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Alzheimer Disease

Scientific Breakthroughs and Translational Challenges

      Abstract

      Alzheimer disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein E ε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ levels build from preclinical through early dementia stages followed by hyperphosphorylated tau–related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early-onset familial AD gave rise to the amyloid hypothesis of AD, which, in turn, has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid, but to date results have been disappointing. Genome-wide association studies have identified multiple additional risk factors, but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease-modifying therapy: who and when to treat, and how to pay for it.

      Abbreviations and Acronyms:

      AD (Alzheimer disease), APOE (apolipoprotein E), APP (amyloid precursor protein), CERAD (Consortium to Establish a Registry for Alzheimer's Disease), CSF (cerebrospinal fluid), DIAD (dominantly inherited Alzheimer disease), FDA (Food and Drug Administration), FDG (fluorodeoxyglucose), MCI (mild cognitive impairment), MRI (magnetic resonance imaging), NFT (neurofibrillary tangle), PET (positron emission tomography), PSEN (presenilin), REVEAL (Risk Evaluation and Education for Alzheimer's Disease), TREM2 (Triggering Receptor Expressed on Myeloid cells 2)
      CME Activity
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      Learning Objectives: On completion of this article, you should able to (1) recognize the basis for the amyloid hypothesis about the pathogenesis of Alzheimer disease and current approaches to disease-modifying therapy; (2) differentiate the effect of multiple genetic risk factors identified in genome-wide screening analyses with the major autosomal dominant forms as well as apolipoprotein E ε4; (3) correlate imaging biomarkers with the neuropathology of Alzheimer disease; and (4) recognize the extended preclinical course of Alzheimer disease, its neuropathological basis, and its expression in the form of biomarkers.
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      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Caselli is an investigator in clinical trials sponsored by Merck and Novartis and receives research support from the National Institute on Aging (grant nos. P30AG19610 and R01AG031581) and the Arizona Alzheimer's Consortium. Dr Beach is an investigator in clinical trials sponsored by Avid Radiopharmaceuticals and Navidea Biopharmaceuticals, has served as a consultant for Avid Radiopharmaceuticals and GE Healthcare; and receives or has received research support from the National Institutes of Health (grant nos. U24NS072026, P30 AG19610, R01 AG044372, R21NS093222, and R21AG044723), the Michael J. Fox Foundation for Parkinson's Research, and the Arizona Alzheimer's Consortium. Dr Knopman serves on a Data Safety Monitoring Board for Lundbeck Pharmaceuticals and for the Dominantly Inherited Alzheimer Network; is an investigator in clinical trials sponsored by Biogen, TauRx Pharmaceuticals, Eli Lilly Pharmaceuticals, and the Alzheimer's Disease Cooperative Study; and receives research support from the National Institutes of Health (grant nos. P50 AG16574, U01 AG06786, and R01 AG41851). Dr Graff-Radford is an investigator in clinical trials sponsored by Biogen, Eli Lilly Pharmaceuticals, TauRx Pharmaceuticals, and Axovant and has served as a consultant for Cytox.
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      Questions? Contact [email protected] .
      Much has changed since November 3, 1906, the day Alois Alzheimer first presented the unusual case of Auguste Deter to the Society of Southwest German Psychiatrists. Her symptoms of delusional jealousy, paranoia, and memory loss began insidiously at the age of 51, ended with her death at age 55, and led to the original conception of Alzheimer disease (AD) as a rare cause of presenile dementia.
      • Alzheimer A.
      Über eine eigenartige Erkrankung der Hirnrinde.
      The first major change occurred 70 years later when Katzman
      • Katzman R.
      Editorial: The prevalence and malignancy of Alzheimer disease. A major killer.
      and Terry
      • Terry R.D.
      My own experience in early research on Alzheimer disease.
      argued that the disease bearing Alzheimer's name was also the cause of senile dementia in the elderly, a much more prevalent condition, and so far from previous conceptions AD came to be understood as highly prevalent, the major cause of dementia at any age, and a major cause of death. A second and more recent major change has been to dispel the notion that AD can only be confirmed at autopsy. Advances in brain imaging have made antemortem confirmation a reality (within the research arena). Genomics and many more advances have further led to our current concept of AD and constitute the bulk of this review.

      Clinical Background

      When symptoms first become apparent, patients are forgetful but still functioning independently. The diagnostic term mild cognitive impairment (MCI) was originally introduced to define a nondisabling but progressive monosymptomatic amnestic syndrome
      • Petersen R.C.
      • Smith G.E.
      • Ivnik R.J.
      • et al.
      Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals.
      • Petersen R.C.
      • Smith G.E.
      • Waring S.C.
      • Ivnik R.J.
      • Tangalos E.G.
      • Kokmen E.
      Mild cognitive impairment: clinical characterization and outcome.
      • Petersen R.C.
      • Stevens J.C.
      • Ganguli M.
      • Tangalos E.G.
      • Cummings J.L.
      • DeKosky S.T.
      Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.
      and evolved into a broader classification of early, nondisabling cognitive deficits.
      • Petersen R.C.
      • Doody R.
      • Kurz A.
      • et al.
      Current concepts in mild cognitive impairment.
      • Winblad B.
      • Palmer K.
      • Kivipelto M.
      • et al.
      Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.
      Longitudinal studies
      • Petersen R.C.
      • Smith G.E.
      • Ivnik R.J.
      • et al.
      Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals.
      • Petersen R.C.
      • Smith G.E.
      • Waring S.C.
      • Ivnik R.J.
      • Tangalos E.G.
      • Kokmen E.
      Mild cognitive impairment: clinical characterization and outcome.
      • Ganguli M.
      • Dodge H.H.
      • Shen C.
      • DeKosky S.T.
      Mild cognitive impairment, amnestic type: an epidemiologic study.
      • Morris J.C.
      • Storandt M.
      • Miller J.P.
      • et al.
      Mild cognitive impairment represents early-stage Alzheimer disease.
      of patients with MCI have shown that approximately 10% to 15% of patients per year lose their ability to function reasonably independently, the defining characteristic of dementia. After 5 years, about half of all patients with MCI will meet criteria for dementia, particularly AD, and after 10 years, most will have AD or another dementia syndrome. At autopsy, 70% to 80% of patients who originally received a diagnosis of MCI prove to have AD as the major component of the dementia.
      • Morris J.C.
      • Storandt M.
      • Miller J.P.
      • et al.
      Mild cognitive impairment represents early-stage Alzheimer disease.
      • Jicha G.A.
      • Parisi J.E.
      • Dickson D.W.
      • et al.
      Neuropathologic outcome of mild cognitive impairment following progression to dementia.
      The latest version of the National Institute on Aging Alzheimer's Disease Center's Uniform Data Set characterizes AD dementia as an “amnestic multidomain dementia syndrome,”
      National Alzheimer's Coordinating Committee
      The Uniform Data Set, Version 3.0.
      meaning progressive memory loss over months to years with the gradual emergence of executive, language, visuospatial, and other deficits with or without behavioral features such as sundowning and paranoia. Diagnostic criteria are summarized in Table 1.
      • McKhann G.M.
      • Knopman D.S.
      • Chertkow H.
      • et al.
      The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workshops on diagnostic guidelines for Alzheimer's disease.
      Alzheimer disease does not always follow the canonical neuropathological pattern, however. Variant syndromes reflect a different pathological topography. Visual variant AD or posterior cortical atrophy reflects progressive visual impairment related to early degenerative involvement of visual cortices.
      • Tang-Wai D.F.
      • Graff-Radford N.R.
      • Boeve B.F.
      • et al.
      Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy.
      Other focal variants of AD affect language, motor, and executive functions.
      • Gorno-Tempini M.L.
      • Brambati S.M.
      • Ginex V.
      • et al.
      The logopenic/phonological variant of primary progressive aphasia.
      • Caselli R.J.
      • Stelmach G.E.
      • Caviness J.N.
      • et al.
      A kinematic study of progressive apraxia with and without dementia.
      • Boeve B.F.
      • Maraganore D.M.
      • Parisi J.E.
      • et al.
      Pathologic heterogeneity in clinically diagnosed corticobasal degeneration.
      • Johnson J.K.
      • Head E.
      • Kim R.
      • Starr A.
      • Cotman C.W.
      Clinical and pathological evidence for a frontal variant of Alzheimer disease.
      Table 1National Institute on Aging-Alzheimer's Association Diagnostic Guidelines for Alzheimer Disease
      Data from Alzheimers Dement.
      • McKhann G.M.
      • Knopman D.S.
      • Chertkow H.
      • et al.
      The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workshops on diagnostic guidelines for Alzheimer's disease.
      1. Criteria for “all-cause dementia” include cognitive or behavioral symptoms that
       (a) interfere with the ability to function at work or at usual activities
       (b) represent a decline from a previous level of functioning and performing
       (c) are not explained by delirium or major psychiatric disorder
       (d) cognitive impairment is detected and diagnosed through a combination of i. history from patient and reliable informant and (ii) objective cognitive testing
       (e) cognitive/behavioral impairment involves at least 2 domains: memory, executive, visuospatial, language, and/or personality
      2. Criteria for probable Alzheimer disease dementia include criteria for all-cause dementia plus
       (a) gradual onset over months to years
       (b) clear-cut worsening of cognition by report or observation
       (c) initial and most prominent deficits are
      i. memory (most common)
      ii. nonamnestic (with deficits in other cognitive domains as well)
      • language (logopenic/word finding)
      • visuospatial
      • executive
      3. Criteria for probable Alzheimer disease dementia with “increased level of certainty”
       (a) documented cognitive decline (longitudinal cognitive testing)
       (b) causative genetic mutation (APP, PSEN1, and PSEN2)
      4. Criteria for possible Alzheimer disease dementia
       (a) atypical course (eg, rapid onset) or
       (b) etiologically mixed presentation/features of other diseases
      5. Probable Alzheimer disease dementia with evidence of the pathophysiological process (biomarkers)
      6. Possible Alzheimer disease dementia with evidence of the pathophysiological process (biomarkers)
      7. Pathophysiologically proved Alzheimer disease dementia (neuropathologically confirmed)
      8. Dementia unlikely to be due to Alzheimer disease
       (a) does not meet clinical criteria for Alzheimer disease dementia and/or
       (b) has evidence of a different disease
       (c) both Aβ and neuronal injury markers are negative

