|Year : 2020 | Volume
| Issue : 3 | Page : 95-100
Physiological and pathological functions of beta-amyloid in the brain and alzheimer's disease: A review
School of Aging Studies, University of South Florida, Tampa, FL, USA; 3rd Medical Faculty, Charles University, Prague, Czech Republic, Europe
|Date of Submission||23-Jan-2020|
|Date of Decision||18-Mar-2020|
|Date of Acceptance||30-Apr-2020|
|Date of Web Publication||23-Jun-2020|
Prof. Ladislav Volicer
2337 Dekan Lane, Land O Lakes, FL 34639
Source of Support: None, Conflict of Interest: None
Alzheimer's disease is a major health problem all over the world. The role of beta-amyloid (Aβ) is at the center of investigations trying to discover the disease pathogenesis and to develop drugs for treatment or prevention on Alzheimer's disease. This review summarizes both physiological and pathological functions of Aβ and factors that may participate in the disease development. Known genetic factors are trisomy of chromosome 21, mutations of presenilin 1 and 2, and apolipoprotein E4. Lifetime stresses that increase the risk of development of Alzheimer's disease are described. Another important factor is the level of education, especially of linguistic ability. Lifestyle factors include mental and physical exercise, head injury, social contacts, and diet. All these factors might potentiate the effect of aging on the brain to increase the risk of development of pathological changes. The review summarizes pathological features of Alzheimer brain, Aβ plaques, neurofibrillary tangles composed of hyperphosphorylated tau, and brain atrophy. Consequences of Alzheimer's disease that are reviewed include cognitive deficit, loss of function, and neuropsychiatric symptoms. Because there is no effective treatment, many persons with Alzheimer's disease survive to severe and terminal stages which they may fear. Alzheimer's disease at this stage should be considered a terminal disease for which palliative care is indicated. Importance of advance directives, promoting previous wishes of the person who was developing dementia and who subsequently lost decision-making capacity, and limitations of these directives are discussed. Information in this review is based on author's knowledge and clinical experience that were updated by searches of PubMed.
Keywords: Alzheimer's disease, amyloid, palliative care
|How to cite this article:|
Volicer L. Physiological and pathological functions of beta-amyloid in the brain and alzheimer's disease: A review. Chin J Physiol 2020;63:95-100
| Introduction|| |
In 1906, Alois Alzheimer found protein deposits, and clumps of fibrils in dead neurons, in brain of a woman who died in her fifties after suffering with memory deficit, dementia, and paranoid delusions. He decided that his finding represented a new disease and published the case report about it. The director of his department decided to name this disease after Dr. Alzheimer to increase the reputation of his department.
For a long time, Alzheimer's disease was considered only in somebody who developed dementia before the age of 65, and dementia in later life was called senile dementia or organic brain syndrome. However, further research showed that the pathological changes in brains of people who died with dementia are identical regardless of the age when dementia developed. Therefore, all cases of dementia with protein deposits and clump of fibrils in dead cells were called Alzheimer's disease. In 1984, it was found that the deposited protein is an amyloid, and it was proposed that the deposits may be causing dementia. This led to development of an amyloid hypothesis that was the dominant theory about Alzheimer's disease pathogenesis.
However, later clinical research did not support this hypothesis. It showed that the amyloid protein is not just toxic, but it also has some physiological functions, and that decreasing amyloid protein in the brain does not improve dementia in people. This review will summarize both physiological and pathological processes involving this brain amyloid, which is called beta-amyloid (Aβ) and features of Alzheimer's disease.
| Physiological Functions of Beta-Amyloid|| |
Aβ peptides have sequence length ranging from 36 to 43, but in normal brain, 80% is Aβ40. Aβ42 is produced mainly under disease conditions.
Aβ40 is present at nanomolar levels in most biological fluids, such as cerebrospinal fluid, plasma, and the medium of cultured cells. Aβ40 promotes proliferation of neuronal stem cells and neurogenesis, while Aβ42 favors gliogenesis. Aβ40 and Aβ42 also exert neuroprotective effects and enhance cell viability in the absence of growth factors. Aβ40 also promotes rat cerebellar granule neuron maturation by modulation of γ-aminobutyric acid type A (GABAA) receptor α6 subunit. Low levels of soluble Aβ increase autophagy of neuronal stem cells, which is important for neuronal stem cell differentiation.
