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geri:dementia:alzheimers [on April 30, 2020]
geri:dementia:alzheimers [on February 9, 2024] (current)
psychdb [Depression]
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 {{INLINETOC}} {{INLINETOC}}
 ===== Primer ===== ===== Primer =====
-**Alzheimer'​s Disease** is the most common type of dementia in the world, characterized by progressive memory loss and [[geri:​dementia:​1-bpsd|behavioural changes]].+**Alzheimer'​s Disease ​(AD)** is the most common type of [[geri:dementia:​home|dementia]] ​in the world, characterized by gradual ​progressive memory loss and [[geri:​dementia:​1-bpsd|behavioural changes]]. Different subtypes of Alzheimer'​s can have memory, visual, language, or frontal lobe deficit involvement. AD is associated with accumulation of amyloid and tau depositions in the brain.
  
-==== Prevalence ==== +== History ​== 
-In developed countriesdementia rates begin at 5-10% for individuals in the seventh decade of lifeincreasing to 25% thereafter. The percentage ​of dementias due to Alzheimer'​s disease ​is at least 50% (with some estimates suggesting 60-90%).+<alert type="​info"​ icon="fa fa-book fa-lg fa-fw">​ 
 +See also: **[[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3181715/​|HippiusH.& Neundörfer,​ G. (2003). The discovery ​of Alzheimer'​s disease. Dialogues in clinical neuroscience,​ 5(1), 101.]]** 
 +</​alert>​
  
-==== Course ​==== +== Epidemiology ​== 
-The onset of symptoms is usually in the eighth and ninth decades of life. Patients with early onset symptoms in their 50s/60s usually have a genetic cause. The mean survival time is 10 years. During the later stages of illness, patients can become mute or bedbound. Death most commonly results from aspiration in those who survive through throughout the course of illness. +  * AD is the most common cause of dementia worldwide, and dementia rates start at 5-10% at age 70. By age 85, between 25% and 50% of people will exhibit signs of Alzheimer'​s disease. The percentage of all dementias due to Alzheimer'​s disease is at least 50% (with some estimates suggesting 60-90%).  
-===== Diagnostic Criteria ===== + 
-<​callout>​The head-turning sign can be a useful sign in the interview of patients suspected ​of having ​AD.[([[https://​www.alzheimersanddementia.com/article/S1552-5260(11)00832-6/abstract|Fukui, T. (2011). The “Head turning sign” can be a clinical marker of Alzheimer'​s disease?. Alzheimer'​s & DementiaThe Journal ​of the Alzheimer'​s ​Association7(4), S244-S245.]])][([[https://​jnnp.bmj.com/​content/​83/8/852|Larner, A. J. (2012). Head turning sign: pragmatic utility in clinical diagnosis of cognitive impairmentJ Neurol Neurosurg Psychiatryjnnp-2011.]])]</​callout>​ +== Prognosis ​== 
-<WRAP group> +  ​* ​The onset of symptoms is usually in the eighth and ninth decades of life. Patients with early onset symptoms in their 50s/60s usually have a genetic cause. The mean survival time is 10 years. During the later stages of illness, patients can become mute or bed bound. Death most commonly results from aspiration in those who survive through throughout the course of illness. 
-<WRAP half column>+ 
 +== Comorbidity ​== 
 +  ​* ​The most common comorbidities in AD include hypertension,​ osteoarthritis,​ [[mood:1-depression:​geriatric|depression]],​ diabetes, and cerebrovascular disease.[([[https://​pubmed.ncbi.nlm.nih.gov/​29660933/​|Wang,​ J. H., Wu, Y. J., Tee, B. L., & Lo, R. Y. (2018). Medical comorbidity in Alzheimer’s disease: a nested case-control study. Journal of Alzheimer'​s Disease, 63(2), 773-781.]])] 
 +  * There can often be a mixed dementia ​in Alzheimer'​s,​ in particular with [[geri:​dementia:​lewy-body|Lewy body]] pathology.[([[https://​pubmed.ncbi.nlm.nih.gov/​25758940/​|Walker,​ L., McAleese, K. E., Thomas, A. J., Johnson, M., Martin-Ruiz,​ C., Parker, C., ... & Attems, J. (2015). Neuropathologically mixed Alzheimer’s and Lewy body disease: burden ​of pathological protein aggregates differs between clinical phenotypes. Acta neuropathologica,​ 129(5), 729-748.]])] 
 + 
 +== Risk Factors == 
 +  * Risk factors for AD include increasing age, sex (female), genetics (APOE4), and a history of [[cl:​tbi|head injury]]. 