      Neuropathology

      Neuropathologically, AD is characterized by 2 hallmark features: amyloid plaques and neurofibrillary tangles (NFTs) (Figure 1). Morphologically, amyloid plaques are described as either diffuse or neuritic. Both types may be seen in individuals without dementia, in whom they may indicate an increased risk of progression to dementia. Neuritic plaque is associated with cognitive impairment, whereas for diffuse plaques this relationship is tenuous. The primary event in plaque formation is the deposition of insoluble Aβ amyloid, whereas the “neuritic” elements (dystrophic axons and dendrites) are a reaction to this and contain pathological bundles of tau proteins that are identical to the NFTs found within neuronal perikarya. Tau is a cytoskeletal protein whose function is to stabilize microtubules that comprise the neuronal cytoskeleton. Tau within dystrophic neurites and NFTs is abnormally phosphorylated. This may impair microtubule binding and facilitate aggregation of tau into paired helical filaments, which are likely to impair the neuron's ability to maintain extensive dendritic and axonal arborizations, ultimately leading to loss of synaptic connectivity and neuronal death.
      Figure thumbnail gr1
      Figure 1Photomicrographs of frequent diffuse and neuritic plaques (A) (Campbell-Switzer silver stain, middle frontal gyrus, original magnification 100×), and neurofibrillary tangles (B) (Gallyas silver stain, cerebral cortex, original magnification 100×) in a patient with Alzheimer disease.
      Because both plaques and tangles can also occur in individuals without dementia, their mere presence is insufficient to diagnose AD, and so neuropathological criteria have been developed to define the likelihood that dementia is a consequence of AD. In 1985, the recommendations of a National Institute on Aging consensus panel focused on neocortical total plaque density as a function of age,
      • Khachaturian Z.S.
      Diagnosis of Alzheimer's disease.
      a recommendation echoed with a focus on neuritic plaques in 1991 by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD).
      • Mirra S.S.
      • Heyman A.
      • McKeel D.
      • et al.
      The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathological assessment of Alzheimer's disease.
      Around this time, Braak and Braak
      • Braak H.
      • Braak E.
      Neuropathological staging of Alzheimer-related changes.
      • Braak H.
      • Braak E.
      Staging of Alzheimer's disease-related neurofibrillary changes.
      reported that there is a predictable 6-stage march of NFT pathology from paralimbic to neocortical regions summarized, from earliest to latest, as transentorhinal (stage I/II), limbic (stage III/IV), and neocortical (stage V/VI). In 1997 a National Institute on Aging and Reagan Institute Working Group
      The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease
      Consensus Recommendations for the postmortem diagnosis of Alzheimer's disease.
      combined CERAD amyloid plaque score and Braak NFT stage to define the likelihood that dementia results from AD. High likelihood is reflected by frequent CERAD neuritic plaque score and Braak NFT stage V/VI; intermediate likelihood by moderate CERAD plaque score and Braak NFT stage III/IV; and low likelihood AD by low CERAD plaque score and Braak NFT stage I/II.
      The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease
      Consensus Recommendations for the postmortem diagnosis of Alzheimer's disease.
      Essential areas to be sampled differ somewhat between criteria but all include limbic, neocortical, and subcortical areas.
      Amyloid plaque distribution, in contrast to NFTs, begins in neocortical regions, and even in the earliest dementia stages it has usually progressed to involve diencephalic regions.
      • Thal D.R.
      • Rub U.
      • Orantes M.
      • Braak H.
      Phases of AB-deposition in the human brain and its relevance for the development of AD.
      It continues to build through Braak stages IV and V with progressively increasing subcortical and eventually brainstem and cerebellar involvement, but the rate of deposition may decline in the late stages of dementia.
      • Thal D.R.
      • Arendt T.
      • Waldmann G.
      • et al.
      Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology.
      As will be discussed, molecular imaging in living patients with positron emission tomography (PET) ligands for amyloid and tau has made it possible to exhibit this neuropathological evolution in real time.
      At autopsy, AD is often found not to be a unitary neuropathological diagnosis but includes prevalent comorbidities, particularly vascular and Lewy body pathology, which may contribute to dementia severity.
      • Dugger B.N.
      • Davis K.
      • Malek-Ahmadi M.
      • et al.
      Neuropathological comparisons of amnestic and nonamnestic mild cognitive impairment.
      • Kawas C.H.
      • Kim R.C.
      • Sonnen J.A.
      • Bullain S.S.
      • Trieu T.
      • Corrada M.M.
      Multiple pathologies are common and related to dementia in the oldest-old: the 90+ study.
      • Zheng L.
      • Vinters H.V.
      • Mack W.J.
      • Weiner M.W.
      • Chui H.C.
      IVD program project
      Differential effects of ischemic vascular disease and Alzheimer's disease on brain atrophy and cognition.
      • White L.R.
      • Edland S.D.
      • Hemmy L.S.
      • et al.
      Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies.
      • Ringman J.M.
      • Monsell S.
      • Ng D.W.
      • et al.
      Neuropathology of autosomal dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.
      • Arvanitakis Z.
      • Capuano A.W.
      • Leurgans S.E.
      • Bennett D.A.
      • Schneider J.A.
      Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross sectional study.
      Table 2 presents the commonly identified major neuropathological comorbidities from the Banner Sun Health Research Institute Brain Bank.
      • Beach T.G.
      • Adler C.H.
      • Sue L.I.
      • et al.
      Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.
      The proportion of patients with relatively pure AD decreases from 38% in sexagenarians to 25% in nonagenarians. This heterogeneity is also seen in patients dying during the MCI stage.
      • Dugger B.N.
      • Davis K.
      • Malek-Ahmadi M.
      • et al.
      Neuropathological comparisons of amnestic and nonamnestic mild cognitive impairment.
      Even in those older patients who come to autopsy without cognitive problems, AD, vascular, and Parkinson disease-related pathologies are frequent findings (Table 3).
      Table 2Decadal Counts of Neuropathological AD Total Comorbidities From Banner Sun Health Research Institute Brain and Body Donation Program/Arizona Study of Aging and Neurodegenerative Disorders
      AD = Alzheimer disease; AD/LB = Alzheimer disease with Lewy body disease insufficient for diagnosis of either Parkinson disease or dementia with Lewy bodies; DLB = dementia with Lewy bodies; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 proteinopathy; HS = hippocampal sclerosis; PD = Parkinson disease; PSP = progressive supranuclear palsy; TDP = TAR DNA binding protein; VaD = vascular dementia.
      ,
      Categories with mixed diagnoses are not mutually exclusive. Note that AD “pure” does not exclude comorbid minor neuropathological diagnoses.
      DecadeAD “pure”
      AD “pure” is defined as AD without any of the other listed diagnoses. AD was defined as a clinically documented dementia with National Institute on Aging–Reagan Institute Working Group intermediate or high AD pathology.
      AD allAD/VaDAD/PDAD/DLBAD/LBAD/PSPAD/HSAD/FTLD-TDP
      50s-60s20 (38%)53011120000
      70s55 (31%)17714233345264
      80s90 (26%)35045335412815227
      90s35 (25%)13838620449165
      100s1 (14%)7300221
      a AD = Alzheimer disease; AD/LB = Alzheimer disease with Lewy body disease insufficient for diagnosis of either Parkinson disease or dementia with Lewy bodies; DLB = dementia with Lewy bodies; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 proteinopathy; HS = hippocampal sclerosis; PD = Parkinson disease; PSP = progressive supranuclear palsy; TDP = TAR DNA binding protein; VaD = vascular dementia.
      b Categories with mixed diagnoses are not mutually exclusive. Note that AD “pure” does not exclude comorbid minor neuropathological diagnoses.
      c AD “pure” is defined as AD without any of the other listed diagnoses. AD was defined as a clinically documented dementia with National Institute on Aging–Reagan Institute Working Group intermediate or high AD pathology.
      Table 3Decadal Changes in Aging and Disease From Banner Sun Health Research Institute Brain and Body Donation Program/Arizona Study of Aging and Neurodegenerative Disorders
      CERAD = Consortium to Establish a Registry for Alzheimer's Disease; F/M = female/male; MMSE = Mini-Mental Status Examination; NA = not available; NFT = neurofibrillary tangle; NP = neuritic plaque; UPDRS III = Unified Parkinson's Disease Rating Scale III.
      Decade (n)Mean control brain weight: F/MMean (SD) control MMSE score
      MMSE score available for 24 (70s), 110 (80s), 69 (90s), and 4 (100s).
      Mean (SD) control UPDRS III score
      UPDRS III score available for 17 (70s), 101 (80s), 71 (90s), and 4 (100s).
      Mean (SD) control CERAD NP scoreMean (SD) control Braak NFT stagePercentage with infarcts/mean total infarct volume (cm3)
      Any number of acute, subacute, or old infarcts were each counted as 1 diagnosis.
      Mean (SD) number of neuropathological diagnoses
      50s and 60s (112)1235
      Based on n≤3.
      /1326
      NANA0.2 (0.4)1.3 (0.7)19/0.5±2.42.4 (1.2)
      70s (311)1141/128228.5±1.33.9±2.50.9±1.12.3±1.239/7.8±412.8±1.3
      80s (595)1130/125728.0±2.07.8±7.21.3±1.23.0±1.049/10.7±623.4±1.4
      90s (259)1110/121627.6±1.911.2±6.61.7±1.23.6±0.757/12.9±553.9±1.6
      100s (13)1069/NA25.5±4.413.5±10.41.4±1.53.75±0.592/5.5±124.6±1.3
      a CERAD = Consortium to Establish a Registry for Alzheimer's Disease; F/M = female/male; MMSE = Mini-Mental Status Examination; NA = not available; NFT = neurofibrillary tangle; NP = neuritic plaque; UPDRS III = Unified Parkinson's Disease Rating Scale III.
      b MMSE score available for 24 (70s), 110 (80s), 69 (90s), and 4 (100s).
      c UPDRS III score available for 17 (70s), 101 (80s), 71 (90s), and 4 (100s).
      d Any number of acute, subacute, or old infarcts were each counted as 1 diagnosis.
      e Based on n≤3.