Administration of low concentrations of Aβ into rat hippocampus improves memory formation while inhibition of endogenous Aβ formation reduces retention of memory. Aβ is released from synapses, and monomeric Aβ40 and Aβ42 are required for synaptic plasticity and neuronal survival. If Aβ is blocked by selective antibodies, mice show significant cognitive impairment, and abrogation of long-term potentiation can be reversed by addition of exogenous Aβ42.
Metal sequestration and antioxidant activity
Monomeric Aβ in low concentrations is scavenging reactive oxygen species that are produced by biochemical redox reactions in mitochondria. This scavenging effect of Aβ42 is present also in a cell-free system, and chelation of iron results in a reduced generation of reactive oxygen radicals. Another study also found that aggregated Aβ40, at either nanomolar or micromolar concentrations, is a highly potent antioxidant but only in cell-free oxidative systems, acting mainly as a radical scavenger.
| Pathological Functions of Beta-Amyloid|| |
The presence of Aβ deposits in brains of people suffering from dementia stimulated further investigation of neurotoxic effects of Aβ. In order to explain the neurotoxic effects of Aβ, several theories were proposed.
Aβ aggregates have the ability to reduce copper and iron, and reduced ions can react with oxygen to produce superoxide anions which can generate hydrogen peroxide. Hydrogen peroxide may react with other reduced metal ions to produce toxic hydroxyl radicals through Fenton reaction. Hydroxyl radicals could be involved in lipid and protein peroxidation eventually leading to neuronal death. The N-terminal region of Aβ has a metal-binding domain, and the binding affects the formation of Aβ fibrils. Copper forms with Aβ toxic oligomeric species, while zinc forms amorphous nonfibrillar aggregates with reduced neurotoxicity. Thus, monomeric Aβ40 has antioxidant properties, while aggregated amyloid produces oxidative stress.
Aβ oligomers bind to glutamate receptors and have high-affinity binding to α7-nicotinic receptors which had an important role in internalization and intracellular accumulation of Aβ in neuronal cells. Aβ also interferes with function of small ubiquitin-like modifier molecules that are required for long-term potentiation and hippocampal-dependent learning.
Aβ aggregated oligomers cause membrane invagination, which is a precursor to the formation of pore structures and ion channels. These channels facilitate entry of calcium into neurons, which leads to cellular damage and neuronal death.
Aggregated form Aβ (Aβ1–40 and Aβ1–42), not Aβ monomer, could inhibit telomerase activity bothin vitro and in living cells. Telomerase adds DNA sequence repeats to DNA strands of the telomere regions which are essential for cell survival. Telomere shortening is related to biological aging and is observed in many age-related diseases. This could be one mechanism that causes accelerated brain aging.
Aβ could be a pathophysiologic stimulus for the initiation of various cell signaling pathways including apoptosis, necrosis, necroptosis, and autophagy which lead to neuronal cell death.
| Precursors of Alzheimer's Disease|| |
Although the detailed pathogenesis of Alzheimer's disease is not known, there are several known factors that either cause the disease or increase the risk of developing it [Figure 1].
Age is the most important risk factor for development of Alzheimer's disease. The prevalence of dementia is increasing from 5% in 65 years old to almost 50% in 85 years old and older, and at least 60% of these dementias are caused by Alzheimer's disease. Deposits of Aβ increase with age but not everybody who has high levels of Aβ in the brain develops dementia. A third of community-dwelling elderly people with Alzheimer's neuropathological changes are not demented. The Nun Study found that the difference between those who were demented and those who were not was the presence or absence of brain vascular changes. This indicates that development of clinical dementia could be prevented by controlling factors involved in vascular changes (high blood pressure and cholesterol levels) even when Aβ deposits are unaffected.
In addition to Aβ deposits, aging affects also neuronal characteristics. Both aging and Aβ independently decrease neuronal plasticity, and Aβ, glutamate, and lactic acid are increasingly toxic as the neuron age. This age-related toxicity is mediated by mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. These age-related changes may also participate in Alzheimer's disease pathogenesis.
