[Miles E. Drake]

INTRODUCTION

Alzheimer’s Disease accounts for about 70 per cent of cases of dementia, and is presently the most prevalent and best-studied neurodegenerative disorder. It is associated with significant morbidity and mortality, and imposes high personal and financial costs on society and on its sufferers and their caregivers. Its pathophysiology is coming to be understood, and some therapeutic options are now available for the disorder[1].

History and Time-line

The Ebers Papyrus, the earliest extant Egyptian medical text, described many medical conditions, including childishness, language difficulties, memory impairment and nocturnal confusion now recognized as dementia and “sundowning”. Pythagoras, Hippocrates and other ancient Greeks ascribed dementia along with other neurobehavioral disturbances to brain disorders rather than to supernatural agencies, and were the first to invoke a chemical or humoral cause. Roman medicine was also cognizant of dementia, and after the observations of Galen on the cerebral arteries tended to invoke circulatory causes; Roman literature such as the Satires of Juvenal featured elderly characters with probable senile dementia, and republican Roman law provided for the guardianship and care of demented adults[2].

There was little attention to dementia during the medieval period, probably because most people did not live long enough for it to be an issue. Survival to the senium was often a rarity, and presenile dementia tended to be classified with the mental disorders, and often treated in a custodial fashion. There are literary examples of possible dementia in Hamlet, Lear and other Renaissance writings, and Francis Bacon around 1600 suggested that the posterior part of the brain was the “home of forgetfulness”. It has also been proposed that symptoms of dementia caused some women in Europe and America to be designated as witches[3].

The term démence or dementia, literally meaning loss of the mind, was first proposed by Phillipe Pinel as part of the revolution in psychiatric treatment he initiated in Paris at the end of the 18th century. Benjamin Rush, the founder of American neurology and psychiatry, introduced the term in the United States soon after, and in both cases it was applied to what are now considered primary psychiatric disorders as well as neurodegenerative diseases. In particular, 19th century clinicians differentiated between senile dementia and cognitive and behavioral symptoms that developed in younger patients (dementia praecox). The German school of neuropsychiatry, most notably Emil Kraepelin and Eugen Bleuler, codified the manifestations of presenile dementia into several psychiatric entities, chiefly schizophrenia[4].

In 1901 one of Kraepelin’s chief lieutenants, Alois Alzheimer, undertook the care of Auguste Deters, a 51-year-old woman hospitalized for cognitive decline, language difficulties, paranoia, hallucinations and delusions and aggressive behavior, considered the symptoms of senile dementia but beginning atypically early. Alzheimer, who was gifted with tenacity and single-mindedness as well as skill in neuropathology, and was independently wealthy and did not need to earn his living by clinical practice, followed her case attentively for 5 years and examined her brain thoroughly after her death. Although other clinicians had observed early occurrence of senile dementia and there had been other reports of the plaques and neurofibrillary tangles that are now recognized as the cardinal pathological changes in the disorder, this comprehensive case report led Kraepelin and others to apply Alzheimer’s name to the disorder[5].

In subsequent years, a variety of variants of the disorder were described. Dementia with predominantly behavioral and language changes had been described by Arnold Pick a decade earlier, and Alzheimer in 1911 identified a variant of  neurofibrillary tangles that he named Pick bodies in what was later to be called frontotemporal dementia. Alzheimer’s student Friedrich Lewy described the following year a dementing disorder associated with inclusion bodies in neurons that now bears his name. Dementia associated with Parkinson’s disease, amyotrophic lateral sclerosis and multiple cerebral infarctions was subsequently described, as well as a dementing disorder characterized by slowly progressive aphasia[6].

During the remainder of the 20th century the incidence of Alzheimer’s disease has increased with more precise diagnosis, longer life-span and progress against other diseases of aging. There has also been an enormous advance in understanding of the cause or causes of the disorder, and considerable progress in its treatment and management. Alzheimer’s disease remains a widespread and costly medical and social problem, however[7].