      Clinical Need

      A total of 5.4 million Americans and 44 million people worldwide have AD, and with the aging population, incidence and prevalence figures are expected to double by 2050.
      • Hebert L.E.
      • Weuve J.
      • Scherr P.A.
      • Evans D.A.
      Alzheimer's disease in the United States (2010-2050) estimated using the 2010 Census.
      In comparison to whites, the relative risk of dementia is twice that in African Americans and 1.5 times that in Hispanic Americans,
      • Gurland B.J.
      • Wilder D.E.
      • Lantigua R.
      • et al.
      Rates of dementia in three ethnoracial groups.
      mainly related to contributory factors such as cardiovascular disease and diabetes,
      • Glymour M.M.
      • Manly J.J.
      Lifecourse social conditions and racial and ethnic patterns of cognitive aging.
      as well as a higher prevalence of apolipoprotein E (APOE)ε4 allele in African Americans.
      • Graff-Radford N.R.
      • Besser L.M.
      • Crook J.E.
      • Kukull W.A.
      • Dickson D.W.
      Neuropathologic differences by race from the National Alzheimer's Coordinating Center.
      Incidence rates for the age groups (in years) 65 to 74, 75 to 84, and 85 and older are 2, 13, and 37 cases per 1000 people per year, respectively, with a lifetime risk for those aged 65 years and older of 9% for men and 17% for women.
      • Hebert L.E.
      • Weuve J.
      • Scherr P.A.
      • Evans D.A.
      Alzheimer's disease in the United States (2010-2050) estimated using the 2010 Census.
      To place recent challenges and developments in context, consider that the January 23, 2014, issue of the New England Journal of Medicine contained 2 back-to-back articles
      • Salloway S.
      • Sperling R.
      • Fox N.C.
      • et al.
      Bapineuzumab 301 and 302 Clinical Trial Investigators
      Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
      • Doody R.S.
      • Thomas R.G.
      • Farlow M.
      • et al.
      Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group
      Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.
      that disappointed a field that anticipated nothing less than a potential cure for AD on the basis of a wealth of evidence that immunotherapy against Aβ amyloid should halt disease progression, yet failed. For the past 25 years, the amyloid hypothesis, which, simply stated, posits the accumulation of Aβ amyloid in the brain as the inciting event that triggers neurodegeneration causing AD, has been the prevailing paradigm for AD pathogenesis, and has therefore guided the development of disease-modifying treatments.
      • Selkoe D.J.
      • Hardy J.
      The amyloid hypothesis of Alzheimer's disease at 25 years.
      Evidence supporting the amyloid hypothesis is strong. Amyloid accumulation begins early in the disease process, and dominantly inherited AD (DIAD) can be caused by highly pathogenic variants in any of the 3 genes, all of which affect cerebral amyloid production or aggregation including the amyloid precursor protein (APP) gene,
      • St George-Hyslop P.H.
      • Tanzi R.E.
      • Polinsky R.J.
      • et al.
      The genetic defect causing familial Alzheimer's disease maps on chromosome 21.
      presenilin 1 (PSEN1),
      • Schellenberg G.D.
      • Bird T.D.
      • Wijsman E.M.
      • et al.
      Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14.
      and presenilin 2 (PSEN2).
      • Levy-Lahad E.
      • Wasco W.
      • Poorkaj P.
      • et al.
      Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
      The PRESENs encode the active site of γ-secretase,
      • De Strooper B.
      • Saftig B.
      • Craessaerts K.
      • et al.
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      a key enzyme that leads to the production of Aβ fragments that are susceptible to aggregation and plaque formation. Furthermore, although most APP variants are pathogenic, one has been described that actually protects against AD by reducing β-secretase 1 cleavage and so Aβ production.
      • Jonsson T.
      • Atwal J.K.
      • Steinberg S.
      • et al.
      A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