There are four well-defined genes that participate in development of Alzheimer's disease. Three of them increase Aβ production and one decreases Aβ removal. Trisomy of chromosome 21, which causes Down's syndrome, increases the production of amyloid precursor protein (APP) and, therefore, also the production of Aβ. Missense mutations of presenilin genes alter proteolytic processing of APP resulting in increased relative production of Aβ42 throughout the life. Accumulation of Aβ42 leads to its oligomerization with deposits in diffuse plaques. Stem cell-derived human neurons from persons with presenilin mutations show first Aβ accumulation and then tau alteration, supporting the amyloid hypothesis of Alzheimer's disease pathogenesis.
Apolipoprotein E4 predisposes carriers to develop Alzheimer's disease earlier than carriers of apolipoprotein 2 or 3. Apolipoprotein E4 decreases the clearance of Aβ from the brain and may be responsible for 40% of Alzheimer's disease cases. There are also some other genes involved in Alzheimer's disease pathogenesis, but their influence is weaker. They include genes involved in cholesterol/sterol metabolism, inflammation and the brain's innate immune system, and endosomal recycling.
Lifetime stress increases the risk of development of Alzheimer's disease. The stresses which were related to this risk included early parental death, posttraumatic syndrome disorder, midlife stressors, and manual work involving good production. The risk of developing Alzheimer's disease is increasing with number of stressors of a person's exposure. Stress was an especially strong influence in increasing the risk in persons with resource problems and less than high school education. The stress involved in parental death during childhood is attenuated by remarriage of the widowed parent.
It is well documented that higher education decreases and low education increases the risk of development of dementia. A recent meta-analysis of prospective cohort studies found that dementia risk is reduced by 7% per year of increase in education. Cognitive ability decreases with age, and this decrease was smaller in more educated persons. There is probably a special aspect of education which is important for Alzheimer risk and that is linguistic ability. Participants of the Nun Study were required to write an autobiography at the age of 22, and these autobiographies were analyzed for idea density. Early-life low idea density was significantly related to late-life cognitive dysfunction, lower brain weight, higher degree of cerebral atrophy, and the likelihood of meeting neuropathologic criteria for Alzheimer's disease. Cognitive impairment in later life was also related to high school English school grades but not to grades from other subjects.
Several lifestyle factors influence the risk of development of Alzheimer's disease. The most important is probably head injury. It has long been recognized that severe traumatic brain injury in early and mid-life occurring during the Second World War is associated with an increased risk of late-life dementia (relative risk: 1.5–5.0). However, even less severe brain trauma, especially if it is repetitive, may result in Alzheimer's disease or other types of dementia. Data on athletic exposure from 34 American football players showed that the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football, and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), 7 with Alzheimer's disease (11%), 11 with Lewy body disease (16%), and 4 with frontotemporal lobar degeneration (6%).
Other lifestyle factors include participation in leisure activities and mental and physical exercise. A prospective study of Swedish twins showed that a greater number of leisure activities were associated with a lower risk of Alzheimer's disease and dementia in general. Physical inactivity is one of the most common preventable risk factors for developing Alzheimer's disease, and higher physical activity levels are associated with a reduced risk of development of Alzheimer's disease. Exercise as a treatment for Alzheimer's disease shows improvement in cognitive function, decreased neuropsychiatric symptoms, and a slower decline in activities of daily living. Physical activity is also beneficial for people with dementia living at home. It seems effective in delaying cognitive function decline and improving changes in behavioral and psychological symptoms of dementia, activities of daily living, health-related physical fitness, and carers' burden. Involvement in cognitive activities and changes in dietary pattern may also increase the synaptic plasticity of older brains.
| Neuropathological Manifestations of Alzheimer's Disease|| |
A combination of precursors and aging may lead to development of the three typical characteristics of the brain that define Alzheimer's disease: amyloid plaques, neurofibrillary tangles formed by hyperphosphorylated tau, and brain atrophy. Alzheimer's disease has a very gradual onset. A cognitive deficit that does not affect daily function is called mild cognitive impairment (MCI) because impairment of functions is a requirement for the diagnosis of dementia. It is possible to distinguish two types of MCIs: amnestic, involving memory problems, and nonamnestic, involving other cognitive functions. Amnestic MCI is an early stage of Alzheimer's disease, and 15% of individuals with MCI are 65 years old and older progress to Alzheimer's disease dementia during 2 years after diagnosis. MCI without memory problems may be a precursor of other dementia types (dementia with Lewy bodies, vascular dementia, and frontotemporal dementia).