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CLINICAL FEATURES

• Alzheimer disease is characterized pathologically by progressive loss of synapses and neurons, the accumulation of amyloid plaques and neurofibrillary tangles and clinically by a spectrum of disease ranging from an asymptomatic state to dementia.
  
• Clinical definitions require only the documentation of cognitive deficits not due to some other cause; if these interfere with daily functioning, the diagnosis is Dementia due to Alzheimer’s disease is given. Evident cognitive decline that does not interfere with with daily functioning is termed Mild Cognitive Impairment due to Alzheimer’s disease.
  
• Two classification systems for the disease are currently in use, and terminology for the phase of the disease depends upon which system is used. A clinical-pathological classification, which is presumptive unless the signature changes of the disease are found by biopsy, is the most useful and commonly used in clinical practice[8]. 
  
• Mild Cognitive Impairment from Alzheimer’s  disease is diagnosed by the presence of mild deficits not attributable to another cause after evaluation. Independent functional ability is preserved, and there is no significant impairment of social or occupational functioning. Cognitive impairment is most commonly in episodic memory. Dementia due to Alzheimer’s disease is diagnosed by the presence of cognitive deficits plus functional decline  not attributable to other cause after evaluation[9].
  
• A clinical-biological diagnostic classification makes the diagnosis of Alzheimer’s disease definitive, but requires some kind of biomarker for confirmation. This is more useful in research settings but may become clinically applicable when validated biomarker testing becomes more available. The diagnosis of  asymptomatic preclinical Alzheimer’s disease is possible if a biomarker is present. Prodromal Alzheimer’s disease (mild cognitive impairment) would be identified by the presence of a biomarker plus episodic memory loss without impairment in activities of daily living.  Alzheimer’s disease dementia would be diagnosed by the presence of a biomarker plus episodic memory impairment plus impairment in activities of daily living[10].
  
• Possible Alzheimer’s disease biomarkers include atrophy of the medial temporal lobe on MRI scan and diminished function of the frontal and temporal lobes or decreased tracer uptake on PET or SPECT scans. Alzheimer’s disease is also apparently associated with altered levels in the cerebrospinal fluid of several forms of amyloid and tau protein, the two proteins that make up the plaques and neurofibrillary tangles characteristic of the disease. Reduced levels in the cerebrospinal fluid of amyloid-ß peptide, elevated levels of tau protein and tau protein that is excessively phosphorylated may be present in early or asymptomatic Alzheimer’s disease[11].
  

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DIAGNOSIS

CLINICAL PRESENTATION

• The history of suspected dementia should be obtained from the patient and from an informant such as a family member, friend, or caregiver[13].
  
• Learning and memory symptoms include early onset of memory impairment, especially episodic memory such as autobiographical recollections of events, times, places, and who was present then.
  

Semantic memory, the recall of facts and concepts, is usually preserved until later in the disease, while the ability to activate semantic memory for purposes of problem solving (working memory) is affected early on[14].

• Executive functioning is very often compromised.
  
• Characteristic symptoms reported by the patient, but often more evident to an observer, include loss of the ability to multitask and confusion when trying to follow simple instructions.
  
• Conversations are often difficult to follow when the subject is changed, even if no conversational difficulty had been evident previously.
  
• Complex attention is also impaired, and it takes longer to complete tasks, the patient is more easily distracted while doing them and mental calculations, solving problems and sequential actions such as dialing a telephone number become increasingly difficult.
  

Language impairment is manifested early, with difficulty in word-finding and use of the wrong word as well as grammatical errors. Reading and language comprehension are also compromised early on. Symptoms of perceptual motor-visual function difficulty include becoming lost in hitherto familiar places, greater reliance than before on maps and written notes and new difficulty using appliances and tools.

The involvement of social cognition may be indicated by behavioral disinhibition and actions that were never done before and are noticeably different from past behavior, although this is usually more characteristic of frontotemporal dementia (Pick’s disease).