      Scientific Background

      The normal roles of APP and amyloid in the brain are far from well understood but shed further light onto their potential role in AD pathogenesis. The APP gene is ancient. The ancestral gene is present in invertebrates, and the amyloidogenic sequence that predisposes to AD is found in all vertebrates.
      • Tharp W.G.
      • Sarkar I.N.
      Origins of amyloid-β.
      Knockouts of the APP gene and its homologues in mice are lethal.
      • von Kock C.S.
      • Zheng H.
      • Chen H.
      • et al.
      Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.
      In a zebra fish model, knockdown of APP results in a deformed fish that is restored by wild-type human APP but not the AD-related Swedish mutation APP.
      • Joshi P.
      • Liang J.O.
      • DiMonte K.
      • Sullivan J.
      • Pimplikar S.W.
      Amyloid precursor protein is required for convergent-extension movements during zebrafish development.
      In postnatal humans, neurogenesis involves approximately a third of hippocampal neurons (including most neurons in the dentate gyrus) at a rate of 700 new neurons in each hippocampus per day, corresponding to an annual turnover of 1.75% within the renewing fraction (0.004% of dentate gyrus neurons daily). By contrast, 51% of nonneuronal cells turn over annually at a rate of 3.5% per year. There is a decline with aging,
      • Spalding K.L.
      • Bergmann O.
      • Alkass K.
      • et al.
      Dynamics of hippocampal neurogenesis in adult humans.
      and the degree of ongoing neurogenesis in the adult human brain is still debated. (A recent estimate indicates that the rates of adult neurogenesis in the subventricular and subgranular zones approach that of the surrounding parenchyma and reflect microglia rather than neurons
      • Dennis C.V.
      • Suh L.S.
      • Rodriguez M.L.
      • Kril J.J.
      • Sutherland G.T.
      Human adult neurogenesis across the ages: an immunohistochemical study.
      ).
      In the nonamyloidogenic (normal aging) pathway, APP is cleaved mostly within the plasma membrane by α-secretase within the Aβ region (destroying the Aβ sequence) releasing a soluble fragment, sAPPα (or Aβ1-40), to the extracellular space. α-Secretase includes members of the ADAM (a disintegrin and metalloproteinase) family, ADAM10 and ADAM17. In the brain, sAPPα levels are particularly high in the subventricular zone, 1 of 2 areas of neurogenesis, and sAPPα is an essential proliferation factor for neural and nonneural adult stem cells.
      • Demars M.P.
      • Batholomew A.
      • Strakova Z.
      • Lazarov O.
      Soluble amyloid precursor protein: a novel proliferation factor of adult progenitor cells of ectodermal and mesodermal origin.
      In the amyloidogenic pathway that leads to AD, APP is first cleaved instead by β-secretase 1, releasing sAPPβ to the extracellular space. sAPPβ drives stem cells toward neural differentiation.
      • Freude K.K.
      • Penjwini M.
      • Davis J.L.
      • LaFerla F.M.
      • Blurton-Jones M.
      Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells.
      sAPPα and sAPPβ are normally produced in a 9:1 ratio and together stimulate neural stem cell proliferation and differentiation.
      • Pimplikar S.W.
      • Ghosal K.
      Amyloid precursor protein: more than just neurodegeneration.
      The remaining membrane-bound C terminal APP stub (C99) is subsequently cleaved by γ-secretase, releasing the insoluble Aβ1-42 peptide (and the APP intracellular domain) (Figure 2). Synaptic activity results in the release of Aβ1-42 peptide into the extracellular space, driving aggregation.
      • Cirrito J.R.
      • Yamada K.A.
      • Finn M.B.
      • et al.
      Synaptic activity regulates interstitial fluid amyloid-β levels in vivo.
      Insoluble Aβ1-42 aggregates into plaques and is thought to trigger tau hyperphosphorylation, although currently it is unknown how that occurs. The result, however, leads to the loss of cytoskeletal structure, dendritic spines, axonal degeneration, synaptic connectivity, and neuronal death.
      Figure thumbnail gr2
      Figure 2Metabolic pathways of amyloid precursor protein illustrating the nonamyloidogenic cleavage by α-secretase and the amyloidogenic cleavage by β-secretase 1 that results in the insoluble Aβ fragment. CTF = carboxyl terminal fragment; sAPP = soluble amyloid precursor protein.
      More recently it has been shown that Aβ amyloid may have antimicrobial properties. In animal models, Aβ oligomers bind to microbial cell walls, inhibit their adhesion to host cells, and mediate agglutination and eventual entrapment of microbes. Aβ deposition is accelerated and colocalized with invading bacteria, suggesting that Aβ deposition in AD may reflect dysregulation of the brain's innate immune system responding to microbial or sterile inflammatory stimuli.
      • Kumar D.K.
      • Choi S.H.
      • Washicosky K.J.
      • et al.
      Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease.
      Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is a microglial surface receptor that has also been linked to AD susceptibility. TREM2 deficiency enhances Aβ accumulation, as dysfunctional microglia fail to cluster around Aβ plaques and become apoptotic.
      • Wang Y.
      • Cella M.
      • Mallinson K.
      • et al.
      TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model.
      Together, these findings raise the possibility of a role for innate immune dysregulation in AD pathogenesis.
      Tau is a microtubule stabilizer that is dynamically phosphorylated and dephosphorylated to allow it to dissociate from microtubules during cellular mitosis. In 2009, Clavaguera et al
      • Clavaguera F.
      • Bolmont T.
      • Crowther R.A.
      • et al.
      Transmission and spreading of tauopathy in transgenic mouse brain.
      found, in a transgenic mouse model, that hyperphosphorylated filamentous tau can spread from neuron to neuron in a prion-like fashion, taken up by neighboring neurons by bulk endocytosis. They
      • Clavaguera F.
      • Akatsu H.
      • Fraser G.
      • et al.
      Brain homogenates from human tauopathies induce tau inclusions in mouse brain.
      subsequently reported that human tau from the brains of patients with progressive supranuclear palsy and related tauopathies, when injected into the brains of transgenic mice, also spread in a prion-like fashion. It has since been shown that amyloid too may spread in a prion-like fashion in human brains,
      • Jaunmuktane Z.
      • Mead S.
      • Ellis M.
      • et al.
      Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.
      but there is currently no evidence of human-to-human transmission.
      • Edgren G.
      • Hjalgrim H.
      • Rostgaard K.
      • et al.
      Transmission of neurodegenerative disorders through blood transfusion: a cohort study.

      Challenges and Pitfalls

      Immunomodulatory strategies for AD were introduced by Schenk et al
      • Schenk D.
      • Barbour R.
      • Dunn W.
      • et al.
      Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
      in 1999 through the demonstration that active immunization of transgenic mice (containing the human APP mutation) with Aβ amyloid prevented the formation of amyloid plaques if immunized when young and reduced pathological burden if immunized when old (and pathology had already developed). This was considered a major discovery and development of human trials proceeded in an expedited fashion. The initial human active immunization trial (AN-1792) resulted in the unexpected occurrence of autoimmune meningoencephalitis with associated cerebral edema in 6% of participants bringing the trial to a halt.
      • Orgogozo J.M.
      • Gilman S.
      • Dartigues J.F.
      • et al.
      Subacute meningoencephalitis in a subset of patients with AD after AB42 immunization.
      Subsequent neuropathological examinations revealed evidence of patchy plaque removal (but equivocal effect on the overall Aβ load
      • Nicoll J.A.
      • Wilkinson D.
      • Holmes C.
      • Steart P.
      • Markham H.
      • Weller R.O.
      Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report.
      • Holmes C.
      • Boche D.
      • Wikinson D.
      • et al.
      Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomized, placebo-controlled phase 1 trial.
      • Patton R.L.
      • Kalback W.M.
      • Esh C.L.
      • et al.
      Amyloid-β peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis.
      ), generally supporting the concept of an immunomodulatory approach and leading ultimately to the launch of passive immunization strategies. Bapineuzumab
      • Salloway S.
      • Sperling R.
      • Fox N.C.
      • et al.
      Bapineuzumab 301 and 302 Clinical Trial Investigators
      Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
      and solanezumab
      • Doody R.S.
      • Thomas R.G.
      • Farlow M.
      • et al.
      Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group
      Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.
      are monoclonal antibodies directed against epitopes of Aβ amyloid. Passive immunization strategies with these agents were shown to engage their molecular targets with improvement in surrogate biomarkers, yet neither reduced the rate of cognitive or functional decline in symptomatic cohorts.
      • Salloway S.
      • Sperling R.
      • Fox N.C.
      • et al.
      Bapineuzumab 301 and 302 Clinical Trial Investigators
      Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
      • Doody R.S.
      • Thomas R.G.
      • Farlow M.
      • et al.
      Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group
      Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.
      A subsequent secondary analysis of those patients in the solanezumab trial with only mild stage AD appeared to show a 34% reduction in the rate of progression over 18 months,
      • Siemers E.R.
      • Sundell K.L.
      • Carlson C.
      • et al.
      Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer's disease patients.
      but recently reported results from a phase 3 trial in mild stage AD failed to achieve a similar outcome. The relative lack of efficacy of this highly strategic approach has caused intense reconsideration of current disease models, trial design, and diagnostic and therapeutic approaches.
      • Karran E.
      • Hardy J.
      A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease.
      Progress in light of these setbacks has led to a greater understanding of AD's extended preclinical phases; the development of imaging and biofluid biomarkers for earlier detection and tracking of disease progression, especially before the onset of symptoms; and the complex genomics of AD with the hope of identifying new therapeutic targets.
      The conclusion reached by many in reaction to the failed immunotherapy trials was that interventions were “too little too late,” but that success might yet be achieved if treatment was initiated earlier in the disease course. The earliest stages of AD are characterized by amyloid deposition and followed later in the disease course by tau pathology. By the time mild to moderate dementia stages are reached, amyloid levels have essentially plateaued and deficits are driven by the progressive tau pathology.
      • Hyman B.T.
      • Marzloff K.
      • Arriagada P.V.
      The lack of accumulation of senile plaques or amyloid burden in Alzheimer's disease suggests a dynamic balance between amyloid deposition and resolution.
      Intervention at the dementia stage therefore could well be too late if amyloid is no longer driving the disease process.
      • Hyman B.T.
      Amyloid-dependent and amyloid-independent stages of Alzheimer disease.
      Tau pathology is primarily intracellular and so would seem to be a less viable immunotherapy target, although passive immunization strategies in mouse models have shown encouraging effects in limiting AD spread.
      • Sankaranarayanan S.
      • Barten D.M.
      • Vana L.
      • et al.
      Passive immunization with phosphor-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models.
      Although cerebral amyloid levels build, patients remain largely asymptomatic. Designing a clinical trial for an asymptomatic cohort requires some understanding of the preclinical phase as well as surrogate disease biomarkers that can be tracked so as to assess potential therapeutic efficacy.

