(See Chapters 2 and 3 for additional information.)
| Definition |
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| Prevalence |
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| Genetic risk |
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| Cognitive symptoms |
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| Diagnostic criteria |
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| Behavioral symptoms |
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| Treatment |
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| Top differential diagnoses |
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An 84-year-old woman was brought in by her daughter for slowly deteriorating thinking and memory over five years. Her phone was disconnected because she forgot to pay the bills, and there was spoiled food in the refrigerator. When interviewed she had pauses in her speech and her daughter often filled in missing words for her. She was not oriented to day, date, month, or year, nor could she name several common items or recall them a few minutes later. A CT scan of the head showed an average (for age) amount of small vessel ischemic disease (see Chapter 6 ) and atrophy of hippocampi, lateral temporal lobes, and parietal lobes.
A 78-year-old man and his wife were both concerned that his memory was not as good as it was last year. He used to be able to remember a short grocery list in his head but now he needed to write it down or he would return with the wrong items. He continued to pay the bills, balance the checkbook, and do household projects although these tasks now took him longer to complete. Evaluation of memory testing in the office showed that he scored below normal when repeating a brief story containing 10 details. His laboratory data were unremarkable, and his MRI showed bilateral atrophy in hippocampi, lateral temporal lobes, and parietal lobes.
Both of these patients show a characteristic pattern of symptoms, cognitive testing, and structural brain imaging suggestive of Alzheimer’s disease, the first consistent with Alzheimer’s disease dementia, the second consistent with mild cognitive impairment due to Alzheimer’s disease.
Prevalence, Prognosis, and Definition ( Figs. 4-1–4-3 )
Alzheimer’s disease is a neurodegenerative disease of the brain typically characterized by a prominent memory impairment and having a specific pathology including senile plaques and neurofibrillary tangles. Over time, Alzheimer’s disease produces neurochemical deficits and prominent brain atrophy. Alzheimer’s disease is by far the most common form of dementia, being the cause of approximately 75% of dementia cases either by itself or in combination with other disorders. The overall prevalence of Alzheimer’s disease dementia in the community is estimated at about 10% in population-based studies. Alzheimer’s disease becomes more prevalent with age, with most cases being diagnosed after the age of 65. In fact, the incidence roughly doubles every five years from ages 65 to 85, starting with an incidence of about 2.5% for 65- to 70-year-olds, and peaking at an incidence of 50% in those over the age of 85. The average patient with Alzheimer’s disease dementia lives approximately 10 years from diagnosis until death, with the range being approximately 4–12 years. On average the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) decline approximately 2 or 3 points per year in these patients. Alzheimer’s disease and related dementias are also some of the most expensive health conditions in the US with a total annual cost for 2013 estimated to be $203 billion for healthcare and long-term care—not including the contribution of unpaid caregivers ( ).
Alzheimer’s Pathology
Brain weight is typically reduced in Alzheimer’s disease by 100–200 grams. Examination of the surface of the brain reveals cortical atrophy of the temporal, parietal, and frontal lobes, as well as the hippocampus ( Fig. 4-4 ). The ventricular system becomes enlarged ( Fig. 4-5 ). The occipital lobes, along with primary sensory and motor cortices, are usually preserved. Microscopically, Alzheimer’s pathology consists of two main features: senile plaques and neurofibrillary tangles ( Figs. 4-6 and 4-7 ). Additional microscopic features include selective loss of neurons and synapses, and an increase in the number and activation of astrocytes. Neuropil threads (short, often curly, silver-stained fibers) also accumulate in the neocortex. The exact relationship between Aβ, plaques, tangles, cognitive impairment, and disease progression is an active area of research.