 +    * Other less established,​ but possible risk factors include low educational status or cognitive reserve, sedentary lifestyle, diet, vascular risk factors, sleep deprivation,​[([[https://​pubmed.ncbi.nlm.nih.gov/29632177/|Shokri-Kojori, E., Wang, G. J., Wiers, C. E., Demiral, S. B., Guo, M., Kim, S. W., ... & Volkow, N. D. (2018). β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proceedings of the National Academy of Sciences, 115(17), 4483-4488.]])] and hormone replacement therapy.  
 +  * Individuals with APP, PSEN1, PSEN2 have an increased risk of early onset (ages 30 to 60) AD. 
 +    * [[child:​genetic-disorders:​down-syndrome-trisomy-21|Down syndrome]] is also a risk factor for early onset Alzheimer'​s 
 +      * About 30% will have AD by their 50s, and this reaches 50% by their 60s.[([[https://​pubmed.ncbi.nlm.nih.gov/​25510383/|Hartley, D., Blumenthal, T., Carrillo, M., DiPaolo, G., Esralew, L., Gardiner, K., ... & Wisniewski, T. (2015). Down syndrome and Alzheimer'​s disease: Common pathways, common goals. Alzheimer'​s & Dementia, 11(6), 700-709.]])] 
 +  * Individuals with APOE4 (on chromosome 19) are at increased risk for late onset AD. 
 +    * The ε4 allele is present in about 20 to 25% of the population, if an individual is a: 
 +      * ε4,ε4 homozygote, there is a 50% chance of AD during their 60s 
 +      * ε4 heterozygote,​ there is a 50% chance of AD during their 70s 
 +      * However, due to low sensitivity and specificity,​ screening for APOE4 is not recommended! 
 +  * Increasing links are being found between the pathophysiology of Alzheimer'​s ​and hyperglycemia.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​29368156|ZhengF., Yan, L., Yang, Z., Zhong, B., & Xie, W. (2018). HbA 1cdiabetes and cognitive decline: the English Longitudinal Study of Ageing. Diabetologia,​ 1-10.]])] Hypertension in lafe-life is also a risk factor for development of Alzhemier'​s pathology.[([[https://​www.ncbi.nlm.nih.gov/pubmed/29997190|Arvanitakis,​ Z., Capuano, A. W., Lamar, M., Shah, R. C., Barnes, L. L., Bennett, D. A., & Schneider, ​J. A. (2018). Late-life blood pressure association with cerebrovascular and Alzheimer disease pathologyNeurology91(6), e517-e525.]])] 
 + 
 +===== DSM-5 Diagnostic Criteria =====
 == Criterion A == == Criterion A ==
 The criteria are met for [[cl:​2-major-neurocog-disorder|major]] or [[cl:​3-mild-neurocog-disorder|mild neurocognitive disorder]]. The criteria are met for [[cl:​2-major-neurocog-disorder|major]] or [[cl:​3-mild-neurocog-disorder|mild neurocognitive disorder]].
  
-</​WRAP>​ 
-<WRAP half column> 
 == Criterion B == == Criterion B ==
 There is insidious onset and gradual progression of impairment in ''​1''​ or more cognitive domains (for [[cl:​2-major-neurocog-disorder|major neurocognitive disorder]], at least ''​2''​ domains must be impaired). There is insidious onset and gradual progression of impairment in ''​1''​ or more cognitive domains (for [[cl:​2-major-neurocog-disorder|major neurocognitive disorder]], at least ''​2''​ domains must be impaired).
  
-</​WRAP>​ 
-</​WRAP>​ 
 == Criterion C == == Criterion C ==
 Criteria are met for either probable or possible Alzheimer’s disease as follows: Criteria are met for either probable or possible Alzheimer’s disease as follows:
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 </​WRAP>​ </​WRAP>​
 </​WRAP>​ </​WRAP>​
 +
 +<callout icon="​fa fa-lightbulb-o"​ type="​success"​ title="​Mnemonic">​
 +The mnemonic ''​**SAMPLE**''​ can be used to remember the [[cognitive-testing:​memory|6 key domains of cognitive function]]:
 +  * ''​**S**''​ - Social cognition
 +  * ''​**A**''​ - Attention (Complex Attention)
 +  * ''​**M**''​ - Memory and Learning
 +  * ''​**P**''​ - Perceptual-Motor
 +  * ''​**L**''​ - Language ​
 +  * ''​**E**''​ - Executive function
 +</​callout>​
  
 == Criterion D == == Criterion 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. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological,​ or systemic disorder.