The usual early symptoms of Alzheimer's disease are memory problems. Short-term memory is affected first, and long-term memories are maintained even in persons with moderate dementia. Other early signs are challenges in planning or solving problems, difficulty completing familiar tasks, confusion with time or place, trouble understanding visual images and spatial relationships, problems with words in speaking or writing, misplacing things and losing the ability to retrace steps, decreased or poor judgment, withdrawal from work or social activities, and changes in mood and personality.
Loss of functions needed for activities of daily living
The course of Alzheimer's disease can be seen as gradual loss of independence. It is possible to recognize four stages of the disease. In the mild stage, people are still independent in all activities of daily living, although they may have to retire because of cognitive problems. Once they require help or reminders to do necessary activities of daily living, they progress to the moderate stage. When they lose the ability to walk, eat, and drink independently, they are in a severe stage. Moreover, if they are unable to walk even with assistance and develop difficulty swallowing, they could be considered to be in the terminal stage.
Psychiatric conditions that occur during the course of Alzheimer's disease include psychotic symptoms (delusions and hallucinations), depression, and anxiety. Hallucinations are more common in dementia with Lewy bodies where they can occur early in the development of the disease. Delusions are often paranoid; for instance a delusion that something was stolen when the person with dementia just does not remember where she/he placed the item. Depression is very common in persons with Alzheimer's disease because the disease causes serotoninergic dysfunction.
There are several behavioral symptoms during the course of Alzheimer's disease, but the three most common are apathy, agitation, and aggression. Apathy may be an early sign and may develop several months before the diagnosis of dementia. Agitation is a term that is sometimes used for all behavioral symptoms of dementia, but which should be reserved for restless behavior, indicating that the person is distressed. It is very important to distinguish it from aggression. The type of aggression in most cases is a reactive aggression, which the person with dementia use to reject activities of care providers that he/she does not understand or thinks that they are not needed. Distinguishing agitation and aggression is important because their optimal managements are different: provision of meaningful activities for agitation and improving communication or changing care strategy for reactive aggression.
Terminal nature of Alzheimer's disease
During the last 20 years, more than 200 medications were investigated for the treatment of Alzheimer's disease. Some of them were designed to decrease Aβ formation or accumulation and were clinically tested based on results from transgenic mice, which carried Aβ producing genes. So far, all of these medications were ineffective in decreasing Alzheimer's disease symptoms or in stopping progression of the disease, even though some of them decreased the amount of Aβ in the brain. This questions the central role of Aβ in pathogenesis of Alzheimer's disease, postulated by the amyloid hypothesis. Supporters of this hypothesis are trying to explain negative results of drug trials by possible problems with drug penetration into the brain, by having only persons with late-mild and moderate stages of Alzheimer's disease involved in the trials, and by trials including some individuals who did not have amyloid deposits. They postulate that some of these drugs may be effective if used for prevention of amyloid deposits in people who may not have any evidence of cognitive impairment. Several trials, using this population, are ongoing, and the results will show if the amyloid hypothesis could be supported.
At this time, the only medications that are used for the treatment of Alzheimer's disease are three cholinesterase inhibitors and memantine, and they cause only a small delay in the disease progression. Therefore, most people with Alzheimer's disease survive to the terminal stage of the disease, if they do not die from an intercurrent disease before that. Some people are afraid of living with advanced dementia when they would be dependent in all activities of daily living and could not communicate verbally and the care would require significant financial resources. They need to realize that there are some programs that can maintain quality of life despite this disease condition.