Senile plaques contain a specific type of amyloid, often referred to as β-amyloid or as “Aβ.” (Note that the amyloid in Alzheimer’s disease is not related to the amyloid in systemic amyloidoses.) Aβ is a 40- or 42-amino acid peptide that is a fragment of a larger, membrane-spanning glycoprotein known as the amyloid precursor protein or APP. The normal function of Aβ is unclear. Up to 50% of the Aβ found in plaques is Aβ42. Senile plaques are extracellular structures that are composed of Aβ, dystrophic neuritic processes (axons and dendrites), astrocytes and their processes, and microglial cells ( Fig. 4-7 ). When axons and dendrites are disrupted the communication between neurons becomes impaired. When microglial cells attempt to remove amyloid and remnants of axons and dendrites, an inflammatory reaction can start causing more damage. Under light microscopy senile plaques appear to have a fluffy central core with surrounding thick irregular processes ( Fig. 4-8 ). Various classifications of senile plaques have been proposed, including diffuse and neuritic types. Neuritic plaques are associated with the destruction of axons and dendrites of neurons. Diffuse plaques do not disrupt these neuronal processes, but are thought to be the precursor of neuritic plaques.
Neurofibrillary tangles are intraneuronal cytoplasmic structures that are composed of paired filaments with a regular helical periodicity ( Fig. 4-7 ). Neurofibrillary tangles appear to be composed primarily of a hyperphosphorylated form of the microtubule-associated protein tau. Microtubules are one of the three major constituents of the neuronal cytoskeleton, an infrastructural element of neurons that participate in functions such as axonal transport and maintenance of the structural integrity of the cell. Among other roles, tau and other microtubule-associated proteins stabilize the microtubule assembly (think of tau as the support beams or rivets for this system). Although neurofibrillary tangles begin as intracytoplasmic structures, they may remain behind after the neuron dies, forming “ghost” or “tombstone” tangles in the neuropil. Under the microscope neurofibrillary tangles look like skeins of yarn ( Fig. 4-8 ).
Neurochemistry
A deficit in acetylcholine is the most consistently found alteration of brain chemistry in Alzheimer’s disease. Early in the disease there is a loss of choline acetyltransferase and reduced high-affinity choline uptake and acetylcholine synthesis ( ). Studies have shown a correlation between the loss of choline acetyltransferase and impairment of cognition ( ). These data have led to the cholinergic hypothesis of Alzheimer’s disease that, in turn, has led to the development of acetylcholinesterase inhibitor therapies to treat this disorder (see Chapter 16 ). Other studies have shown that, in addition to acetylcholine, many other neurotransmitters also become disrupted as the disease progresses, including norepinephrine, serotonin, glutamate, and dopamine (see Fig. 4-9 ).
Diagnostic Criteria
There are several different diagnostic criteria that are used for Alzheimer’s disease. The two most common are from the Diagnostic and Statistical Manual of Mental Disorders (DSM; current edition 5) and the National Institute on Aging—Alzheimer’s Association Criteria ( ; ) ( Boxes 4-1–4-5 ). Each has provided criteria for Alzheimer’s disease dementia (called Major Neurocognitive Disorder due to Alzheimer’s Disease in DSM-5) and Mild Cognitive Impairment due to Alzheimer’s disease (called Mild Neurocognitive Disorder due to Alzheimer’s disease in DSM-5).
- A.
The criteria are met for major or mild neurocognitive disorder.
- B.
There is insidious onset and gradual progression of impairment in one or more cognitive domains (for major neurocognitive disorder, at least two domains must be impaired).
- C.
Criteria are met for either probable or possible Alzheimer’s disease as follows:
For major neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if either of the following is present; otherwise possible Alzheimer’s disease should be diagnosed.
- 1.
Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.
- 2.
All three of the following are present:
- a.
Clear evidence of decline in memory and learning and at least one other cognitive domain (based on detailed history or serial neuropsychological testing).
- b.
Steadily progressive, gradual decline in cognition, without extended plateaus.
- c.
No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline).
- a.
- 1.
For mild neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if there is evidence of a causative Alzheimer’s disease genetic mutation from either genetic testing or family history.