 +
 +==== Signs and Symptoms ====
 +  * The "​head-turning sign" can be a useful sign in the interview of patients suspected of having AD.[([[https://​www.alzheimersanddementia.com/​article/​S1552-5260(11)00832-6/​abstract|Fukui,​ T. (2011). The “Head turning sign” can be a clinical marker of Alzheimer'​s disease?. Alzheimer'​s & Dementia: The Journal of the Alzheimer'​s Association,​ 7(4), S244-S245.]])][([[https://​jnnp.bmj.com/​content/​83/​8/​852|Larner,​ A. J. (2012). Head turning sign: pragmatic utility in clinical diagnosis of cognitive impairment. J Neurol Neurosurg Psychiatry, jnnp-2011.]])]
  
 ===== NIA-AA Criteria ===== ===== NIA-AA Criteria =====
-In 2011, the National Institute on Aging (NIA) at National Institutes of Health (NIH) and the Alzheimer'​s Association (AA) published the latest guidelines (NIA-AA) for the diagnosis of Alzheimer'​s disease.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​21514250|McKhann,​ G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack Jr, C. R., Kawas, C. H., ... & Mohs, R. C. (2011). The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer'​s disease. Alzheimer'​s & dementia, 7(3), 263-269.]])] ​This diagnostic framework continues to be revised as of 2018.[([[https://​www.alzheimersanddementia.com/​article/​S1552-5260(18)30072-4/​fulltext?​code=jalz-site|Jack,​ C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., ... & Liu, E. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer'​s disease. Alzheimer'​s & Dementia, 14(4), 535-562.]])]+In 2011, the National Institute on Aging (NIA) at National Institutes of Health (NIH) and the Alzheimer'​s Association (AA) published the latest guidelines (NIA-AA) for the diagnosis of Alzheimer'​s disease.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​21514250|McKhann,​ G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack Jr, C. R., Kawas, C. H., ... & Mohs, R. C. (2011). The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer'​s disease. Alzheimer'​s & dementia, 7(3), 263-269.]])] ​These criteria are much more comprehensive than DSM-5 criteria, and the diagnostic framework continues to be revised as of 2018.[([[https://​www.alzheimersanddementia.com/​article/​S1552-5260(18)30072-4/​fulltext?​code=jalz-site|Jack,​ C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., ... & Liu, E. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer'​s disease. Alzheimer'​s & Dementia, 14(4), 535-562.]])]
 ==== Probable ==== ==== Probable ====
 <WRAP group> <WRAP group>
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 <panel type="​info"​ title="​Diagnostic Criteria"​ subtitle="​McKhann,​ Guy M., et al. Recommendations from the NIA-AA workgroup. Alzheimer'​s and dementia 7.3 (2011)263-269."​ no-body="​true">​ <panel type="​info"​ title="​Diagnostic Criteria"​ subtitle="​McKhann,​ Guy M., et al. Recommendations from the NIA-AA workgroup. Alzheimer'​s and dementia 7.3 (2011)263-269."​ no-body="​true">​
-^ Criteria for all-cause dementia ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           +^ Criteria for all-cause dementia ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
-| **1.** Interfere with the ability to function at work or at usual activities; and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          +| **1.** Interfere with the ability to function at work or at usual activities; and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
-| **2.** Represent a decline from previous levels of functioning and performing; and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         ​+| **2.** Represent a decline from previous levels of functioning and performing; and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             ​
-| **3.** Are not explained by delirium or major psychiatric disorder; ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       +| **3.** Are not explained by delirium or major psychiatric disorder; ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
-| **4.** Cognitive impairment is detected and diagnosed through a combination of (1) history-taking from the patient and a knowledgeable informant and (2) an objective cognitive assessment, either a “bedside” mental status examination or neuropsychological testing. Neuropsychological testing should be performed when the routine history and bedside mental status examination cannot provide a confident diagnosis. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               +| **4.** Cognitive impairment is detected and diagnosed through a combination of (1) history-taking from the patient and a knowledgeable informant and (2) an objective cognitive assessment, either a “bedside” mental status examination or neuropsychological testing. Neuropsychological testing should be performed when the routine history and bedside mental status examination cannot provide a confident diagnosis. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