If despite that, they would rather die than live in this condition, they could switch their type of care from one that tries to maintain life at all cost to palliative care, where the goal of care is comfort of the person with dementia and his/her family, without trying to prolong survival. Palliative care can be requested by making an advance directive refusing aggressive medical interventions (cardiopulmonary resuscitation, transfer to an acute care setting, use of antibiotics for treatment of generalized infections, and tube feeding) and by designating a proxy who knows about goals of care the person had and would ask the treatment team to honor them.
However, it is possible that people with advanced dementia may not require any of these life-sustaining interventions. If they realize that they may survive to advanced dementia despite these advance directives, they may commit a suicide in a mild stage of dementia when they still are able to do it. To be sure that a person will not live with terminal dementia, the person can request that at certain stage of the disease, when he/she cannot eat and drink independently, the assistance with eating drinking should stop. This would result in death from dehydration, which is not causing any distress apart of dryness of the mouth that can be easily treated. This way of dying was acceptable to relatives of people who died with advanced dementia and to physicians and nurses working in long-term care facilities.
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Conflicts of interest
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| References|| |
Glenner GG, Wong CW. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885-90.
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016;8:595-608.
Ricciarelli R, Fedele E. The amyloid cascade hypothesis in Alzheimer's disease: It's time to change our mind. Curr Neuropharmacol 2017;15:926-35.
Luo Y, Hawver DB, Iwasaki K, Sunderland T, Roth GS, Wolozin D. Physiological levels of β-amyloid peptide stimulate protein kinase C in PC12 cells. Brain Res 1997;769:287-95.
Fonseca M, Sola S, Xavier J, Dionisio P, Rodrigues CP. Amyloid ß peptides promote autophagy-dependent differentiation of mouse neural stem cells: Aß-mediated neural differentiation. Mol Neurobiol 2013;48:829-40.
Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, et al
. Beta-amyloid monomers are neuroprotective. J Neurosci 2009;29:10582-7.
Zhan XQ, Yao JJ, Liu DD, Ma Q, Mei YA. Aß40 modulates GABAA
receptor α6 subunit expression and rat cerebellar granule neuron maturation through the ERK/mTOR pathway. J Neurochem 2013;128:350-62.
Garcia-Osta A, Alberini CM. Amyloid beta mediates memory formation. Learn Mem 2009;16:267-72.
Parihar MS, Brewer GJ. Amyloid-ß as a modulator of synaptic plasticity. J Alzheimers Dis 2010;22:741-63.
Zou K, Gong JS, Yanagisawa K, Michikawa M. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 2002;22:4833-41.
Sinha M, Bhowmick P, Banerjee A, Chakrabarti S. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. Free Radic Biol Med 2013;56:184-92.
Baruch-Suchodolsky R, Fischer B. Aβ40
, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. Biochemistry 2009;48:4354-70.
Butterfield DA, Swomley AM, Sultana R. Amyloid ß-peptide (1-42)-induced oxidative stress in Alzheimer disease: Importance in disease pathogenesis and progression. Antioxid Redox Signal 2013;19:823-35.
Sharma AK, Pavlova ST, Kim J, Kim J, Mirica LM. The effect of Cu2+
on the Aß42 peptide aggregation and cellular toxicity. Metallomics 2013;5:1529-36.
Ni R, Marutle A, Nordberg A. Modulation of α7 nicotinic acetylcholine receptor and fibrillar amyloid-ß interactions in Alzheimer's disease brain. J Alzheimers Dis 2013;33:841-851.
Lee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, et al
. Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease. Sci Rep 2014;4:7190.
Zhao LN, Long G, Mu Y, Chew LY. The toxicity of amyloid ß oligomers. Int J Mol Sci 2012;13:7303-7327.
Wang J, Zhao C, Zhao A, Li M, Ren J, Qu X. New insights in amyloid beta interactions with human telomerase. J Am Chem Soc 2015;137:1213-9.
Leong YQ, Ng KY, Chye SM, Ling APK, Koh RY. Mechanisms of action of amyloid-beta and its precursor protein in neuronal cell death. Metab Brain Dis 2020;35:11-30.
Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 2016;8:23.