Possible Alzheimer’s disease is diagnosed if there is no evidence of a causative Alzheimer’s disease genetic mutation from either genetic testing or family history, and all three of the following are present:
- 1.
Clear evidence of decline in memory and learning.
- 2.
Steadily progressive, gradual decline in cognition, without extended plateaus.
- 3.
No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological or systemic disease or condition likely contributing to cognitive decline).
- 1.
- D.
The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder.
Probable AD Dementia is Diagnosed when the Patient
- 1.
Meets NIA-AA criteria for dementia described in Chapter 3 , *
* Refers to Chapter 3 : Approach to the Patient with Memory Loss, Mild Cognitive Impairment, or Dementia, in this work.
and in addition, has the following characteristics:
- a.
Insidious onset. Symptoms have a gradual onset over months to years, not sudden over hours or days;
- b.
Clear-cut history of worsening of cognition by report or observation; and
- c.
The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories.
- 1)
Amnestic presentation: It is the most common syndromic presentation of AD dementia. The deficits should include impairment in learning and recall of recently learned information. There should also be evidence of cognitive dysfunction in at least one other cognitive domain, as defined in the NIA-AA criteria for dementia described in Chapter 3 . *
- 2)
Nonamnestic presentations:
- •
Language presentation: The most prominent deficits are in word-finding, but deficits in other cognitive domains should be present.
- •
Visuospatial presentation: The most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, and alexia. Deficits in other cognitive domains should be present.
- •
Executive dysfunction: The most prominent deficits are impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present.
- •
- 1)
- d.
The diagnosis of probable AD dementia should not be applied when there is evidence of (a) substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or (b) core features of Dementia with Lewy bodies other than dementia itself; or (c) prominent features of behavioral variant frontotemporal dementia; or (d) prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or (e) evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition.
- a.
Note:
- 1.
Meets criteria for probable AD dementia as described in Box 4-2 .
- a.
Probable AD dementia with documented decline : evidence of progressive cognitive decline on subsequent evaluations based on information from informants and cognitive testing in the context of either formal neuropsychological evaluations or standardized mental status examinations.
- b.
Probable AD dementia in a carrier of a causative AD genetic mutation : evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2).
- a.
A diagnosis of possible AD dementia should be made in either of the following circumstances:
- 1.
Atypical course : meets the core clinical criteria in terms of the nature of the cognitive deficits for AD dementia, but either has a sudden onset of cognitive impairment or demonstrates insufficient historical detail or objective cognitive documentation of progressive decline.
Or
- 2.
Etiologically mixed presentation : meets all core clinical criteria for AD dementia but has evidence of (a) concomitant cerebrovascular disease, defined by a history of stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden; or (b) features of Dementia with Lewy bodies other than the dementia itself; or (c) evidence for another neurological disease or a non-neurological medical comorbidity or medication use that could have a substantial effect on cognition.
Establish Clinical and Cognitive Criteria for MCI
- •
Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time)
- •
Objective evidence of impairment in one or more cognitive domains, typically including memory (i.e., formal or bedside testing to establish level of cognitive function in multiple domains)
- •
Preservation of independence in functional abilities
- •
Not demented
Examine Etiology of MCI Consistent with AD Pathophysiological Process
- •
Rule out vascular, traumatic, medical causes of cognitive decline, where possible
- •
Provide evidence of longitudinal decline in cognition, when feasible
- •
Report history consistent with AD genetic factors, where relevant
AD, Alzheimer’s disease; MCI, mild cognitive impairment.
Related posts:
Approach to the Patient with Memory Loss, Mild Cognitive Impairment, or Dementia
Chronic Traumatic Encephalopathy
Legal and Financial Issues in Memory Loss, Alzheimer’s Disease, and Dementia
Life Adjustments for Memory Loss, Alzheimer’s Disease, and Dementia
Evaluating the Behavioral and Psychological Symptoms of Dementia
Other Disorders That Cause Memory Loss or Dementia
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