Social interactions are more often preserved in the early stages of Alzheimer’s disease, although there may be occasional reports of inappropriate behavior or poor judgement that was not evident in the past. Other psychiatric symptoms usually develop later but may be occasionally evident early on . These include depression, anxiety, apathy and irascibility.

The physical and neurological examination and standard cognitive testing may well be normal in the prodromal stages of Alzheimer’s disease. When mild cognitive impairment has begun the examination is usually normal, but cognitive testing may show difficulties with memory, particularly episodic memory. Physical examination findings after dementia has become established vary with its severity: there may be evidence of poor nutrition and hygiene, infections at skin creases and in irritated places, perineal skin irritation or breakdown if incontinent and decubitus ulcers if confined to bed. The neurologic examination may be normal except for increasingly abnormal cognition.

When  present, neurologic signs can include slowed gait, impaired coordination and abnormal reflexes, particularly the “frontal release signs” associated with frontal lobe injury or deterioration, such as the snout or palmomental reflex. Brief cognitive testing such as the Mini-mental state examination, Mini Cognitive Assessment instrument or Montreal Cognitive Assessment test will show abnormality, or if done before will demonstrate a decline from previous performance.

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CAUSES OF ALZHEIMER'S DISEASE AND RISK FACTORS

About 10 per cent of Alzheimer’s diseases cases are familial, but 50 per cent of early-onset dementia is inherited. 

• Sporadic disease, which is usually late in onset but can begin in early adulthood, comprises the other 90 per cent, and remains of unknown cause.
  

Early-onset disease is defined as onset before age 40, while late-onset dementia begins after age 65 and most typically between 75 and 85.

• Increasing age is the strongest risk factor, with prevalence doubling every 5 years after age 65; prevalence in patience older than 85 years ranges from 25 to 47 per cent in different studies. The incidence of Alzheimer’s disease is similar in women and men, but prevalence is higher in women because they are longer-lived[15]
  
• One of the strongest risk factors is family history, particularly of early-onset Alzheimer’s disease. 
  
• Early-onset familial cases generally show a mutation in a gene on chromosome 2q that codes for amyloid precursor protein; less frequent mutations include one on chromosome 14 that encodes the protein presenelin 1 and another involving a gene on chromosome 1 responsible for presenelin 2. 
  
• Alzheimer’s disease of late onset has been associated with polymorphism of apolipoprotein E, encoded by chromosome 19. This is apparently a “housekeeper” protein involved in the clearance of proteins such as amyloid and tau, and individuals with the E4 allele may be more likely to develop the disease. The relationship is not absolute, however, as the presence of the allele does not always result in Alzheimer’s disease and its absence does not always protect against the disease.
  
  

Black and Hispanic populations have a higher incidence of Alzheimer’s disease, and other potential risk factors include low educational level, past history of head injury and the presence of chronic inflammation, which may also be associated with the apolipoprotein E gene[16].

DIAGNOSTIC PROCEDURES

The disease is identified primarily by history, a screening assessment of cognition and the assessment of daily functioning to distinguish between dementia and mild cognitive impairment. Several quick tests may detect dementia but not necessarily milder degrees of cognitive impairment, such as the Mini Cognitive Assessment instrument, the Mini Mental State Examination or the Montreal Cognitive Assessment. The widely-used first version of the Mini Mental State Examination (MMSE-1) may be sensitive to education, race and socioeconomic status, and a more generally applicable version (MMSE-2) is now available. These results can be clarified if necessary through neuropsychological tests like the Wechsler Adult Intelligence Scale or Halsted-Reitan Battery.

The patient’s ability to carry out the activities of daily living may be assessed through a nonstructured interview with the patient and an informant. There are also more structured methods of inquiry, such as the Assessment of Instrumental Activities of Daily Living and the Functional Assessment Questionnaire.

