Contents

Search

Alzheimer's disease (AD)

Classifcation: - see CSF proteomic analysis of Alzheimer's disease subtypes Etiology: 1) idiopathic neurodegenerative disease of aging 2) see etiology of Alzheimer's disease Epidemiology: 1) 4 million persons in USA affected a) 4th leading cause of death; 46,000 deaths/year b) deaths due to Alzheimer's disease rose 71% from 2000-2013 [29] c) deaths due to Alzheimer disease 36.9 per 100,000 in 1st quarter of 2017 [34] 3) 35% of dementia pure AD; 15% mixed AD/vascular dementia - 60-80% of dementia cases [2] 4) 5% age 65-74; 15-25% age 75-84; 35-50% > 85 years of age 5) prevalence of 42% by age 82 years [33] 6) 70% of women & 17% of men > age 90 (ADAMS study, 2006) 7) prevalence of neuropathologically-defined AD may be substantially higher than clinically-defined AD (2x) [8] 8) < 1/2 of patients or their caregivers with Alzheimer's disease acknowledge being told of the diagnosis [28] 9) costliest disease to society - cost of care for patients with Alzheimer's disease & other types of dementia in 2015 are estimated at $226 billion [29] Pathology: see pathology of Alzheimer's disease Genetics: see genetics of Alzheimer's disease History: - medication review - family history - alcohol use - also see dementia Clinical manifestations: grossly, function is lost in Alzheimer's disease in a reversal of the order that it was acquired during development. [22] - compare functional assessment staging & developmental staging also see dementia for general features 1) progressive memory loss (short & long term) a) patients will in early AD still able to learn [21] b) subjective memory impairment may precede clinically-defined AD [23] c) memory impairment predominant (amnestic) mild cognitive impairment often precedes Alzheimer's disease [40] d) no benefit of cueing e) early-onset (familial) Alzheimer's disease may not present with memory impairment 2) impairment in at least one other area of cognitive function a) abstract thinking b) executive dysfunction - judgment, problem-solving, multitasking c) visuospatial dysfunction - getting lost in familiar places is pathological & consistent with dementia [2,17] - partial memory impairment due to brain remapping dysfunction [39] d) language - aphasia characterized by word finding difficulties frequently occurs early [2] e) apraxia (70-80% of patients with moderate AD) - dressing apraxia, constructional apraxia f) agnosia g) personality change 3) impairment of social functioning a) home b) job c) activities of daily living 4) impairment of smell may be an early symptom (see UPSIT) but not universal (see olfaction & Alzheimer's disease) 5) clear sensorium (no delirium) 6) left-right confusion [21] 7) abnormal mini mental status examination 8) absence of other causes of dementia 9) depression may occur at any stage 10) behavioral disturbances & personality changes a) apathy occurs in 70% of patients [7] b) psychosis, including delusions & hallucinations may occur at any stage (see psychosis in Alzheimer's disease) c) hallucinations are more common in mid-to-late phase - hallucinations generally involve people from the past, intruders, animals, objects [17] d) delusions generally involve beliefs of theft, infidelity, abandonment, persecution e) delusions decrease in late phases of the disease [17] f) agitation, irritability, aggression, anxiety, mistrust, disinhibition, wandering, disturbances in sleep & appetite, impulsivity (pathologic gambling), emotional lability, egocentricity - some of these changes may occur prior to cognitive changes [17,25,31] 11) extrapyramidal signs may be present a) generally a late feature b) bradykinesia & rigidity more common than tremors [17] c) paratonia 12) gait apraxia: a) shuffling gait b) without festination, retropulsion or en-bloc turning of Parkinson's disease [17] 13) late manifestations: a) loss of bowel & bladder function 1] urinary incontinence 2] fecal incontinence b) loss of motor skills (apraxia) c) patient becomes bedridden & incontinent d) seizures e) myoclonus* f) corticobasal syndrome* 14) sleep disorder frequent [24] - earlier bedtime - higher wake onset after sleep - longer REM sleep latency [24] 15) atypical presentations - early visuospatial dysfunction or executive dysfunction [38] with relatively intact memory [2] 16) common features - memory impairment, getting lost, difficulty finding words, difficulty with dressing, grooming & doing housework [2] 17) individual trajectories in commonly used cognitive measures variable [41] * may also be present with early-onset AD Diagnostic criteria: - ATN classification system based on biomarkers [35] - see diagnostic criteria for Alzheimer's disease Laboratory: 1) see laboratory evaluation of Alzheimer's disease 2) also see laboratory evaluation of dementia Special laboratory: 1) electroencephalogram (EEG): seizure disorder - Fastball EEG: investigational evaluation of early Alzheimer's disease 2) small bowel biopsy to rule out intestinal lipodystrophy (Whipple's disease) 3) brain biopsy: only definitive test 4) cognitive testing - mini-Cog, memory impairment screen, Montreal Cognitive Assessment 5) evaluate for depression (PHQ-9) 6) evaluate for sleep disorder Radiology: - see radiology of Alzheimer's disease - neuroimaging takes precedence over lumbar puncture [27] Differential diagnosis: - see differential diagnosis of Alzheimer's disease Complications: - see dementia Management: 1) see management section of dementia & guidelines for AD management 2) pharmaceutical agents (see pharmaceuticals for treatment of AD) - FDA proposes approval of new drugs for treatment of preclinical Alzheimer's disease based on changes in biomarkers without demonstration of actual clinical benefit [36] 3) associated behavioral syndromes (see pharmaceuticals for treatment of AD) 4) bright light +/- melatonin may reduce cognitive decline & improve physical function [16] 5) adequate nutrition 6) regular exercise 7) prognosis: a) associated with shortened survival [13] b) mean life span 9.6 +/- 3.5 years after diagnosis [15] c) prognosis dependent upon several factors - psychosis, agitation/aggression, affective symptoms predict more rapid progression [26] - cognitive decline is the strongest predictor of shorter life expectancy [42] - older age, male, white, motor symptoms, functional impairment, & neuropsychiatric symptoms also predict shorter life expectancy [42] - also see prognosis for patients with dementia 8) patient education a) caregiver support - caregiver support may delay institutionalization of AD patients (1.5 years) without increasing caregiver burden [17,32] b) financial planning c) home care needs d) advanced directives 9) also see guidelines for Alzheimer's disease (AD) management 10) Alzheimer's disease may be a reportable disease - see dementia, driving & California state law 11) Follow-up: - every 3-6 months - assess & document cognitive decline & behavioral changes - health maintenance - assess caregiver burden 12) investigational therapies 13) screening for Alzheimer's disease 14) prevention of Alzheimer's disease Notes: - category of preclinical Alzheimer's disease prior to cognitive changes may be diagnosed with neuroimaging & CSF analysis [19] - cognitive assessment by general practitioners for diagnosis of dementia is more specific than sensitive [43] - false negatives more likely in elderly with less severe impairment - false positives may occur in those with depression [43]