      Possible Solutions

      Evidence for a preclinical phase of AD, a time when AD pathology is building yet no symptoms are evident, originally came from autopsy studies of elderly patients who appeared clinically healthy yet harbored moderate degrees of AD pathology in their brains.
      • Dayan A.D.
      Quantitative histological studies on the aged human brain. I. Senile plaques and neurofibrillary tangles in “normal” patients.
      • Katzman R.
      • Terry R.
      • DeTeresa R.
      • et al.
      Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques.
      With the discovery that the APOEε4 allele is a prevalent and powerful genetic risk factor for AD,
      • Corder E.H.
      • Saunders A.M.
      • Strittmatter W.J.
      • et al.
      Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
      • Saunders A.M.
      • Strittmatter W.J.
      • Schmechel D.
      • et al.
      Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease.
      such preclinical pathology was found to correlate with APOEε4.
      • Kok E.
      • Haikonen S.
      • Luoto T.
      • et al.
      Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age.
      • Caselli R.J.
      • Walker D.
      • Sue L.
      • Sabbagh M.
      • Beach T.
      Amyloid load in nondemented brains correlates with APOE e4.
      Among APOEε4 carriers dying of unrelated causes in their 50s, approximately 40% harbor AD relevant pathology in the form of either amyloid plaques or medial temporal NFTs,
      • Kok E.
      • Haikonen S.
      • Luoto T.
      • et al.
      Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age.
      and autopsy studies of elderly APOEε4 carriers without dementia has shown that they harbor higher amyloid levels in cerebral parenchyma and vasculature than APOEε4 noncarriers.
      • Caselli R.J.
      • Walker D.
      • Sue L.
      • Sabbagh M.
      • Beach T.
      Amyloid load in nondemented brains correlates with APOE e4.
      Fluorodeoxyglucose (FDG)–PET studies
      • Reiman E.M.
      • Caselli R.J.
      • Yun L.S.
      • et al.
      Preclinical evidence of Alzheimer's disease in persons homozygous for the ε4 allele for apolipoprotein E.
      • Reiman E.M.
      • Caselli R.J.
      • Chen K.
      • Alexander G.E.
      • Bandy D.
      • Frost J.
      Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease.
      of asymptomatic APOEε4 carriers in their 50s reveal metabolic patterns resembling AD. Volumetric magnetic resonance imaging (MRI) studies
      • Reiman E.M.
      • Uecker A.
      • Caselli R.J.
      • et al.
      Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease.
      • den Heijer T.
      • Oudkerk M.
      • Launer L.J.
      • van Duijn C.M.
      • Hofman A.
      • Breteler M.M.
      Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes.
      report accelerated hippocampal atrophy in advance of MCI diagnosis, and longitudinal neuropsychological studies
      • Caselli R.J.
      • Dueck A.C.
      • Osborne D.
      • et al.
      Longitudinal modeling of age-related memory decline and the APOE ε4 effect.
      • Caselli R.J.
      • Locke D.E.
      • Dueck A.C.
      • et al.
      The neuropsychology of normal aging and preclinical Alzheimer's disease.
      report accelerated memory decline beginning in the mid to late 50s and early 60s, an estimated 10 to 15 years in advance of MCI symptoms (Figure 3). Evidence from the Nun study suggested that preclinical changes may exist even during young adulthood,
      • Snowdon D.A.
      • Kemper S.J.
      • Mortimer J.A.
      • Greiner L.H.
      • Wekstein D.R.
      • Markesbery W.R.
      Linguistic ability in early life and cognitive function and Alzheimer's disease in late life: findings from the Nun Study.
      supported by imaging,
      • Reiman E.M.
      • Chen K.W.
      • Alexander G.E.
      • et al.
      Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.
      and some neuropathological evidence as well.
      • Valla J.
      • Yaari R.
      • Wolf A.B.
      • et al.
      Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene.
      Possibly such early differences are developmental rather than early-stage AD, a possibility indirectly supported by subtle neuroanatomical differences found in APOEe4-positive infants.
      • Dean III, D.C.
      • Jerskey B.A.
      • Chen K.
      • et al.
      Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross sectional imaging study.
      Figure thumbnail gr3
      Figure 3Porcupine plots of longitudinal memory performance on the Auditory Verbal Learning Test (AVLT) long-term memory score in apolipoprotein E ε4 homozygotes (blue), heterozygotes (orange), and noncarriers (brown), illustrating APOEε4 gene dose-related preclinical decline in memory performance in ε4 carriers.
      With the advent of amyloid ligands suitable for PET, it has become possible to noninvasively exhibit that cerebral amyloid increases with age and is accelerated in a gene-dose fashion by APOEε4.
      • Reiman E.M.
      • Chen K.
      • Liu X.
      • et al.
      Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease.
      • Fleisher A.S.
      • Chen K.
      • Liu X.
      • et al.
      Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease.
      Such studies are now being incorporated into trial design to address another possible reason for previous therapeutic failures: up to a third of APOEε4 noncarriers with clinically diagnosed AD lack significant amounts of cerebral amyloid, thus implying that they lack the target for an immunotherapeutic agent.
      • Monsell S.E.
      • Kukull W.A.
      • Roher A.
      • et al.
      Characterizing apolipoprotein E ε4 carriers and noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia and minimal β-amyloid plaques.
      Recently published results of a phase 1 trial of aducanumab,
      • Sevigny J.
      • Chiao P.
      • Bussière T.
      • et al.
      The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.
      a human monocloncal antibody that selectively targets aggregated Aβ, in which all patients enrolled were required to have exhibited cerebral amyloid on PET scans reported the wisdom of this approach by achieving robust dose- and time-dependent amyloid clearing and even a hint of possible cognitive benefit.
      These preclinical data were synthesized into operational research criteria for preclinical AD in 2011 that defined the stages of asymptomatic cerebral amyloidosis followed by neurodegeneration and finally preclinical cognitive decline.
      • Sperling R.A.
      • Aisen P.S.
      • Beckett L.A.
      • et al.
      Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
      Further refinement of the preclinical AD concept came from Jack et al,
      • Jack Jr., C.R.
      • Knopman D.S.
      • Weigand S.D.
      • et al.
      An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease.
      who used a combination of amyloid and neurodegeneration biomarkers, specifically amyloid PET and volumetric MRI, respectively, to describe 4 possible stages for preclinical AD: stage 0 (amyloid negative, neurodegeneration negative), stage 1 (amyloid positive, neurodegeneration negative), stage 2 (amyloid positive, neurodegeneration positive), and suspected non-Alzheimer pathology (amyloid negative, neurodegeneration positive), the pathological basis of which is likely heterogeneous and largely composed of age-associated tauopathy and cerebrovascular and Lewy body pathology.
      • Nelson P.T.
      • Head E.
      • Schmitt F.A.
      • et al.
      Alzheimer's disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies.
      The Dominantly Inherited Alzheimer Network is a multicenter study pooling members from kindreds with differing genetic backgrounds that share a disease-causing autosomal dominant mutation. Individuals carrying one of the known DIAD mutations offer the advantage that the age window of expected symptomatic onset (within a kindred) is known, allowing investigators to time presymptomatic biomarker and cognitive change. The Dominantly Inherited Alzheimer Network has shown that biomarker changes follow a sequence with the earliest change being declining cerebrospinal fluid (CSF) Aβ amyloid levels occurring as much as 25 years in advance of predicted symptomatic onset, followed by increasing CSF tau, accelerated cortical atrophy on MRI, declining cerebral metabolic glucose rates on FDG-PET, falling memory scores, and finally falling mental status test scores 5 years before symptoms begin.
      • Bateman R.J.
      • Xiong C.
      • Benzinger T.L.
      • et al.
      Dominantly Inherited Alzheimer Network
      Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
      Analogous results were observed in a large Colombian kindred harboring a PSEN1 mutation.
      • Reiman E.M.
      • Quiroz Y.T.
      • Fleisher A.S.
      • et al.
      Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.
      Both cohorts have become the focus of secondary prevention trials using agents that target amyloid.

      Biomarkers

      Biomarkers reflect disease-specific pathology that may appear before the onset of clinically evident symptoms. Imaging and CSF biomarkers in particular have made possible the exposition of disease-specific pathology in real time, and although not currently recommended for most clinical purposes, they have revolutionized preclinical diagnosis, disease tracking, and clinical trial design (Figure 4).
      Figure thumbnail gr4
      Figure 4A 58-year-old woman with a 3-year history of symptoms of visual dysfunction diagnosed as the visual variant of Alzheimer disease (posterior cortical atrophy). A, Pittsburgh imaging compound B amyloid positron emission tomography (PET) scan illustrating diffuse increased tracer retention throughout the cortex. B, 18F-AV-1451 tau-PET scan illustrating marked tracer retention in the posterior cortical regions. C, Statistical surface reconstruction of fluorodeoxyglucose (FDG)–PET illustrating asymmetric posterior parietal hypometabolism.