-| **5.** The cognitive or behavioural impairment involves a minimum of two of the following domains: \\ \\ • Impaired ability to acquire and remember new information (repetitive questions or conversations,​ misplacing personal belongings, forgetting events or appointments,​ getting lost on a familiar route). \\ \\ • Impaired reasoning and handling of complex tasks, poor judgment (poor understanding of safety risks, inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities). \\ \\ • Impaired visuospatial abilities (inability to recognize faces or common objects or to find objects in direct view despite good acuity, inability to operate simple implements, or orient clothing to the body). \\ \\ • Impaired language functions (speaking, reading, writing problems - difficulty thinking of common words while speaking, hesitations;​ speech, spelling, and writing errors). \\ \\ • Changes in personality,​ behaviour, or comportment (uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviours, socially unacceptable behaviours). ​ |+| **5.** The cognitive or behavioural impairment involves a minimum of two of the following domains: \\ \\ • Impaired ability to acquire and remember new information (repetitive questions or conversations,​ misplacing personal belongings, forgetting events or appointments,​ getting lost on a familiar route). \\ \\ • Impaired reasoning and handling of complex tasks, poor judgment (poor understanding of safety risks, inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities). \\ \\ • Impaired visuospatial abilities (inability to recognize faces or common objects or to find objects in direct view despite good acuity, inability to operate simple implements, or orient clothing to the body). \\ \\ • Impaired language functions (speaking, reading, writing problems - difficulty thinking of common words while speaking, hesitations;​ speech, spelling, and writing errors). \\ \\ • Changes in personality,​ behaviour, or comportment (uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, ​[[teaching:​apathy|apathy]], loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviours, socially unacceptable behaviours). ​ |
  
 </​panel>​ </​panel>​
Line 78: Line 107:
 | **B.** Clear-cut history of worsening of cognition by report or observation;​ and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | | **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 ''​1''​ of the following categories. \\ \\ a. __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 ''​1''​ other cognitive domain, as defined earlier in the text. \\ \\ b. __Nonamnestic presentations__:​\\ ​ • Language presentation:​ word-finding deficits, but deficits in other cognitive domains should be present.\\ ​ • Visuospatial presentation:​ spatial cognition deficits, including object agnosia, impaired face recognition,​ simultanagnosia,​ and alexia. Deficits in other cognitive domains should be present.\\ • Executive dysfunction:​ deficits of impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present. ​ | | **C.** The initial and most prominent cognitive deficits are evident on history and examination in ''​1''​ of the following categories. \\ \\ a. __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 ''​1''​ other cognitive domain, as defined earlier in the text. \\ \\ b. __Nonamnestic presentations__:​\\ ​ • Language presentation:​ word-finding deficits, but deficits in other cognitive domains should be present.\\ ​ • Visuospatial presentation:​ spatial cognition deficits, including object agnosia, impaired face recognition,​ simultanagnosia,​ and alexia. Deficits in other cognitive domains should be present.\\ • Executive dysfunction:​ deficits of impaired reasoning, judgment, and problem solving. Deficits in other cognitive domains should be present. ​ |
-| **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 [[geri:​stroke|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 [[geri:​dementia:​lewy-body|Dementia ​with Lewy bodies]] other than dementia itself; or \\ c. Prominent features of behavioural variant [[geri:​dementia:​frontotemporal|frontotemporal dementia]]; or \\ d. Prominent features of semantic variant [[geri:​dementia:​primary-progressive-aphasia-ppa|primary progressive aphasia]] or nonfluent/​agrammatic variant [[geri:​dementia:​primary-progressive-aphasia-ppa|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. ​                                                                                                                 |+| **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 [[geri:​stroke|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 [[geri:​dementia:​lewy-body|dementia ​with Lewy bodies]] other than dementia itself; or \\ c. Prominent features of behavioural variant [[geri:​dementia:​frontotemporal|frontotemporal dementia]]; or \\ d. Prominent features of semantic variant [[geri:​dementia:​primary-progressive-aphasia-ppa|primary progressive aphasia]] or nonfluent/​agrammatic variant [[geri:​dementia:​primary-progressive-aphasia-ppa|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. ​                                                                                                                 |