Interactions

disease interactions

Related

Alzheimer, Alois criteria for Alzheimer's disease diagnostic criteria for Alzheimer's disease differential diagnosis of Alzheimer's disease epidemiology Alzheimer's disease etiology/risk of Alzheimer's disease exercise & Alzheimer's disease genetics of Alzheimer's disease guidelines for Alzheimer's disease management investigational therapies for treatment of Alzheimer's disease laboratory evaluation of Alzheimer's disease limbic-predominant age-related TDP-43 encephalopathy (LATE); limbic-predominant amnestic neurodegenerative syndrome (LANS) pathology of Alzheimer's disease (AD) pharmaceutical agents for treatment of Alzheimer's disease (Alzheimer's agent) predictors of Alzheimer's disease prevention of Alzheimer's disease/dementia radiology of Alzheimer's disease

Specific

Alzheimer's disease in physician early-onset Alzheimer's disease familial Alzheimer's disease (FAD) Lewy body variant of Alzheimer's disease (AD) posterior cortical atrophy preclinical Alzheimer's disease psychosis in Alzheimer's disease

General

dementia; Alzheimer's disease & related dementias (ADRD) neurodegenerative disease

Properties

PATHOLOGY: neurofibrillary tangle amyloid plaque cerebral amyloid angiopathy granulovacuolar change Hirano body

