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Review
. 2019 Oct 3;179(2):312-339.
doi: 10.1016/j.cell.2019.09.001. Epub 2019 Sep 26.

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Justin M Long  1 , David M Holtzman  2
Affiliations
Review

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Justin M Long et al. Cell. .

Abstract

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.

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Conflict of interest statement

DECLARATIONS OF INTEREST: J.M.L. reports serving as sub-investigator on the Lilly TRAILBLAZER trial but receives no financial compensation. D.M.H. reports being a cofounder of C2N Diagnostics, LLC; being on the scientific advisory board of C2N Diagnostics, Denali, and Genentech; and being a consultant for AbbVie and Idorsia. D.M.H is an inventor on a submitted patent #PCT/US2013/049333 “Antibodies to tau” that is licensed by Washington University to C2N Diagnostics. This patent was subsequently licensed to AbbVie.D.M.H. is an inventor on patent number 8,591,894 “Humanized antibodies that sequester amyloid beta” that was licensed by Washington University to Eli Lilly. D.M.H. is an inventor on patent number 8,232,107 “Methods for measuring the metabolism of neurally derived biomolecules in vivo” that was licensed by Washington University to C2N Diagnostics, LLC.

Figures

Figure 1.
Figure 1.
Timing of major AD pathophysiological events in relation to clinical course. A protracted preclinical phase of disease is characterized by the early onset of amyloid deposition. This is detected by a reduction in CSF and plasma levels of Aβ42 or increased global signal on amyloid PET imaging. Concurrently, there are early neuroinflammatory changes (such as microglial activation). Microgliosis can be detected longitudinally via use of PK11195 PET imaging though better agents are needed. This is followed by the spread of neurofibrillary tangle (NFT) tau pathology from the medial temporal lobes into neocortex. Increased signal on tau PET imaging and increased CSF phospho-tau levels mark this change in patients. Synaptic dysfunction, synapse loss and neurodegeneration accumulates with pathologic spread of tau aggregates. Imaging analysis of hippocampal and cortical volumes allows for longitudinal tracking of neurodegenerative changes. Onset and progression of cognitive impairment correlates with accumulation of tau and hippocampal volume loss but not amyloid deposition. Onset and severity of clinical symptoms in AD can be staged by use of the Clinical Dementia Rating (CDR) scale, where a score of 0 indicates normal cognition and scores of 0.5, 1, 2 and 3 indicate questionable, mild, moderate and severe dementia, respectively.
Figure 2.
Figure 2.
Selected roles of Aβ and tau in AD pathophysiology. (A) Aβ is derived from APP via the proteolytic functions of BACE1 and γ-secretase. BACE1 and APP are co-localized to endosomes, which is the location of intracellular Aβ production. Aβ is secreted into the interstitial fluid via a pathway that is enhanced in the setting of neuronal activity. Following secretion, Aβ aggregates into higher order oligomers and fibrils that have numerous effects on cellular function, including impaired synaptic activity and synapse loss, impaired cerebral capillary blood flow and direct promotion of tau pathology by stimulating tau hyperphosphorylation as well as other pathways. (B) Pathological tau aggregation (blue shading) in the medial temporal lobes occurs with aging and is not always associated with cognitive impairment (primary age-related tauopathy). The earliest accumulation of Aβ deposition (red shading) is in the precuneus and posterior cingulate. Longitudinal CSF and imaging biomarker studies suggest that global amyloid accumulation is required for the pathologic spread of tau from the medial temporal lobes to other cortical regions in AD. In this way, AD may represent an amyloid-facilitated tauopathy. (C) Pathologic spread of tau aggregates in AD usually occurs in a stereotyped fashion along neuroanatomically connected networks. Misfolded tau likely acts in a prion-like manner to promote templated misfolding of native monomers, leading to seeding of new pathological tau aggregates. Tau pathology can subsequently spread trans-synaptically to distant neurons, representing a molecular correlate for pathologic tau spreading noted in human AD brain.
Figure 3.
Figure 3.
Postulated roles of ApoE in AD pathophysiology. (A) ApoE enhances seeding and fibrillization of Aβ leading to enhanced amyloid deposition. ApoE (especially E4) impedes Aβ clearance from brain parenchyma by competitively binding to Aβ receptors on glial cells. (B) ApoE (especially E4) enhances tau pathogenicity. Presence of ApoE leads to exacerbation of tau-mediated neurodegeneration, increased microgliosis and enhanced neuroinflammatory cytokine release from glial cells. (C) ApoE regulates the microglial response to amyloid plaques. In the presence of ApoE, phagocytically-active disease-associated microglia (DAM) and microglial neurodegenerative phenotype (MGnD) are located near plaques. Tight microglial clustering results in plaque compaction. In the absence of ApoE, periplaque microglia are sparser and amyloid plaques become larger and less compact. Neuritic dystrophy is significantly increased. On the other hand, if apoE levels are lower but not absent, neuritic dystrophy is lower. (D) ApoE may contribute to AD pathophysiology via direct effects on neurons and neuronal network activity. In cell culture, exogenously supplied ApoE4 inhibits neurite outgrowth relative to ApoE3. ApoE4 also contributes to dysfunctional neuronal network activity as evidenced by reduced hilar GABAergic interneurons, increase hippocampal network activity and propensity for seizures in ApoE4 target replacement mice. (E) ApoE4 may directly impair blood-brain barrier (BBB) function in AD by failing to efficiently bind to LRP1 expressed on cells such as pericytes. There is evidence that this leads to increased activation of cyclophilin A signaling pathways and ultimate breakdown of BBB, resulting in passage of serum proteins (such as fibrin) into the brain parenchyma and eventual neuronal death.
Figure 4.
Figure 4.
Selected roles of the innate immune system in AD pathophysiology. (A) Transcriptomic analyses of microglia isolated from mice with amyloid pathology have demonstrated a unique microglial subpopulation (DAM/MGnD) only found in diseased animals and defined by reduced expression of homeostatic genes and increased expression of genes involved in phagocytosis and microglial activation. Expression of ApoE and TREM2 is necessary for the development of this disease-specific subpopulation. (B) Microglial activation and phagocytosis have disparate effects based on the prominent pathology studied. TREM2 KO results in a microglial phenotype that is less activated and less phagocytic. In mouse models of amyloid deposition, TREM2 KO leads to reduced peri-plaque microglial clustering, increased Aβ seeding and deposition, and increased dystrophic neurites with enhanced plaque-associated tau pathology. Conversely, in PS19 tauopathy mice, TREM2 KO leads to reduced neurodegeneration and microgliosis. Similarly, near total microglial depletion in PS19 mice expressing ApoE4 leads to significant reduction in neurodegeneration and microgliosis. (C) Aβ phagocytosis leads to increased microglial activation. Lysosomal damage by Aβ can lead to activation of NLRP3 inflammasome, resulting in IL-1β secretion. Extracellular ASC specks released from activated microglial can then further cross-seed fibrillization of Aβ into fibrils.
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