The cognitive screening and functional assessment together may indicate either dementia, not necessarily of the Alzheimer type, or mild cognitive impairment. The criteria for identifying dementia of all causes are significant decline in one or more cognitive domains that is not due to delirium or some other psychiatric disorder; this can include impaired ability to acquire and recall new information; impaired reasoning, ability to handle complex tasks or judgement; impaired visuospatial abilities; impaired language functions, whether spoken, read or written; or changes in personality and behavior. These problems must interfere with the performance of everyday activities, including occupational and social function15.

The diagnostic requirements for mild cognitive impairment from any cause are concern about mental decline and modest impairment in one or more cognitive domains that do not interfere with independence. The concern may be voiced by the patient, expressed by the informant or noticed by the clinician, and the cognitive impairment should be demonstrated by appropriate testing and will usually involve memory. Although the symptoms must not interfere with the activities of daily living, the patient may require more time and effort, need accommodation or use compensatory strategies. Social and occupational function are not affected in mild cognitive impairment15.

The American Academy of Neurology has recommended that medical causes of dementia or mild cognitive impairment be sought with complete blood count, electrolyte determinations and measurement of thyroid stimulating hormone (TSH) and vitamin B12 level along with brain CT scan or MRI. Lumbar puncture is appropriate when infection or inflammation of the central nervous system are suspected? Perform routine investigations to assess for medical causes of dementia/mild cognitive impairment: the American Academy of Neurology recommends CBC, electrolytes, TSH, vitamin B12, and brain CT or MRI; lumbar puncture is indicated when central nervous system infection or inflammation is reasonably probable.

With respect to diagnostic biomarkers, the level of amyloid-ß-protein in the cerebrospinal fluid is useful measure in demented individuals but has a low yield in patients with mild cognitive impairment; it may nevertheless be appropriate when there is a family history of Alzheimer’s disease and the patient desires an early diagnosis and wishes to be considered for clinical trials and early interventions. The level of tau protein is usually elevated in Alzheimer’s disease, and is again appropriate when family history is positive and the earliest possible diagnosis is desired17. Genetic counseling is appropriate for any patient who has or may have familial Alzheimer’s disease, but recent reviews do not recommend routine PET scanning because it is costly and the threshold for determination of test positivity has not yet been agreed on18

With respect to imaging, structural brain MRI is preferred over CT scan, because it will exclude other brain lesions and disorders even if it cannot conclusively identify Alzheimer’s disease. The presence of atrophy of the medial temporal lobe may predict progression from mild cognitive impairment to demential. Volumetric MRI measurements may be more sensitive in identifying atrophy, but this is not yet generally available or recommended in terms of cost effectiveness19. PET scanning accurately discriminates between Alzheimer’s disease patients and normal subjects, and a negative PET scan indicates a low probability of the disease while a positive scan with a positive cerebrospinal fluid biomarker make the diagnosis of Alzheimer’s disease very likely. A positive PET scan by itself is not specific for the disease, however, and the test is not yet clinically recommended20

DIFFERENTIAL DIAGNOSIS

The most common alternative diagnosis is cerebrovascular or muli-infarct dementia, which is the second most common dementing disorder. The presentation depends on the location of the strokes and can be gradual or rapid in onset or incremental in progression. There is a history of strokes or transient ischemic attacks, and the cognitive impairment usually involves complex attention or executive function. CT or MRI imaging will show white matter lesions, small lacunar strokes or large infarcts in the distributions of one or more cerebral arteries15.

The other major differential possibility is frontotemporal dementia or neurocognitive disorder, previously called frontotemporal lobar degeneration and before that Pick’s disease. The onset is between age 50 and 60 in 75 per cent of patients, and memory and other cognitive symptoms are often subordinate to disinhibited behavior and social withdrawal. Neuroimaging shows diferent degrees of atrophy of frontal or temporal lobe structures. A language variant of the disorder has been described with 3 subtypes: a fluent aphasia with blunting of emotions and perseverative behavior, a slowly progressive nonfluent aphasia with halting speech and word-finding difficulty and a progressive logopenic aphasia, with marked reduction of speech and difficulty comprehending language and naming objects15.