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1053-55
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Prescriber's Letter 7(2):10, Feb. 2000
  4. Role of cholinergic therapy in treatment of Alzheimer's disease & other dementias, Farlow, M et al, 2001
  5. Journal Watch 21(15):125, 2001 Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ. 2001 Jun 16;322(7300):1447-51. PMID: 11408299
  6. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  7. McPherson, S. Director, Neuropsychology Laboratory UCLA ADRC
  8. Polvikoski et al, Prevalence of Alzhmeimer' disease in very elderly people: a prospective neuropathological study Neurology 56:1690, 2001 PMID: 11425935
  9. Selkoe D. Alzheimer's disease: genes, proteins, and therapy. Physiological Reviews 81:741, 2001 PMID: 11274343
  10. Journal Watch 22(7):56-57, 2002 Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83. PMID: 11844848
  11. Prescriber's Letter 9(4):22 2002
  12. Journal Watch 23(12):93, 2003 Tan ZS, Seshadri S, Beiser A, Wilson PW, Kiel DP, Tocco M, D'Agostino RB, Wolf PA. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch Intern Med. 2003 May 12;163(9):1053-7. PMID: 12742802
  13. Journal Watch 24(10):80-81, 2004 Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, Kukull WA. Survival after initial diagnosis of Alzheimer disease. Ann Intern Med. 2004 Apr 6;140(7):501-9. PMID: 15068977
  14. Smith GE et al, A plateau in pre-Alzheimer memory decline: Evidence for compensatory mechanisms. Neurology 2007, 69:133 PMID: 17620545
  15. Olichney JM et al, Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology 1998, 51:351 PMID: 9710002
  16. Riemersma-van der Lek RF et al, Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: A randomized controlled trial. JAMA 2008, 299:2642 PMID: 18544724
  17. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  18. Alzheimer Disease International World Alzheimer Report 2013. Journey of Caring. An analysis of long-term care for dementia. http://www.alz.co.uk/research/WorldAlzheimerReport2013.pdf
  19. Vos SJB et al. Preclinical Alzheimer's disease and its outcome: A longitudinal cohort study. Lancet Neurol 2013 Oct; 12:957 PMID: 2401237
  20. Montine TJ et al. Recommendations of the Alzheimer's Disease-Related Dementias Conference. Neurology 2014 Jul 30; PMID: 25080517
  21. Studies Suggest People with Early AD Can Still Learn http://www.alzheimers.org/nianews/nianews67.html
  22. Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci. 2004 Nov;22(7):507-14. Review. PMID: 15465280
  23. Jorm AF, Masaki KH, Davis DG, Hardman J, Nelson J, Markesbery WR, Petrovitch H, Ross GW, White LR. Memory complaints in nondemented men predict future pathologic diagnosis of Alzheimer disease. Neurology. 2004 Nov 23;63(10):1960-1. PMID: 15557525
  24. Liguori C et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014 Oct 13; PMID: 25322206 - Ferini-Strambi L. Possible role of orexin in the pathogenesis of Alzheimer disease. JAMA Neurol 2014 Oct 13 PMID: 25317720
  25. Masters MC et al. "Noncognitive" symptoms of early Alzheimer disease: A longitudinal analysis. Neurology 2015 Jan 14 PMID: 25589671 http://www.neurology.org/content/early/2015/01/13/WNL.0000000000001238
  26. Peters ME et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer's dementia and death: The Cache County Dementia Progression Study. Am J Psychiatry 2015 Jan 13 PMID: 25585033 http://psychiatryonline.org/doi/abs/10.1176/appi.ajp.2014.14040480
  27. N Engl J Med Knowledge+ Question of the Week. March 17, 2015 - Mayeux R. Clinical practice. Early Alzheimer's disease. N Engl J Med 2010 Jun 19; 362:2194. PMID: 20558370 - Knopman DS et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001 May 9; 56:1143 PMID: 11342678
  28. Alzheimer's News, 3/24/15 New Alzheimer's Association report finds less than half of people with Alzheimer's disease say they were told the diagnosis. http://www.alz.org/news_and_events_facts_figs_told_diagnosis.asp
  29. U.S. Department of Health and Human Services (HHS) White House Conference on Aging: Combating Alzheimer's and Other Dementias. July 13, 2015 http://www.hhs.gov/news/press/2015pres/07/20150713b.html
  30. Alzheimers Association 2015 Alzheimer's disease facts and figures The Journal of the Alzheimer's Association. March 2015 11(3):332 http://www.alzheimersanddementia.com/article/S1552-5260%2815%2900058-8/fulltext
  31. Balsis S, Carpenter BD, Storandt M. Personality change precedes clinical diagnosis of dementia of the Alzheimer type. J Gerontol B Psychol Sci Soc Sci. 2005 Mar;60(2):P98-P101. PMID: 15746024