      Magnetic Resonance Imaging

      Medial temporal NFT pathology underlies the amnestic syndrome that characterizes AD.
      • Hyman B.T.
      • Van Hoesen G.W.
      • Damasio A.R.
      • Barnes C.L.
      Alzheimer's disease: cell-specific pathology isolates the hippocampal formation.
      Hippocampal volume declines early in patients with AD and progresses in parallel with dementia severity, an observation that led Jack et al
      • Jack Jr., C.R.
      • Petersen R.C.
      • O'Brien P.C.
      • Tangalos E.G.
      MR-based hippocampal volumetry in the diagnosis of Alzheimer's disease.
      to pioneer hippocampal volumetry as perhaps the first readily accessible AD biomarker. Since its initial descriptions, it has been included in the multicenter Alzheimer's Disease Neuroimaging Initiative,
      • Jack Jr., C.R.
      • Bernstein M.A.
      • Fox N.C.
      • et al.
      The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods.
      and commercially available adaptations have been derived that are now available for clinical application.
      • Yu P.
      • Sun J.
      • Wolz R.
      • et al.
      Coalition Against Major Diseases and the Alzheimer's Disease Neuroimaging Initiative
      Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size.
      More recent recommendations from Knopman et al
      • Knopman D.S.
      • Jack Jr., C.R.
      • Wiste H.J.
      • et al.
      Age and neurodegeneration imaging biomarkers in persons with Alzheimer disease dementia.
      are that cortical/gray matter thickness may be a more consistent, age-independent AD biomarker in contrast to hippocampal volumes that must account for age-specific norms and head size. Many other MRI-based techniques are used including ventricular volume, white matter tract integrity (diffusion tensor imaging), resting state functional MRI, and activation paradigm-based functional MRI that all share the general principle of progressive decline in cerebral anatomy and functional integrity reflecting AD progression.

      Molecular Imaging

      A little over a decade ago, Klunk et al
      • Klunk W.E.
      • Engler H.
      • Nordberg A.
      • et al.
      Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.
      described the first human trial of an amyloid ligand adapted for PET termed Pittsburgh compound B that imaged a key molecular component of AD in living patients, Aβ amyloid. Its short half-life limited its general accessibility and spurred the development of amyloid ligands with longer half-lives that make them more accessible to medical centers lacking the ability to generate radiopharmaceuticals. All have been validated for the detection of moderate or frequent neuritic plaques by large antemortem-postmortem correlation studies.
      • Wong D.F.
      • Rosenberg P.B.
      • Zhou Y.
      • et al.
      In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir F18).
      • Vandenberghe R.
      • Van Laere K.
      • Ivanoiu A.
      • et al.
      18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.
      • Clark C.M.
      • Pontecorvo M.J.
      • Beach T.G.
      • et al.
      AV-45-A16 Study Group
      Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study.
      • Curtis C.
      • Gamez J.E.
      • Singh U.
      • et al.
      Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density.
      • Sabri O.
      • Sabbagh M.N.
      • Seibyl J.
      • et al.
      Florbetaben Phase 3 Study Group
      Florbetaben PET imaging to detect amyloid β plaques in Alzheimer's disease: phase 3 study.
      • Beach T.G.
      • Schneider J.A.
      • Sue L.I.
      • et al.
      Theoretical impact of florbetapir (18F) amyloid imaging on diagnosis of Alzheimer dementia and detection of preclinical cortical amyloid.
      Clinical interpretations of amyloid scans are dichotomized into positive or negative depending on the relative cerebral amyloid burden compared with the cerebellum (an area typically spared by AD), but amyloid accumulation is detectable preclinically.
      • Reiman E.M.
      • Chen K.
      • Liu X.
      • et al.
      Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease.
      Correlations between cerebral amyloid levels or its topographical distribution and cognitive deficits have been weak.
      • Nelson P.T.
      • Alafuzoff I.
      • Bigio E.H.
      • et al.
      Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.
      More recently, tau PET has entered into research applications
      • Johnson K.A.
      • Schultz A.
      • Betensky R.A.
      • et al.
      Tau positron emission tomographic imaging in aging and early Alzheimer disease.
      and topographical patterns of ligand distribution correlate well with clinical deficits.
      • Ossenkoppele R.
      • Schonhaut D.R.
      • Schöll M.
      • et al.
      Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease.
      Taken together, amyloid and tau imaging essentially recapitulate in living patients the major neuropathology of AD.

      Metabolic Imaging

      Fluorodeoxyglucose-PET typically reveals reduced cerebral metabolic glucose rates in parietal, lateral temporal, and posterior cingulate cortices in patients with AD. Analyzing FDG-PET images from 146 patients with mild to moderate dementia who were subsequently followed for at least 2 years and 139 patients who had postmortem neuropathological assessments an average of 3 years later, FDG-PET readings were associated with approximately 93% sensitivity and 75% specificity in predicting subsequent clinical decline and the neuropathological diagnosis of AD.
      • Hoffman J.M.
      • Welsh-Bohmer K.A.
      • Hanson M.
      • et al.
      FDG-PET imaging in patients with pathologically verified dementia.
      On the basis of these and other findings, the US Centers for Medicare & Medicaid Services determined that FDG-PET is reasonable and necessary in patients with documented cognitive decline and a recently established diagnosis of dementia who meet clinical criteria for both AD and frontotemporal dementia, who have been evaluated for specific alternate neurodegenerative diseases or causative factors, and for whom the cause of the clinical symptoms remains uncertain (Decision Memo CAG-00088R, September 15, 2004).

      Cerebrospinal Fluid

      With disease progression, soluble Aβ amyloid aggregates into insoluble amyloid plaques, raising brain amyloid levels while reducing soluble CSF levels. As neurons die, total and phosphorylated tau is released into the CSF, raising tau levels. Cerebrospinal fluid total tau, phosphotau, and Aβ reliably distinguish patients with AD from controls.
      • Olsson B.
      • Lautner R.
      • Andreasson U.
      • et al.
      CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.
      Serial sampling of CSF within individuals has shown that CSF Aβ levels fluctuate over the day in a sinusoidal fashion. Average maximum values are 200% those of minimum values.
      • Bateman R.J.
      • Wen G.
      • Morris J.C.
      • Holtzman D.M.
      Fluctuations of CSF amyloid-β levels: implications for a diagnostic and therapeutic biomarker.
      Differences between diagnostic laboratories have also resulted in high variability in CSF biomarker levels, highlighting the need for standardization.
      • Mattsson N.
      • Andreasson U.
      • Persson S.
      • et al.
      The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
      Plasma levels of Aβ have been less reliable in distinguishing patients and controls, possibly owing to peripheral production of Aβ. Plasma levels of total tau distinguish the groups better, but significant interstudy variability makes this unreliable presently as a diagnostic test.
      • Olsson B.
      • Lautner R.
      • Andreasson U.
      • et al.
      CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.

      Genomics

      Genes can inform disease susceptibility, and in symptomatic patients, they confirm the specific genetic basis for a familial disease. Freer et al
      • Freer R.
      • Sormanni P.
      • Vecchi G.
      • Ciryam P.
      • Dobson C.M.
      • Vendruscolo M.
      A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease.
      recently reported that genomics can inform tissue vulnerability as well. They reported genomic profiles of brain regions related to Aβ and tau aggregation in a composite vulnerability score and found that brain regions with higher scores (greater vulnerability) closely matched Braak NFT stage.

      Mendelian Forms

      Dominantly inherited AD can be caused by rare autosomal dominant variants in the APP,
      • St George-Hyslop P.H.
      • Tanzi R.E.
      • Polinsky R.J.
      • et al.
      The genetic defect causing familial Alzheimer's disease maps on chromosome 21.
      PSEN1,
      • Schellenberg G.D.
      • Bird T.D.
      • Wijsman E.M.
      • et al.
      Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14.
      and PSEN2
      • Levy-Lahad E.
      • Wasco W.
      • Poorkaj P.
      • et al.
      Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
      genes, which together account for approximately 5% to 10% of young-onset AD. Of the 39 APP mutations reported to date in 93 families, all shift APP proteolysis toward Aβ1-42 production, resulting in greater amyloid aggregation.
      • Gatz M.
      • Reynolds C.A.
      • Fratiglioni L.
      • et al.
      Role of genes and environments for explaining Alzheimer disease.
      Patients with Down syndrome (trisomy 21) have an extra copy of the APP gene resulting in greater Aβ production and consequently fibrillar amyloid deposition.
      • Van Cauwenberghe C.
      • Van Broeckhoven C.
      • Sleegers K.
      The genetic landscape of Alzheimer disease: clinical implications and perspectives.
      If a patient with Down syndrome lives beyond the age of 40 years, there will be neuropathological evidence of AD at autopsy. Progressive dementia increases with age and peaks at approximately 40% to 75% over the age of 60. Analysis of the amyloid plaques has revealed that trisomy 21 predisposes to larger plaques, presumably reflecting increased production of Aβ amyloid.
      • Head E.
      • Lott I.T.
      Down syndrome and β-amyloid deposition.
      The PRESENs encode the active site of γ-secretase,
      • De Strooper B.
      • Saftig B.
      • Craessaerts K.
      • et al.
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      leading to the production of insoluble Aβ amyloid that is susceptible to aggregation and plaque formation. PSEN1 is the most prevalent of the autosomal dominant mutations, and PSEN2 mutations are the least prevalent. In PSEN1 DIAD, mutant γ-secretase results in longer aggregation-susceptible peptides.
      • Szaruga M.
      • Veugelen S.
      • Benurwar M.
      • et al.
      Qualitative changes in human γ-secretase underlie familial Alzheimer's disease.

