheimer's disease is a progressive brain disease. It is characterized by changes in the brain—including amyloid plaques and neurofibrillary, or tau, tangles—that result in loss of neurons and their connections. These and other changes affect a person’s ability to remember and think and, eventually, to live independently.


Initially, the individual exhibits forgetfulness with day-to-day occurrences. Items may be frequently misplaced and appointments may go unattended. Following the establishment of memory loss, further cognitive decline becomes more evident. The patient may develop a halting manner to his or her speech because of the failure of recall of certain words. As the speech deficits increase, characteristics of expressive and/or receptive aphasias become more pronounced. Other cognitive difficulties include dyscalculia, disruption of visuospatial orientation, and ideational and ideomotor apraxias. The patient may eventually develop difficulty with locomotion and may become confined to bed. The incidence and prevalence of AD increase with age. The majority of patients are over the age of 60, but AD has also been diagnosed in much younger patients. Certain forms of AD have a familial occurrence, but these account for less than 1 percent of all cases. The most well-described familial trends follow an autosomal dominant inheritance. The early onset of AD has also been linked with Down syndrome. The most important aspect of the diagnosis of AD is the exclusion of treatable forms of dementia. While imaging of the brain may demonstrate diffuse atrophy with thinning of the cerebral gyri and enlargement of the sulci and ventricles in the advanced stages, it is more important to identify mass lesions, such as chronic subdural hematomas, which may account for the symptoms. On histological specimens, AD is associated with the diffuse loss of neurons in the cerebral cortex. In particular, neuronal loss in the nucleus basalis of Meynert is associated with decreased levels of the neurotransmitter acetylcholine. There are intracytoplasmic deposition of neurofibrillary tangles in neurons composed of paired, helical filaments, immunoreactive for tau protein and neuritic plaques composed of paired, helical filaments of fibrillar beta amyloid. In the amyloid hypothesis of AD, it was the deposition of fibrillar beta amyloid in the form of neuritic plaques which was believed to be the main cause of the progressive cognitive dysfunction. However, the spatial and temporal patterns of plaque formation did not correlate well with the level of cognitive decline. Newer research into the pathophysiology of AD points to the role of nonfibrillar amyloid beta peptide (A-β), the precursor of neuritic plaques, accumulating in synapses. This has been termed the synaptic amyloid beta hypothesis. Amyloid precursor protein (APP), a protein, is embedded in the membrane of the presynaptic terminal of the neuron. Cleavage of APP results in the release of A-β into the synapse, which acts as a synaptotoxin impairing glutaminergic transmission and compromising synaptic function. The elucidation of this new model of AD may point to the development of new therapeutic treatments in the future.




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Amyloid plaques and neurofibrillary, or tau, tangles—that result in loss of neurons and their connections. These and other changes affect a person’s ability to remember and think and, eventually, to live independently.

Alzheimer disease is the most common degenerative disorder of the brain, accounting for 50% of all diagnosed dementias.


Approximately 10% of all persons over the age of 70 have significant memory loss, and in more than half, the cause is Alzheimer disease (AD). AD can occur in any decade of adulthood, but it is the most common cause of dementia in the elderly. AD most often presents with an insidious onset of memory loss followed by a slowly progressive dementia over several years. Pathologically, atrophy is distributed throughout the medial temporal lobes, as well as lateral and medial parietal lobes and lateral frontal cortex. Microscopically, there are neurofibrillary tangles composed of hyperphosphorylated tau filaments, and accumulation of amyloid in blood vessel walls in cortex and leptomeninges. The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and spreading to language and visuospatial deficits. Yet, approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In the early stages of the disease, the memory loss may go unrecognized or be ascribed to benign forgetfulness. Slowly the cognitive problems begin to interfere with daily activities, such as keeping track of finances, following instructions on the job, driving, shopping, and housekeeping. Some patients are unaware of these difficulties (anosognosia), whereas others remain acutely attuned to their deficits. Social graces, routine behavior, and superficial conversation may be surprisingly intact. Language becomes impaired—first naming, then comprehension, and finally fluency. In some patients, aphasia is an early and prominent feature. Word-finding difficulties and circumlocution may be a problem even when formal testing demonstrates intact naming and fluency. Visuospatial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures. Simple calculations and clock reading become difficult in parallel. Loss of judgment and reasoning is inevitable. Delusions are common and usually simple, with common themes of theft, infidelity, or misidentification. In end-stage AD, patients become rigid, mute, incontinent, and bedridden. Hyperactive tendon reflexes and myoclonic jerks may occur spontaneously or in response to physical or auditory stimulation. Generalized seizures may also occur. Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. The typical duration of AD is 8–10 years, but the course can range from 1 to 25 years. For unknown reasons, some AD patients show a steady decline in function, while others have prolonged plateaus without major deterioration.


There is no definitive treatment for AD.

Antipsychotic medications or benzodiazepines may be administered to help treat certain behavioral disturbances common with Alzheimer Disease.



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A woman brings her 68-year-old father to your office for an examination. She states that over the past several years, “he has become increasingly forgetful.” Initially, her father could not remember where he had left his wallet and keys from earlier in the day. Now she has to constantly remind him of what they have just discussed. While he used to be an avid storyteller, he has become much less gregarious of late. Most recently, she states that the neighbors found her father wandering around the block without an explanation of where he was going or from where he had just come. You diagnose her father with Alzheimer disease (AD).

Summary: A 68-year-old man with a several-year history of progressive cognitive decline is diagnosed with Alzheimer disease.

What is the most likely finding on a postmortem brain biopsy?

Amyloid plaques and neurofibrillary tangles are clearly visible by microscopy. Amyloid plaques are hard, insoluble plaques of protein fragments that form between neurons. Neurofibrillary tangles consist of insoluble microtubules that accumulate because of abnormal tau proteins.


Which neurotransmitter would most likely be deficient?

The oldest of the three major competing theories on the cause of the disease is the “cholinergic hypothesis,” which posits that AD is caused by restricted biosynthesis of acetylcholine; thus acetylcholine would be the most deficient.


Clinical Correlation



You answered D.

An 80-year-old man has experienced a progressive decline of cognitive function over the past 5 years. Currently, he does not remember any family members, with the exception of his wife. He sometimes gets lost within his own house. Evaluation of his brain will reveal cellular accumulations of






An 80-year-old man has experienced a progressive decline of cognitive function over the past 5 years. Currently, he does not remember any family members, with the exception of his wife. He sometimes gets lost within his own house. Evaluation of his brain will reveal cellular accumulations of

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The correct answer is C.

The patient has Alzheimer disease, which is characterized by the intracellular accumulations of tau protein.



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