 </​panel>​ </​panel>​
 </​WRAP>​ </​WRAP>​
Line 96: Line 125:
 </​panel>​ </​panel>​
  
-===== Frontal ​variant ===== +===== Subtypes ===== 
-Individuals with Alzheimer'​s disease (AD) may have executive dysfunction,​ language impairment, and/or behavioural changes early in the disease, this can make it challenging to differentiate from [[geri:​dementia:​frontotemporal|frontotemporal dementia]].[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​19823987|Woodward,​ M., Jacova, C., Black, S. E., Kertesz, A., Mackenzie, I. R., Feldman, H., & ACCORD investigator group. (2010). Differentiating the frontal variant of Alzheimer'​s disease. International journal of geriatric psychiatry, 25(7), 732-738.]])]+AD can present under different subtypes, primarily:​ 
 +  * **Amnestic** 
 +    * This is the most common and "​typical"​ presentation 
 +  * **Non-amnestic** 
 +    * Visual impairment: [[geri:​dementia:​posterior-cortical-atrophy-pca|posterior cortical atrophy (PCA)]] 
 +    * Language impairment: logopenic [[geri:​dementia:​primary-progressive-aphasia-ppa|primary progressive aphasia]] 
 +    * Behavioural impairment: frontal-variant ​Alzheimer'​s 
 +==== Frontal Variant (fvAD) ​==== 
 +<alert type="​info"​ icon="​fa fa-book fa-lg fa-fw">​ 
 +See also: **[[https://​clinicalmovementdisorders.biomedcentral.com/​articles/​10.1186/​s40734-017-0052-4|Sawyer,​ R. P. et al. (2017). Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road. Journal of clinical movement disorders, 4(1), 1-9.]]** 
 +</​alert>​ 
 + 
 +  * Individuals with frontal variant ​Alzheimer'​s disease (fvAD) may have executive dysfunction,​ language impairment, and/or behavioural changes early in the disease, this can make it challenging to differentiate from the behavioural variant of [[geri:​dementia:​frontotemporal|frontotemporal dementia]] ​(bvFTD).[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​19823987|Woodward,​ M., Jacova, C., Black, S. E., Kertesz, A., Mackenzie, I. R., Feldman, H., & ACCORD investigator group. (2010). Differentiating the frontal variant of Alzheimer'​s disease. International journal of geriatric psychiatry, 25(7), 732-738.]])] 
 +  * Symptomatically,​ the presentation of fvAD can be very similar to bvFTD. 
 +    * In general, fvAD patients present with greater executive impairment and milder behavioral symptoms compared to bvFTD. 
 +    * Greater accuracy in diagnosis and patient management may be achieved with neuropsychological tests, biomarkers, and neuroimaging. 
 +  * Some studies have suggested that fvAD accounts for approximately 2–3% of AD cases, but is likely to be an underestimate.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC5333400/​|Sawyer,​ R. P., Rodriguez-Porcel,​ F., Hagen, M., Shatz, R., & Espay, A. J. (2017). Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road. Journal of clinical movement disorders, 4(1), 1-9.]])]
  
 ===== Pathophysiology ===== ===== Pathophysiology =====
-The amyloid cascade hypothesis and the tau hypothesis are the two predominant theories behind the pathogenesis of AD. Both amyloid plaques and neurofibrillary tangles are found in post-mortem pathology. ​Individuals with polymorphism in apolipoprotein E4 have an increased risk of AD and earlier age of onset, particularly ​in homozygous individuals. Increasing links are being found between ​the pathophysiology of Alzheimer'​s and hyperglycemia.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​29368156|Zheng,​ F., Yan, L., Yang, Z., Zhong, B., & Xie, W. (2018). HbA 1c, diabetes and cognitive decline: the English Longitudinal Study of Ageing. Diabetologia,​ 1-10.]])] Hypertension in lafe-life ​is also a risk factor for development ​of Alzhemier'​s ​pathology.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​29997190|Arvanitakis,​ Z., Capuano, A. W., Lamar, M., Shah, R. C., Barnes, L. L., Bennett, D. A., & Schneider, J. A. (2018). Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. Neurology, 91(6), e517-e525.]])]+The amyloid cascade hypothesis and the tau hypothesis are the two predominant theories behind the pathogenesis of AD. Both amyloid plaques and neurofibrillary tangles are found in post-mortem pathology. ​The loss of cholinergic neurons ​in the limbic system ​is also thought to be core part of AD pathology.
  
 +==== Amyloid ====
 +Amyloid precursor protein (APP) is metabolized by alpha-, beta- and gamma- secretase, which generates a small peptide, A-beta (Aβ). Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains. Aβ42 is more prone to aggregation,​ and is the main component of the amyloid plaques found AD. As Aβ42 deposits accumulate, this is thought to lead to the formation of senile plaques (SPs) and neurofibrillary tangles (NFTs), leading to neuronal cell death, and ultimately dementia.
