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The Neuropathological Diagnosis of Alzheimer's Disease

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The Neuropathological Diagnosis of Alzheimer's Disease DeTure and Dickson Molecular Neurodegeneration (2019) 14:32 https://doi.org/10.1186/s13024-019-0333-5 REVIEW Open Access The neuropathological diagnosis of Alzheimer’s disease Michael A. DeTure and Dennis W. Dickson* Abstract Alzheimer’s disease is a progressive neurodegenerative disease most often associated with memory deficits and cognitive decline, although less common clinical presentations are increasingly recognized. The cardinal pathological features of the disease have been known for more than one hundred years, and today the presence of these amyloid plaques and neurofibrillary tangles are still required for a pathological diagnosis. Alzheimer’s disease is the most common cause of dementia globally. There remain no effective treatment options for the great majority of patients, and the primary causes of the disease are unknown except in a small number of familial cases driven by genetic mutations. Confounding efforts to develop effective diagnostic tools and disease-modifying therapies is the realization that Alzheimer’s disease is a mixed proteinopathy (amyloid and tau) frequently associated with other age-related processes such as cerebrovascular disease and Lewy body disease. Defining the relationships between and interdependence of various co-pathologies remains an active area of investigation. This review outlines etiologically-linked pathologic features of Alzheimer’s disease, as well as those that are inevitable findings of uncertain significance, such as granulovacuolar degeneration and Hirano bodies. Other disease processes that are frequent, but not inevitable, are also discussed, including pathologic processes that can clinically mimic Alzheimer’s disease. These include cerebrovascular disease, Lewy body disease, TDP-43 proteinopathies and argyrophilic grain disease. The purpose of this review is to provide an overview of Alzheimer’s disease pathology, its defining pathologic substrates and the related pathologies that can affect diagnosis and treatment. Keywords: Alzheimer’s disease, Neuropathology, Amyloid plaques, Neurofibrillary tangles Background capable of assessing amyloid and tau burden in living pa- Historical information tients are challenging this historic paradigm [4]. AD is Alois Alzheimer first described the neurodegenerative also characterized by a long asymptomatic preclinical disease that would bear his name more than 100 years phase, and cognitively normal individuals can also have ago, and today the cardinal features of amyloid plaques the disease [5]. Furthermore, AD is rarely found without and neurofibrillary tangles that he described are still re- other neurodegenerative co-pathologies as observed in quired for its pathological diagnosis [1]. Alzheimer’s dis- the Mayo Clinic Brain Bank data in Table 1.Itisso ease (AD) is a progressive neurodegenerative disease tightly associated with old age that there is speculation it most often characterized by initial memory impairment is a normal part of aging [6]. Currently, there are no dis- and cognitive decline that can ultimately affect behavior, ease modifying therapies for Alzheimer’s disease [7]. speech, visuospatial orientation and the motor system, and it is the most common form of dementia [2]. Variant syndromes with early focal atrophy do not always follow Epidemiology this traditional presentation, and pathological subtypes It is estimated that more than 47 million people in the of AD have been described [3]. Clinical AD dementia world are affected by dementia, and as of 2018 the cost of cannot be definitively diagnosed until post-mortem neu- these diseases was expected to surpass $1 trillion annually ropathologic evaluation, though research institutes [8]. AD is the most common form of dementia, account- ing for 60 to 80% of the cases, with less than half expected to be pure AD and the majority expected to be mixed de- * Correspondence: [email protected] Department of Neuroscience, The Mayo Clinic Florida, 4500 San Pablo Road, mentias [9]. The other most common causes of dementia Jacksonville, FL 32224, USA include vascular dementia, Lewy body dementia and © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. DeTure and Dickson Molecular Neurodegeneration (2019) 14:32 Page 2 of 18 Table 1 Comorbidities in 1153 Patients with Pathologic Diagnosis of AD. The majority of AD cases were observed to have pathologic comorbidities as observed in the Mayo Clinic Brain Bank 2007–2016. Plus sign (+) in the column on pathological