      Apolipoprotein E

      The APOEε4 allele located on chromosome 19 accounts for more cases of AD than any other. It is associated with late-onset familial and “sporadic” AD affecting both overall disease risk and age of onset with a generally deleterious gene-dose effect of ε4 and protective effect of ε2.
      • Corder E.H.
      • Saunders A.M.
      • Strittmatter W.J.
      • et al.
      Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
      • Saunders A.M.
      • Strittmatter W.J.
      • Schmechel D.
      • et al.
      Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease.
      Prevalence varies worldwide from approximately 5% to 10% in Mediterranean and Asian regions to approximately 30% in parts of northern Europe (and ∼23% in North America).
      • Gerdes L.U.
      • Klausen I.C.
      • Sihm I.
      • Faergeman O.
      Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world.
      • Corbo R.M.
      • Scacchi R.
      Apolipoprotein E (APOE) allele distribution in the world: is APOE*4 a ‘thrifty’ allele?.
      Overall, AD risk is increased 3- to 4-fold in APOEε4 heterozygotes and 14-fold in APOEε4 homozygotes, with some variance depending on age, sex, and race.
      • Farrer L.A.
      • Cupples A.
      • Haines J.L.
      • et al.
      Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease.
      Whether there is a single key effect of APOE is unclear, but both amyloid (eg, enhanced aggregation and reduced clearance) and nonamyloid (eg, neurotoxic carboxyl fragments and enhanced tau phosphorylation) effects have been described.
      • Huang Y.
      • Mahley R.W.
      Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases.
      APOE does not follow typical Mendelian patterns of disease causation, but has been proposed to represent a low penetrant autosomal semidominant form on the basis of absolute disease risk estimates.
      • Genin E.
      • Hannequin D.
      • Wallon D.
      • et al.
      APOE and Alzheimer disease: a major gene with semi-dominant inheritance.
      An additional controversy is the potential contribution of the gene for translocase of the outer mitochondrial membrane (TOMM40) to AD risk. TOMM40 is adjacent to APOE on chromosome 17 and has been proposed by Roses et al
      • Roses A.D.
      • Lutz M.W.
      • Amrine-Madsen H.
      • et al.
      A TOMM40 variable length polymorphism predicts the age of late-onset Alzheimer's disease.
      to contribute to AD risk and possibly may account for some of the risk attributed to APOE itself.

      Non-Mendelian Forms

      For expansion of gene symbols in this section, see www.genenames.org. With the advent of large-scale genome-wide association studies, the number of genetic associations with AD risk has accelerated. Unlike Mendelian inheritance, or even APOE, the effect of each such variant is low. If a single copy of the APOEε4 allele increases AD risk by 300% to 400%, the effect of the “genome-wide association study” variants averages 10% to 25%, though they are higher for some.
      • Van Cauwenberghe C.
      • Van Broeckhoven C.
      • Sleegers K.
      The genetic landscape of Alzheimer disease: clinical implications and perspectives.
      Population surveys find that these variants occur in clinically unaffected individuals as well as those with AD. Some affected genes lend themselves to pathway categorization, including cholesterol metabolism (eg, APOE and ABCA7), intracellular vesicle trafficking (eg, SORL1 and ABCA7), synaptic/membrane function (eg, PICALM, BIN1, and EPHA1), innate immunity (eg, TREM2, CR1, and CD33), and of course Aβ metabolism (eg, APP, PSEN1, and PSEN2). It is an attractive concept but fraught with challenges. Not all genes lend themselves to simple functional categorization. A gene's known major function may be disturbed, yet the resulting disease may result from an unrelated and unknown effect. A single variant might be classified as benign owing to its prevalence in the healthy population, but a single gene can harbor multiple benign variants whose cumulative effect is unknown. Nonetheless, given the heritability of AD, it seems likely that some combination of variants explain disease susceptibility, age of onset, progression rate, and other phenotypic differences.

      Unresolved Clinical Questions: Diagnosis

      The overriding principle of diagnosis remains the exclusion of reversible mimics. To that end, a standard clinical evaluation includes a thorough history and physical examination, structural brain imaging, basic laboratory studies, and cognitive assessment that may be an office-based Brief Mental Status Examination or detailed neuropsychological assessment to establish the quality and severity of the cognitive syndrome. Spinal fluid examination, electroencephalography, and many other tests are possible, depending on individual circumstances. The main controversies in diagnosis are the utility of genetic and biomarker tests.
      Genetic counseling and testing (for APP, PSEN1, and PSEN2) should be offered to any patient or family with suspected DIAD. Typically the age of onset in these cases is below 60 years, and there is usually a strong family history of dementia on 1 parent's side. Identification of the causative mutation in the patient offers the chance to test first-degree relatives, and particularly children who may alter their life plans depending on their understanding of their own disease risk and expected age of onset. APOE testing is another story. The negative predictive value of APOEε4 is low, so its absence does not rule out AD, but the presence of an APOEε4 allele in a patient with dementia has high positive predictive value for a diagnosis of AD.
      • Nalbantoglu J.
      • Gilfix B.M.
      • Bertrand P.
      • et al.
      Predictive value of apolipoprotein E genotyping in Alzheimer's disease: results of an autopsy series and an analysis of several combined studies.
      APOE status does not affect the therapeutic alternatives for a patient with dementia or their family members in the way that DIAD genes do. Therefore, although APOE testing is possible, it is not currently recommended for routine clinical purposes.
      • Knopman D.S.
      • DeKosky S.T.
      • Cummings J.L.
      • et al.
      Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.
      Biomarker tests are not generally useful for identifying potentially reversible mimics, but they may enhance diagnostic certainty,
      • Beach T.G.
      • Schneider J.A.
      • Sue L.I.
      • et al.
      Theoretical impact of florbetapir (18F) amyloid imaging on diagnosis of Alzheimer dementia and detection of preclinical cortical amyloid.
      especially in patients with clinically atypical presentations, and there are a few scenarios in which they can be particularly helpful. For example, a young patient still working becomes disabled by memory loss and needs positive proof of AD, not simply tests that “rule out” other causes. Another example is that of a patient being considered for ventriculoperitoneal shunting for suspected normal pressure hydrocephalus. Alzheimer disease is the most frequent reason for therapeutic failure,
      • Pomeraniec I.J.
      • Bond A.E.
      • Lopes M.B.
      • Jane Sr., J.A.
      Concurrent Alzheimer's pathology in patients with clinical normal pressure hydrocephalus: correlation with high-volume lumbar puncture results, cortical brain biopsies, and outcomes.
      so a biomarker test indicating the presence of AD pathology may help avoid unnecessary surgery. Whether an older patient with clinically probable AD should also undergo biomarker testing to further enhance diagnostic confidence is less clear. Biomarker tests add substantially to the cost of the evaluation and have only a minor effect on therapeutic decisions.
      • Caselli R.J.
      • Woodruff B.K.
      The clinical impact of amyloid PET: is it worth the cost?.
      More controversial is the utility of presymptomatic testing. Many people express a desire for such testing even in the absence of an effective therapy. The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study has examined the effect of APOE genotype disclosure on healthy volunteers. The main message of the REVEAL study has been interpreted to be that disclosure can be done safely,
      • Green R.C.
      • Roberts J.S.
      • Cupples L.A.
      • et al.
      REVEAL Study Group
      Disclosure of APOE genotype for risk of Alzheimer's disease.
      but the careful screening and follow-up used by the REVEAL study is unlikely to accompany widespread clinical practice and does not now accompany direct-to-consumer marketing. In the absence of such a best practice, respondents to an Internet-based survey generally endorsed positively adaptive reactions (such as leading a healthier lifestyle and obtaining long-term care insurance) to “bad news,” but more than 18% endorsed spending all their money and approximately 11% endorsed consideration of suicide. Responses were similar for biomarker testing.
      • Caselli R.J.
      • Langbaum J.
      • Marchant G.E.
      • et al.
      Public perceptions of presymptomatic testing for Alzheimer disease.
      With the advent of presymptomatic trials as well as the commercial availability of genetic tests, such testing is happening, despite these caveats.