 +
 +==== Tau ====
 +Tau build up (also known as aggregation of hyperphosphorylated tau protein) is another hypothesized mechanism for AD. It is hypothesized to be due to increased activity of tau kinases, which causes the tau protein to misfold and clump, forming neurofibrillary tangles (NFTs). The tau filaments in AD are called paired helical filaments.
 ===== Differential Diagnosis ===== ===== Differential Diagnosis =====
 The differential diagnosis for Alzheimer'​s disease is broad, as it overlaps with other [[geri:​dementia:​home|neurodegenerative disorders]]. In older adults, it is particularly important to rule out primary psychiatric disorders (depression in particular) which can mimic dementia. The differential diagnosis for Alzheimer'​s disease is broad, as it overlaps with other [[geri:​dementia:​home|neurodegenerative disorders]]. In older adults, it is particularly important to rule out primary psychiatric disorders (depression in particular) which can mimic dementia.
  
 ===== Investigations ===== ===== Investigations =====
-The diagnosis of Alzheimer'​s Disease remains a clinical diagnosis, though neuroimaging and biomarkers are beginning to play a larger role in diagnosis. ​Amyloid-based diagnostic tests such as amyloid imaging on brain positron emission tomography (PET) scans and measuring amyloid beta-42 (look for reduced levels) in the [[neurology:​lumbar-puncture-lp|cerebrospinal ​fluid]] (CSF) may sometimes be helpful. Signs of neuronal injurysuch as hippocampal ​and temporoparietal cortical atrophy on MRI or temporoparietal hypometabolism on fluorodeoxyglucose ​PET scan may provide non-specific evidence for AD.+The diagnosis of Alzheimer'​s Disease remains a clinical diagnosis, though neuroimaging and biomarkers are beginning to play a larger role in diagnosis. 
 + 
 +==== CSF ==== 
 +  * [[neurology:​lumbar-puncture-lp|Cerebrospinal ​fluid]] (CSF) 
 +    * Decreased levels ​of CSF Abeta-42 are seen 
 +    * Increased total tau is also seen, but is not specific to AD, and is just biomarker of neuronal injury 
 +    * Phosphorylated tau is also increased.[([[https://​pubmed.ncbi.nlm.nih.gov/​11309456|Sjögren,​ M., Davidsson, P., Tullberg, M., Minthon, L., Wallin, A., Wikkelso, C., ... & Blennow, K. (2001). Both total and phosphorylated tau are increased in Alzheimer'​s disease. Journal of Neurology, Neurosurgery & Psychiatry, 70(5), 624-630.]])] 
 +==== Neuroimaging ==== 
 +  * [[neurology:​pet|Positron Emission Tomography (PET)]] amyloid imaging 
 +    * Can visualize amyloid plaques[([[https://​pubmed.ncbi.nlm.nih.gov/​25539279/​|Shivamurthy,​ V. K., Tahari, A. K., Marcus, C., & Subramaniam,​ R. M. (2015). Brain FDG PET and the diagnosis of dementia. American Journal of Roentgenology,​ 204(1), W76-W85.]])] 
 +  * Fluorodeoxyglucose (FDG) PET scans may provide non-specific evidence for AD, including:​ 
 +    * Hypometabolism in the bilateral temporoparietal regions[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC4332800/​|Marcus,​ C., Mena, E., & Subramaniam,​ R. M. (2014). Brain PET in the diagnosis of Alzheimer’s disease. Clinical nuclear medicine, 39(10), e413.]])] 
 +    * Hypometabolism in posterior cingulate cortex (PCC) 
 +    * There is also increased amyloid tracer retention 
 +  * [[neurology:​mri|MRI]]  
 +    * Atrophy with a characteristic pattern involving the medial temporal lobes (MTL), hippocampus,​ paralimbic and/or temporoparietal cortex[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC2888989/​|Whitwell,​ J. L., Jack Jr, C. R., Przybelski, S. A., Parisi, J. E., Senjem, M. L., Boeve, B. F., ... & Josephs, K. A. (2011). Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiology of aging, 32(9), 1531-1541.]])]