diagnosis of AD indicates additional pathologies beyond the primary and secondary diagnoses listed. Bold indicates significance from the pure AD cases (Student t-Test, p < 0.01) Pathological Dx Cases (n) Age (yr) Brain (g) Braak Thal AD 243 76.5 ± 10.8 1077 ± 159 5.5 ± 0.7 4.7 ± 0.6 AD/LBD 175 76.0 ± 10.2 1053 ± 151 5.6 ± 0.6 4.8 ± 0.6 AD/LBD+ 206 81.8 ± 9.3 1025 ± 170 5.6 ± 0.6 4.8 ± 0.5 AD/Vas 113 84.5 ± 7.9 1070 ± 164 5.3 ± 0.8 4.6 ± 0.8 AD/Vas+ 77 86.0 ± 6.4 1043 ± 142 5.3 ± 0.7 4.8 ± 0.6 AD/CAA 42 76.1 ± 11.6 1089 ± 163 5.6 ± 0.6 4.6 ± 0.6 AD/CAA+ 110 80.1 ± 9.0 1086 ± 163 5.6 ± 0.6 4.7 ± 0.7 AD/HpScl 27 86.0 ± 6.9 1088 ± 158 5.4 ± 0.7 5.0 ± 0.0 AD/HpScl+ 51 87.8 ± 6.9 1012 ± 174 5.4 ± 0.7 4.8 ± 0.6 AD/Other 59 79.3 ± 10.9 1044 ± 164 5.4 ± 0.8 4.7 ± 0.7 AD/Other+ 50 81.9 ± 11.2 1019 ± 186 5.3 ± 0.8 4.5 ± 0.8 Parkinson’s disease with dementia, frontotemporal lobar 65 [14]. More common late onset AD (LOAD) is consid- degeneration and normal pressure hydrocephalus with ered sporadic, although genetic risk factors have been each of these accounting for between 5 and 10% of cases; identified, most notably apolipoprotein E gene (APOE) and of these, vascular dementia and Lewy body dementia [7]. Age, family history in a first degree relative, and are most often associated with mixed pathology, including APOE4 genotype confer the greatest risks of developing concurrent AD [9]. These debilitating and financially dev- AD [14]. Individuals carrying a single copy of the APOE4 astating diseases are expected to increase into the middle polymorphism have an odds ratio for AD of 3 compared of the century, and it is anticipated that greater than 131 to non-carriers. Those homozygous for APOE4 have an million individuals will be affected by 2050 as the popula- odds ratio of 12 [7]. Furthermore, APOE4 allele appears tion ages [8]. Aging is the strongest risk factor for AD, to confer risk for vascular dementia, Lewy body demen- with the incidence for all dementias doubling every 6.3 tia, Down’s syndrome and traumatic brain injury [15]. years from 3.9 per 1000 for ages 60–90 to 104.8 per 1000 Other risk factors for LOAD including TREM2, above age 90 [10]. Prevalence is estimated at 10% for indi- ADAM10 and PLD3 have been identified using genome viduals over 65 years and 40% for those over 80 years [2]. wide association studies to implicate nearly 30 genes The exploding personal and financial costs call for effect- that not only affect APP and tau directly but also modu- ive pre-clinical diagnosis and treatments to halt disease late cholesterol metabolism, endocytosis and immune re- progression before symptomatic onset. sponse, among those with known functions [16, 17]. Understanding the role of these and newly identified risk Etiology factors should provide insight into mechanisms that Dominantly inherited familial AD (FAD) can be caused drive Alzheimer’s pathogenesis. by mutations in amyloid precursor protein (APP), prese- nilin 1 (PSEN1)orPSEN2 genes. These rare familial Pathology of Alzheimer’s disease forms of AD account for less than 1% of the cases. FAD Macroscopic features can present as early as age 20, with the average age of The pathologic diagnosis of AD remains the gold stand- onset of 46.2 years [11]. Early onset Alzheimer’s disease ard for diagnosis. While certain features of AD can be (EOAD) is defined by those affected before age 65; and ascertained on macroscopic examination, no single fea- though they are slightly more common than FAD cases, ture or combination of features is specific, but certain they account for fewer than 5% of the pathologically di- features are highly suggestive of AD. The AD brain often agnosed AD cases. EOAD often has an atypical presenta- has at least moderate cortical atrophy that is most tion and an aggressive course [12]. Similarly, most marked in multimodal association cortices and limbic Down’s syndrome patients with a partial or full chromo- lobe structures. The frontal and temporal cortices often some 21 trisomy, which includes the region on chromo- have enlarged sulcal spaces with atrophy of the gyri, some 21 where APP resides [13], have Alzheimer type while primary motor and somatosensory cortices most pathology by age 40 with many developing clinical often appear unaffected [18]. There is increasing recog- symptoms after 50; the majority have dementia by age nition of atrophy in posterior cortical areas in AD, most DeTure and Dickson Molecular Neurodegeneration (2019) 14:32 Page 3 of 18 notable the precuneus and posterior cingulate gyrus, especially affecting frontal lobes, with volume loss driven in part by functional imaging studies [19, 20].
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