Dementia or neurocognitive disorder with Lewy bodies sometimes resembles Parkinson’s disease but begins around the age range for Alzheimer’s disease (70 to 85 years) and is often characterized by severe cognitive impairment and visual hallucinations. The protein-filled Lewy bodies are seen pathologically, but the disease can be recognized radiologically by MRI atrophy or deficient dopamine transporter uptake in  the basal ganglia on SPECT or PET scans; while the electroencephalogram (EEG) is sometimes normal and often nonspecifically abnormal in most dementing disorders, Lewy body disease is accompanied by temporal lobe sharp transients resembling those in epilepsy on the EEG15.

TREATMENT

Until the 1980s there were essentially no effective therapies for dementia in general and Alzheimer’s disease in particular. The demonstration of degeneration and loss of acetylcholine-containing neurons and cholinergic synapses in several brain regions has led to the development of  somewhat effective drugs that enhance the amount or prolong the effectiveness of the available acetylcholine at the surviving synapses/ The goals of treatment are to improve the memory and other cognitive symptoms of the disease , and to ameliorate behavioral symptoms such as anxiety, depression, apathy and aggression.

For mild-to-moderate dementia, acetylcholinesterase inhibitors produce moderate improvement in the primary symptom of memory loss and modest improvement in cognition and behavioral functioning. The first centrally-acting cholinesterase inhibitor and cholinergic agonist, tacrine, was approved in 1993 but had to be withdrawn due to a possible association with hepatotoxicity and bone marrow suppression, and its manufacture was discontinued in 2013. Subsequent drugs with better adverse event profiles were donepezil, rivgastigmine and galantamine; numerous studies have shown little difference in efficacy between them but there are fewer adverse effects with donepezil.

Donepezil is the only cholinesterase inhibitor presently approved for moderate-to-severe dementia, in  which language and executive function are affected as well as memory. Memantine, which affects several different receptor types, has been shown to have some cognitive benefit in more advanced Alzheimer’s disease. Memantine is primarily an antagonist of the excitatory neurotransmitter glutamate that blocks the N-methyl-D-aspartate (NMDA) receptor that is apparently involved in neuronal cell death; it also affects the nicotinic acetylcholinergic receptors and antagonizes one of the serotonin receptor types (5-HT3) and the D2 dopamine receptor, both of which may be involved in the behavioral manifestations of dementia. Its effects are more marked on the more severe and widespread symptoms of advanced Alzheimer’s disease than on mild-to-moderate memory symptoms.

An alternative to pharmacologic treatment is cognitive stimulation therapy, which involves activities which involve thinking and memory, such as discussion groups, puzzles, word games, listening to music and the pursuit, assisted if necessary, of hobbies such as cooking or gardening. This is usually done at centers or facilities for outpatient treatment of Alzheimer’s disease, but can be carried out at home. Several studies have shown beneficial effect on cognition in mild-to-moderate dementia.

PROGNOSIS AND OUTLOOK

More than 50 per cent of patients with mild cognitive impairment will progress to dementia within 5 years after diagnosis. The mean survival thereafter is around 10 years. There are no known protective factors, although eating a Mediterranean diet has been suggested to be beneficial. Higher levels of physical activity may be associated with a better prognosis, and people in highly cognitive occupations and professions may have a lower incidence of the disorder. Recent studies have suggested that the statins, which lower cholesterol levels by inhibiting the enzyme HMG-coA reductase which is crucial to cholesterol production in the liver, may have a protective effect against dementia in general. These and other observations suggest that Alzheimer’s disease is more manageable than it was a generation ago. The growing concensus about the cause of many neurodegenerative disorders, the improving understanding of the role of genetics in susceptibility to the disease and the significant increase in therapeutic options are grounds for cautious optimism about its future management.

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