Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies. Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies. Dementia describes an intra-individual pattern of decline in memory and thinking impairing at least two domains of cognition (McKhann et al., 2011McKhann G.M. Knopman D.S. Chertkow H. Hyman B.T. Jack Jr., C.R. Kawas C.H. Klunk W.E. Koroshetz W.J. Manly J.J. Mayeux R. et al.The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement. 2011; 7: 263-269Google Scholar). Alzheimer disease (AD) is the most common cause of dementia. The majority of cases occur after age 65, constituting late-onset AD (LOAD), while cases occurring earlier than age 65 are considerably rarer, constituting less than 5% of all cases and are termed early-onset AD (EOAD) (Alzheimer’s Association, 2019Alzheimer’s Association2019 Alzheimer’s disease facts and figures.Alzheimers Dement. 2019; 15: 321-387Google Scholar). Approximately 1%–2% of AD is inherited in an autosomal dominant fashion (ADAD) and can present with very early age of onset and a more rapid rate of progression, and it is sometimes associated with other neurologic symptoms seen less frequently in sporadic AD (Bateman et al., 2012Bateman R.J. Xiong C. Benzinger T.L.S. Fagan A.M. Goate A. Fox N.C. Marcus D.S. Cairns N.J. Xie X. Blazey T.M. et al.Dominantly Inherited Alzheimer NetworkClinical and biomarker changes in dominantly inherited Alzheimer’s disease.N. Engl. J. Med. 2012; 367: 795-804Google Scholar). Clinical syndromes consistent with AD are defined by classical symptoms and cognitive profiles. However, AD as a distinct entity is now defined biologically by the presence of a specific neuropathological profile (Jack et al., 2018aJack Jr., C.R. Bennett D.A. Blennow K. Carrillo M.C. Dunn B. Haeberlein S.B. Holtzman D.M. Jagust W. Jessen F. Karlawish J. et al.ContributorsNIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease.Alzheimers Dement. 2018; 14: 535-562Google Scholar): extracellular deposition of β-amyloid (Aβ) in the form of diffuse and neuritic plaques and the presence of intraneuronal neurofibrillary tangles (NFTs) and neuropil threads within dystrophic neurites consisting of aggregated hyperphosphorylated tau protein (Duyckaerts et al., 2009Duyckaerts C. Delatour B. Potier M.-C. Classification and basic pathology of Alzheimer disease.Acta Neuropathol. 2009; 118: 5-36Google Scholar). Dementia due to AD is associated with the onset of significant and progressive disability throughout the disease course, with death an inevitable outcome generally occurring within 5–12 years of symptom onset (Vermunt et al., 2019Vermunt L. Sikkes S.A.M. van den Hout A. Handels R. Bos I. van der Flier W.M. Kern S. Ousset P.-J. Maruff P. Skoog I. et al.Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype.Alzheimers Dement. 2019; 15: 888-898Google Scholar). The burden on caregivers and the public health sector is enormous (Alzheimer’s Association, 2019Alzheimer’s Association2019 Alzheimer’s disease facts and figures.Alzheimers Dement. 2019; 15: 321-387Google Scholar). There is a dire need for disease-modifying therapies that may prevent or slow the rate of disease progression, but unfortunately none are currently available. The history of pharmaceutical development for AD has been plagued by a seemingly endless parade of mid-to-late-stage clinical trial failures. Nonetheless, significant strides have been made in recent years in clarifying key aspects of the underlying pathobiology of AD. Though the therapeutic pipeline has faced struggles and some pharmaceutical companies have chosen to abandon their AD drug development divisions, novel therapeutic strategies are still being actively developed and tested. This Review discusses recent advances in our understanding of the pathobiology of AD and summarizes treatment strategies as well as the challenges and opportunities on the path to development of truly disease-modifying treatments. Symptomatic AD follows an insidious and progressive course. Typical amnestic cases are characterized by early impairment in learning and memory, followed by later impairments in complex attention, executive function, language, visuospatial function, praxis, gnosis, and behavior and/or social comportment (McKhann et al., 2011McKhann G.M. Knopman D.S. Chertkow H. Hyman B.T. Jack Jr., C.R. Kawas C.H. Klunk W.E. Koroshetz W.J. Manly J.J. Mayeux R. et al.The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement. 2011; 7: 263-269Google Scholar). Symptomatic AD may also present as atypical clinical syndromes in which there is early impairment in non-memory domains. Posterior cortical atrophy presents with early deficits in visuospatial function, praxis, and gnosis (Tang-Wai et al., 2004Tang-Wai D.F. Graff-Radford N.R. Boeve B.F. Dickson D.W. Parisi J.E. Crook R. Caselli R.J. Knopman D.S. Petersen R.C. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy.Neurology. 2004; 63: 1168-1174Google Scholar). Logopenic variant of primary progressive aphasia is characterized by dysfluent language with prominent word-finding impairment and severe impairment in repetition (Gorno-Tempini et al., 2008Gorno-Tempini M.L. Brambati S.M. Ginex V. Ogar J. 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Also, a rare APP mutation A673T that reduces risk of developing AD causes decreased Aβ production (Jonsson et al., 2012Jonsson T. Atwal J.K. Steinberg S. Snaedal J. Jonsson P.V. Bjornsson S. Stefansson H. Sulem P. Gudbjartsson D. Maloney J. et al.A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline.Nature. 2012; 488: 96-99Google Scholar, Martiskainen et al., 2017Martiskainen H. Herukka S.-K. Stančáková A. Paananen J. Soininen H. Kuusisto J. Laakso M. Hiltunen M. Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers.Ann. Neurol. 2017; 82: 128-132Google Scholar). In addition, the strongest genetic risk factor for LOAD, apolipoprotein E (APOE), in large part appears to increase risk via influencing Aβ seeding and clearance (Bales et al., 1997Bales K.R. Verina T. Dodel R.C. Du Y. Altstiel L. Bender M. Hyslop P. Johnstone E.M. Little S.P. 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For example, there is minimal correlation between phases of amyloid deposition and degree of cognitive decline (Nelson et al., 2012Nelson P.T. Alafuzoff I. Bigio E.H. Bouras C. Braak H. Cairns N.J. Castellani R.J. Crain B.J. Davies P. Del Tredici K. et al.Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.J. Neuropathol. Exp. Neurol. 2012; 71: 362-381Google Scholar). Also, patterns of regional cerebral amyloid deposition do not correlate with patterns of regional cerebral hypometabolism on functional neuroimaging (Altmann et al., 2015Altmann A. Ng B. Landau S.M. Jagust W.J. Greicius M.D. Alzheimer’s Disease Neuroimaging InitiativeRegional brain hypometabolism is unrelated to regional amyloid plaque burden.Brain. 2015; 138: 3734-3746Google Scholar, Edison et al., 2007Edison P. Archer H.A. Hinz R. Hammers A. Pavese N. Tai Y.F. Hotton G. Cutler D. Fox N. Kennedy A. et al.Amyloid, hypometabolism