Azarpazhooh MR, Avan A, Cipriani LE, Munoz DG, Erfanian M, Amiri A, et al
. A third of community-dwelling elderly with intermediate and high level of Alzheimer's neuropathologic changes are not demented: A meta-analysis. Ageing Res Rev 2019;58:101002.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997;277:813-7.
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al
. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increasedin vivo
by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med 1996;2:864-870.
Moore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, et al
. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep 2015;11:689-96.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al
. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261:921-3.
Castellano JM, Km J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al
. Human apoE isoforms differentially regulate brain amyloid-ß peptide clearance. Sci Transl Med 2011;3:89ra57.
Norton MC, Smith KR, Østbye T, Tschanz JT, Schwartz S, Corcoran C, et al
. Early parental death and remarriage of widowed parents as risk factors for Alzheimer disease: The Cache County study. Am J Geriatr Psychiatry 2011;19:814-24.
Gilsanz P, Quesenberry CP Jr., Mayeda ER, Glymour MM, Farias ST, Whitmer RA. Stressors in midlife and risk of dementia: The role of race and education. Alzheimer Dis Assoc Disord 2019;33:200-5.
Qiu C, Karp A, von Strauss E, Winblad B, Fratiglioni L, Bellander T. Lifetime principal occupation and risk of Alzheimer's disease in the Kungsholmen project. Am J Ind Med 2003;43:204-11.
Xu W, Tan L, Wang HF, Tan MS, Tan L, Li JQ, et al
. Education and risk of dementia: Dose-response meta-analysis of prospective cohort studies. Mol Neurobiol 2016;53:3113-23.
Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA 1996;275:528-32.
Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, et al
. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 2000;55:1158-66.
McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al
. The spectrum of disease in chronic traumatic encephalopathy. Brain 2013;136:43-64.
Crowe M, Andel R, Pedersen NL, Johansson B, Gatz M. Does participation in leisure activities lead to reduced risk of Alzheimer's disease? A prospective study of Swedish twins. J Gerontol B Psychol Sci Soc Sci 2003;58:249-55.
Cass SP. Alzheimer's disease and exercise: A literature review. Curr Sports Med Rep 2017;16:19-22.
Almeida SI, da Silva G, Marques AS. Home-based physical activity programs for people with dementia: Systematic review and meta-analysis. Gerontologist 2019. pii: gnz176.
Phillips C. Lifestyle modulators of neuroplasticity: How physical activity, mental engagement, and diet promote cognitive health during aging. Neural Plast 2017;2017:3589271.
Petersen RC, Lopez O, Armstrong MJ, Getchius TS, Ganguli M, Gloss D, et al
. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018;90:126-35.
Volicer L. Alzheimer's disease: Course, management, and the hospice approach. Nurs Home Med 1993;1:31-7.
Volicer L, Frijters DH, Van der Steen JT. Underdiagnosis and undertreatment of depression in nursing home residents. Eur Geriat Med 2011;2:332-7.
Cohen-Mansfield J, Jensen B. Assessment and treatment approaches for behavioral disturbances associated with dementia in the nursing home: Self-reports of physicians' practices. J Am Med Dir Assoc 2008;9:406-13.
Volicer L, Galik E. Agitation and aggression are 2 different syndromes in persons with dementia. J Am Med Dir Assoc 2018;19:1035-8.
Volicer L, Citrome L, Volavka J. Measurement of agitation and aggression in adult and aged neuropsychiatric patients: Review of definitions and frequently used measurement scales. CNS Spectr 2017;22:407-14.
Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol Med Rep 2019;20:1479-87.
Volicer L. Fear of dementia. J Am Med Dir Assoc 2016;17:875-8.
Volicer L. Review of programs for persons facing death with dementia. Healthcare (Basel) 2019;7:62.
Volicer L. Goals of care in advanced dementia: Quality of life, dignity and comfort. J Nutr Health Aging 2007;11:481.
Volicer L, Pope TM, Steinberg KE. Assistance with eating and drinking only when requested can prevent living with advanced dementia. J Am Med Dir Assoc 2019;20:1353-5.
Volicer L, Stets K. Acceptability of an advance directive that limits food and liquids in advanced dementia. Am J Hosp Palliat Care 2016;33:55-63.
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