      Unresolved Clinical Questions: Therapy

      In the absence of disease-modifying therapy, the overriding principle of treatment is maximizing quality of life through symptom management. A systematic approach that considers prevention (or mitigation of symptom progression), intellectual impairment, behavioral problems, sleep disorders, commonly associated problems (eg, parkinsonism), abrupt or unexpected clinical decline, and lifestyle issues (particularly driving, weapons, advanced directives, and assisted living/extended care) are all part of Good Clinical Practice. Medications that are specifically identified as AD therapy are limited to the cholinesterase inhibitors
      • Rogers S.L.
      • Farlow M.R.
      • Doody R.S.
      • Mohs R.
      • Friedhoff L.T.
      Donepezil Study Group
      A 24-week, double-blind, placebo controlled trial of donepezil in patients with Alzheimer's disease.
      • Rösler M.
      • Anand R.
      • Cicin-Sain A.
      • et al.
      Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial.
      • Raskind M.A.
      • Peskind E.R.
      • Wessel T.
      • Yuan W.
      The Galantamine USA-1 Study Group
      Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension.
      and the N-methyl-d-aspartate receptor antagonist memantine.
      • Reisberg B.
      • Doody R.
      • Stöffler A.
      • Schmitt F.
      • Ferris S.
      • Möbius H.J.
      Memantine Study Group
      Memantine in moderate-to-severe Alzheimer's disease.
      All cholinesterase inhibitors are Food and Drug Administration (FDA) approved for the treatment of mild to moderate stages of dementia caused by AD, and memantine is FDA approved for the moderate to late stages of AD. An unresolved question is when to discontinue them, but the decision is typically individualized according to a family's wishes.
      With regard to AD prevention and the mitigation of symptom progression, there is no level 1 evidence for a neuroprotective effect for anything despite television advertisements claiming such and numerous news stories generally extrapolated from animal model or epidemiological findings. There is, in fact, level 1 evidence against protective effects for nonsteroidal anti-inflammatory drugs,
      • Aisen P.S.
      • Schafer K.A.
      • Grundman M.
      • et al.
      Alzheimer's Disease Cooperative Study
      Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.
      estrogen replacement therapy in women,
      • Shumaker S.A.
      • Legault C.
      • Rapp S.R.
      • et al.
      WHIMS Investigators
      Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.
      vitamin E,
      • Petersen R.C.
      • Thomas R.G.
      • Grundman M.
      • et al.
      Alzheimer's Disease Cooperative Study Group
      Vitamin E and donepezil for the treatment of mild cognitive impairment.
      vitamin B–mediated homocysteine lowering,
      • Aisen P.S.
      • Schneider L.S.
      • Sano M.
      • et al.
      Alzheimer Disease Cooperative Study
      High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial.
      Ginkgo biloba,
      • DeKosky S.T.
      • Williamson J.D.
      • Fitzpatrick A.L.
      • et al.
      Ginkgo Evaluation of Memory (GEM) Study Investigators
      Ginkgo biloba for prevention of dementia: a randomized controlled trial.
      statins,
      • Feldman H.H.
      • Doody R.S.
      • Kivipelto M.
      • et al.
      LEADe Investigators
      Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe.
      and other agents as well. Epidemiological evidence has supported a modestly protective effect for Mediterranean diet,
      • Scarmeas N.
      • Stern Y.
      • Tang M.X.
      • Mayeux R.
      • Luchsinger J.A.
      Mediterranean diet and risk for Alzheimer's disease.
      physical exercise,
      • Geda Y.E.
      • Roberts R.O.
      • Knopman D.S.
      • et al.
      Physical exercise, aging, and mild cognitive impairment: a population-based study.
      and recreational cognitive activity
      • Sajeev G.
      • Weuve J.
      • Jackson J.W.
      • et al.
      Late-life cognitive activity and dementia: a systematic review and bias analysis.
      against dementia in general, although it is less clear to what extent the effect is specific to AD or cerebrovascular contributions to dementia. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability
      • Ngandu T.
      • Lehtisalo J.
      • Solomon A.
      • et al.
      A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial.
      was a randomized trial of a multidomain intervention combining diet, exercise, cognitive training, and vascular risk monitoring, and it reported a modestly protective effect against cognitive decline in this elderly cohort. Similarly, higher educational background, intellectually oriented occupations, and related characteristics have been linked to the phenomenon of cognitive reserve in which greater intellectual attainment seems to mitigate the adverse effect of dementia pathology.
      • Stern Y.
      • Albert S.
      • Tang M.X.
      • Tsai W.Y.
      Rate of memory decline in AD is related to education and occupation: cognitive reserve?.
      However, cognitive reserve proxies have been shown to primarily affect cerebrovascular components of dementia,
      • Bennett D.A.
      • Arnold S.E.
      • Valenzuela M.J.
      • Brayne C.
      • Schneider J.A.
      Cognitive and social lifestyle: links to neuropathology and cognition in later life.
      and when a developmental proxy (sex-based memory advantage) is used instead, there does not appear to be any mitigation of preclinical memory decline.
      • Caselli R.J.
      • Dueck A.C.
      • Locke D.E.
      • Baxter L.C.
      • Woodruff B.K.
      • Geda Y.E.
      Sex-based memory advantages and cognitive aging: a challenge to the cognitive reserve construct?.
      Of the various behavioral problems experienced by patients with dementia, the most problematic are agitation and psychosis. There are no agents that have received FDA approval for the specific treatment of agitation or psychosis in patients with AD (although recently pimavanserin was approved for the treatment of Parkinson disease–related psychosis
      • Cummings J.
      • Isaacson S.
      • Mills R.
      • et al.
      Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial.
      ). In the absence of level 1 evidence, anecdotal experience and meta-analysis suggest that atypical antipsychotic drugs may be the preferred agents for AD-related agitation,
      • Schneider L.S.
      • Dagerman K.
      • Insel P.S.
      Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials.
      but because they lack FDA approval for such an indication, clinical judgment is essential. Common patterns of usage in a community-based setting
      • Schneider L.S.
      • Tariot P.N.
      • Dagerman K.S.
      • et al.
      CATIE-AD Study Group
      Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.
      as well as more aggressive regimens aimed at higher minimum doses
      • Kurlan R.
      • Cummings J.
      • Raman R.
      • Thal L.
      Alzheimer's Disease Cooperative Study Group
      Quetiapine for agitation or psychosis in patients with dementia and parkinsonism.
      often fail to achieve therapeutic benefit. Furthermore, the FDA has required a black box warning label on the use of atypical antipsychotic drugs in treating patients with dementia because of data suggesting an increased risk of mortality.

      US Food and Drug Administration. Safety alerts for human medical products. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150688.htm. Accessed March 16, 2017.

      The “typical” antipsychotic drugs such as haloperidol have a high likelihood of causing or exacerbating parkinsonism or tardive dyskinesia (if used chronically) and confer an even higher mortality risk as compared with the newer atypical neuroleptic drugs.
      • Wang P.S.
      • Schneeweiss S.
      • Avorn J.
      • et al.
      Risk of death in elderly users of conventional vs. atypical antipsychotic medications.
      Perhaps the greatest controversy, however, is one that has not yet materialized, but may be looming: balancing the cost of therapy with efficacy. Immunotherapy trials involving monoclonal antibodies have failed to halt AD progression, but with earlier intervention, agents targeting different epitopes, and other factors, it seems quite possible that one day such an agent will achieve statistical significance in its primary end point. If we may infer the potential cost of these agents from their counterparts in the oncological realm, they are going to be expensive, ranging in the tens of thousands of dollars annually, and quite possibly resulting in a national cost that exceeds the current total dementia care cost of more than $200 billion annually. If such an agent fails to halt disease progression but only slows it by 10% to 30%, would that justify the cost to society? Should patients with late-stage dementia receive such treatment, or should treatment be limited to those with mild-stage disease? Should taxes be raised to provide the needed supplemental dollars to entitlement programs that may not otherwise be funded to shoulder such a cost given the huge number of patients affected by AD? And if such treatment were preventive, should the 2% of the US population that is an APOEε4 homozygote receive treatment, and beginning at what age? What about ε4 heterozygotes? What about everyone with Down syndrome and the less common DIAD gene carriers?

      Conclusion

      The challenges raised by AD may be unlike any other disease. When it strikes younger people, it is undeniably a disease. When we find traces of it in the brains of nonagenarians without dementia, we confront its association with normal aging. Our ability to diagnose it is increasing in precision, and our therapies may be getting closer to disease modification, but at a cost. The greatest challenges ahead may lie not in the laboratory or the clinic but in our social conscience and government.

      Supplemental Online Material

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