 ===== Treatment ===== ===== Treatment =====
 Current treatments do not alter the course of the disease. Medications only serve to reduce the rate of decline, and symptomatic improvement. ​ Current treatments do not alter the course of the disease. Medications only serve to reduce the rate of decline, and symptomatic improvement. ​
Line 112: Line 177:
 ==== Caregivers ==== ==== Caregivers ====
 It is extremely important for education about the illness to be provided to both the patient and their families. Caregiver support is also extremely important as the disease progresses. Better caregiver support and interventions helps delay institutionalization.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​8314099|Mittelman,​ M. S., Ferris, S. H., Steinberg, G., Shulman, E., Mackell, J. A., Ambinder, A., & Cohen, J. (1993). An intervention that delays institutionalization of Alzheimer'​s disease patients: treatment of spouse-caregivers. The Gerontologist,​ 33(6), 730-740.]])] It is extremely important for education about the illness to be provided to both the patient and their families. Caregiver support is also extremely important as the disease progresses. Better caregiver support and interventions helps delay institutionalization.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​8314099|Mittelman,​ M. S., Ferris, S. H., Steinberg, G., Shulman, E., Mackell, J. A., Ambinder, A., & Cohen, J. (1993). An intervention that delays institutionalization of Alzheimer'​s disease patients: treatment of spouse-caregivers. The Gerontologist,​ 33(6), 730-740.]])]
 +
 +==== Behavioural Symptoms ====
 +<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​See main article: **[[geri:​dementia:​1-bpsd|]]**</​alert>​
 ==== Dementia ==== ==== Dementia ====
-  * Acetylcholinesterase ​inhibitors ([[meds:​dementia:​donepezil|donepezil]],​ [[meds:​dementia:​rivastigmine|rivastigmine]],​ and [[meds:​dementia:​galantamine|galantamine]]) as a class are modestly efficacious ​for mild to moderate AD, and a trial of these medications is recommended for most patients diagnosed with AD.  +  * For **mild-to-moderate AD**, acetylcholinesterase ​inhibitors ([[meds:​dementia:​donepezil|donepezil]],​ [[meds:​dementia:​rivastigmine|rivastigmine]],​ and [[meds:​dementia:​galantamine|galantamine]]) as a class are modestly efficacious,​ and a trial of these medications is recommended for most patients diagnosed with AD
-  * [[meds:​dementia:​memantine|Memantine]] monotherapy is another treatment option for patients ​with moderate to severe stages of AD. Use of memantine in mild AD is //not recommended//​.+    * The estimated number needed to treat (NNT) for cognitive improvement is 10.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC191283/​|Lanctôt,​ K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., & Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer'​s disease: a meta-analysis. Cmaj, 169(6), 557-564.]])] 
 +    * The estimated NNT for global improvement is 12.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC191283/​|Lanctôt,​ K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., & Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer'​s disease: a meta-analysis. Cmaj, 169(6), 557-564.]])] 
 +    * The number needed to harm (NNH) is 13. 
 +    * Most studies for acetylcholinesterase inhibitors are short in duration (< 1 year) 
 +    * Note that [[cl:​3-mild-neurocog-disorder|mild cognitive impairment]] due to AD should not be treated with acetylcholinesterase inhibitors
 +  * For **moderate-to-severe stages** of AD, in addition to acetylcholinesterase inhibitors,[[meds:​dementia:​memantine|Memantine]] monotherapy is another treatment option for patients 
 +    * Note that memantine in mild AD is //not recommended//​.
   *  There is insufficient evidence to recommend for or against the combination treatment with an acetylcholinesterase inhibitor and memantine.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3980908/​|Herrmann,​ N., Lanctôt, K. L., & Hogan, D. B. (2013). Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer'​s research & therapy, 5(1), S5.]])]   *  There is insufficient evidence to recommend for or against the combination treatment with an acetylcholinesterase inhibitor and memantine.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3980908/​|Herrmann,​ N., Lanctôt, K. L., & Hogan, D. B. (2013). Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer'​s research & therapy, 5(1), S5.]])]