  32. Mittelman MS, Haley WE, Clay OJ, Roth DL. Improving caregiver well-being delays nursing home placement of patients with Alzheimer disease. Neurology. 2006 Nov 14;67(9):1592-9. PMID: 17101889
  33. Barclay LL Alzheimer's Prevention: A Summary of What We Know Medscape - Aug 23, 2017. http://www.medscape.com/viewarticle/884615 - Galvin JE. Prevention of Alzheimer's Disease: Lessons Learned and Applied. J Am Geriatr Soc. 2017 Aug 2. PMID: 28766695
  34. Ahmad FB, Bastian B. Quarterly provisional estimates for selected indicators of mortality, 2016-Quarter 2, 2017. National Center for Health Statistics. National Vital Statistics System, Vital Statistics Rapid Release Program. 2017. https://www.cdc.gov/nchs/nvss/vsrr/mortality-dashboard.htm
  35. Jack CR Jr, Bennett DA, Blennow K et al NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers & Dementia. April 2018, 14(4):535-562 PMID: 29653606 http://www.alzheimersanddementia.com/article/S1552-5260(18)30072-4/fulltext - Jack CR Jr, Bennett DA, Blennow K et al A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2;87(5):539-47. Epub 2016 Jul 1. Review. PMID: 27371494 Free PMC Article
  36. MedPage Today Staff. February 15, 2018 Sea Change for Alzheimer's Drug Development (FDA) Agency may approve drugs for 'preclinical' disease solely on biomarker effects. https://www.medpagetoday.com/neurology/alzheimersdisease/71185 - U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Early Alzheimer's Disease: Developing Drugs for Treatment Guidance for Industry. Draft Guidance. February 2018 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM596728.pdf
  37. Brooks M. First Alzheimer's Guidelines for Clinical Practice Released. Medscape Medical News. WebMD, Inc. July 23, 2018. https://www.medscape.com/viewarticle/899674 - First Practice Guidelines for Clinical Evaluation of Alzheimer's Disease and Other Dementias for Primary and Specialty Care. Alzheimer's Association. Chicago. July 22, 2018. https://www.alz.org/aaic/releases_2018/AAIC18-Sun-clinical-practice-guidelines.asp
  38. Stetka B In Alzheimer's Disease, It's Not Always Memory That Goes Medscape - Jul 10, 2020. https://www.medscape.com/viewarticle/933537
  39. ScienceDaily. Aug 19, 2020 Brain remapping dysfunction causes spatial memory impairment in Alzheimer's disease. A step towards a treatment of wandering behaviors in dementia patients.
  40. Lutsep HL Fast Five Quiz: Memory Loss and Cognitive Impairment Medscape. April 28, 2021 https://reference.medscape.com/viewarticle/949619
  41. George J Early Alzheimer's Trajectories May Vary Widely. High heterogeneity could influence clinical trial results, simulation shows. MedPage Today June 4, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/92934 - Jutten RJ, Sikkes SAM, Van der Flier WM et al Finding treatment effects in Alzheimer trials in the face of disease progression heterogeneity. Neurology 2021. May 31 PMID: 34550903 Free PMC article. https://n.neurology.org/content/96/22/e2673 - Buckley RF, Knopman DS Cognitive heterogeneity in Alzheimer clinical trials: harnessing noise to achieve meaningfulness. Neurology 2021. May 31 PMID: 34550902 https://n.neurology.org/content/96/22/1017 - Jutten RJ, Sikkes SAM, Amariglio RE Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease. J Int Neuropsychol Soc. 2021 May;27(5):426-438 PMID: 33046162 Free PMC article.
  42. Schaffert J, LoBue C, Hynan LS et al Predictors of Life Expectancy in Autopsy-Confirmed Alzheimer's Disease. Journal of Alzheimer's Disease 2022;86(1)271-281 PMID: 35034898 https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215200
  43. Creavin ST et al Clinical judgement by primary care physicians for the diagnosis of all- cause dementia or cognitive impairment in symptomatic people. Cochrane Library. 2022. June 16. PMID: 35709018 PMCID: PMC9202995 Free PMC article https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012558.pub2/full
  44. Dolphin H, Dyer AH, Morrison L, Shenkin SD, Welsh T, Kennelly SP. New horizons in the diagnosis and management of Alzheimer's Disease in older adults. Age Ageing. 2024 Feb 1;53(2):afae005. PMID: 38342754 PMCID: PMC10859247 Free PMC article. Review.
  45. NINDS Alzheimer's Disease Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Alzheimers-Disease-Information-Page
  46. ADEAR: Alzheimer's Disease Fact Sheet http://adear.niapublications.org/pubs/adfact.html

Databases & Figures

OMIM correlations MORBIDMAP correlations Figures/diagrams/slides/tables related to Alzheimer's disease