 +
 +<panel type="​info"​ title="​Pharmacotherapy for AD" subtitle=""​ no-body="​true"​ footer="">​
 +<​mobiletable 1>
 +^ Medication ​                                  ^ Type                            ^ Starting Dose          ^ Maintenance ​            ^ Side effects ​                                                     ^
 +^ [[meds:​dementia:​rivastigmine|Rivastigmine]] ​ | Acetylcholinesterase inhibitor ​ | 1.5 mg PO BID          | 6 mg PO BID (maximum) ​  | Nausea, vomiting, diarrhea, weight loss, anorexia. ​               |
 +^ [[meds:​dementia:​donepezil|Donepezil]] ​       | Acetylcholinesterase inhibitor ​ | 5mg PO                 | 10 mg PO (maximum) ​     | Nausea, vomiting, diarrhea, weight loss, anorexia. Vivid dreams. ​ |
 +^ [[meds:​dementia:​galantamine|Galantamine]] ​   | Acetylcholinesterase inhibitor ​ | 4 mg PO BID x 4 weeks  | 12 mg PO BID (maximum) ​ | Similar to rivastigmine ​                                          |
 +^ [[meds:​dementia:​memantine|Memantine]] ​       | NMDA antagonist ​                | 5 mg PO qAM            | 10 mg PO BID (maximum) ​ | Headaches, somnolence, dizziness, agitation/​confusion ​            |
 +</​mobiletable>​
 +</​panel>​
  
 ==== Depression ==== ==== Depression ====
-If the patient had an inadequate response to the nonpharmacological interventions or has a major affective disorder, severe dysthymia or severe emotional lability, a trial of an [[meds:​antidepressants:​home|antidepressant]] //could// be considered.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3980908/​|Herrmann,​ N., Lanctôt, K. L., & Hogan, D. B. (2013). Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer'​s research & therapy, 5(1), S5.]])]+  * For depressive symptoms, if a patient had an inadequate response to the nonpharmacological interventions or has a major affective disorder, severe dysthymia or severe emotional lability, a trial of an [[meds:​antidepressants:​home|antidepressant]] //could// be considered.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3980908/​|Herrmann,​ N., Lanctôt, K. L., & Hogan, D. B. (2013). Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer'​s research & therapy, 5(1), S5.]])] 
 +  * However, the response rates are low and possibly lower than non-pharmacological interventions.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC7988455/​|Watt,​ J. A., Goodarzi, Z., Veroniki, A. A., Nincic, V., Khan, P. A., Ghassemi, M., ... & Straus, S. E. (2021). Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis. bmj, 372.]])]
  
 +==== Deprescribing ====
 +<alert type="​info"​ icon="​fa fa-book fa-lg fa-fw">​
 +See also: **[[https://​pubmed.ncbi.nlm.nih.gov/​20849673/​|Herrmann,​ N. et al. (2011). Discontinuing cholinesterase inhibitors: results of a survey of Canadian dementia experts. International psychogeriatrics,​ 23(4), 539-545.]]**
 +</​alert>​
 +
 +  * Consider [[geri:​1-giants#​polypharmacy|deprescribing]] medications that may worsen cognition, including [[meds:​toxidromes:​anticholinergic-cholinergic|anticholinergic medications]].
 +    * Deprescribing can be safe and effective.[([[https://​pubmed.ncbi.nlm.nih.gov/​26482056/​|Herrmann,​ N., O'​Regan,​ J., Ruthirakuhan,​ M., Kiss, A., Eryavec, G., Williams, E., & Lanctot, K. L. (2016). A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease. Journal of the American Medical Directors Association,​ 17(2), 142-147.]])]
 +  * If deprescribing does not go well and there are increased behavioural symptoms, restart the medication at the //lowest// dose and **not** back to the original dose, as patients may develop prominent GI symptoms including nausea and vomiting!
 ===== Resources ===== ===== Resources =====
 +
 +<WRAP group>
 +<WRAP quarter column>
 +== For Patients ==
 +  * [[https://​www.youtube.com/​watch?​v=C7NQahSxDkk|YouTube:​ Diagnosing Alzheimer’s Disease]]
 +</​WRAP>​
 +
 +<WRAP quarter column>
 +== For Providers ==
 +  * **[[https://​www.nature.com/​articles/​nrdp201556|Masters,​ C. L. et al. (2015). Alzheimer'​s disease. Nature reviews. Disease primers, 1, 15056-15056.]]**
 +</​WRAP>​
 +<WRAP quarter column>
 +== Articles ==
   * [[https://​www.theatlantic.com/​health/​archive/​2018/​01/​the-startling-link-between-sugar-and-alzheimers/​551528/​|The Atlantic: The Startling Link Between Sugar and Alzheimer'​s]]   * [[https://​www.theatlantic.com/​health/​archive/​2018/​01/​the-startling-link-between-sugar-and-alzheimers/​551528/​|The Atlantic: The Startling Link Between Sugar and Alzheimer'​s]]
   * [[https://​www.nytimes.com/​2018/​04/​18/​opinion/​menopause-alzheimers-connection.html|NYT:​ The Menopause-Alzheimer’s Connection]]   * [[https://​www.nytimes.com/​2018/​04/​18/​opinion/​menopause-alzheimers-connection.html|NYT:​ The Menopause-Alzheimer’s Connection]]
 +</​WRAP>​
 +<WRAP quarter column>
 +== Research ==
 +
 +</​WRAP>​
 +</​WRAP>​
 +
 +