Acta NeuropathologicaPathology and Mechanisms of Neurological Disease
© Springer-Verlag Berlin Heidelberg 2014

Primary age-related tauopathy (PART): a common pathology associated with human aging

John F. Crary , John Q. Trojanowski2, Julie A. Schneider3, Jose F. Abisambra4, Erin L. Abner5, Irina Alafuzoff6, Steven E. Arnold7, Johannes Attems8, Thomas G. Beach9, Eileen H. Bigio10, Nigel J. Cairns11, Dennis W. Dickson12, Marla Gearing13, Lea T. Grinberg14, 15, Patrick R. Hof16, Bradley T. Hyman17, Kurt Jellinger18, Gregory A. Jicha19, Gabor G. Kovacs20, David S. Knopman21, Julia Kofler22, Walter A. Kukull23, Ian R. Mackenzie24, Eliezer Masliah25, Ann McKee26, Thomas J. Montine27, Melissa E. Murray12, Janna H. Neltner28, Ismael Santa-Maria1, William W. Seeley29, Alberto Serrano-Pozo30, Michael L. Shelanski1, Thor Stein31, Masaki Takao32, Dietmar R. Thal33, Jonathan B. Toledo2, Juan C. Troncoso34, Jean Paul Vonsattel1, Charles L. White3rd35, Thomas Wisniewski36, Randall L. Woltjer37, Masahito Yamada38 and Peter T. Nelson39  
Department of Pathology and Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA
Department of Pathology, Division of Neuropathology, University of Pennsylvania, Philadelphia, PA 19104, USA
Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Department of Public Health and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden
Departments of Psychiatry and Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE45PL, UK
Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA
Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Department of Pathology and Laboratory Medicine (Neuropathology), Emory University School of Medicine, Atlanta, GA 30322, USA
Departments of Neurology and Pathology, UC, San Francisco, CA 94110, USA
Department of Pathology, University of Sao Paulo, Sao Paulo, Brazil
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129, USA
Institute of Clinical Neurobiology, 1070 Vienna, Austria
Department of Neurology and the Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
Institute of Neurology, Medical University Vienna, 1090 Vienna, Austria
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Department of Epidemiology, University of Washington, Seattle, WA 98104, USA
Department of Pathology, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada
Departments of Neurosciences and Pathology, University of California, San Diego, La Jolla, CA 92093, USA
Department of Pathology (Neuropathology), Boston University, Boston, MA 02118, USA
Department of Pathology, University of Washington, Seattle, WA 98104, USA
Department of Pathology, University of Kentucky, Lexington, KY 40536, USA
Departments of Neurology and Pathology, University of California, San Francisco, CA 94143, USA
Department of Neurology, University of Iowa Hospitals and Clinics, Iowa city, IA 52242, USA
Department of Pathology (Neuropathology), VA Medical Center and Boston University School of Medicine, Boston, MA 02118, USA
Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan
Laboratory of Neuropathology, University of Ulm, 89081 Ulm, Germany
Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX 75390, USA
Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, New York, NY 10016, USA
Department of Pathology L113, Oregon Health Sciences University, Portland, OR 97239, USA
Departments of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan
Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
John F. Crary (Corresponding author)
Peter T. Nelson (Corresponding author)
Received: 24 July 2014Revised: 26 September 2014Accepted: 28 September 2014Published online: 28 October 2014
We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
TPSD TOD Braak Neuropathology Consensus


We propose a new term, “primary age-related tauopathy” (PART), to describe a pathologic continuum ranging from focally distributed neurofibrillary tangles (NFTs) observed in cognitively normal aged individuals, through the pathology observed in persons with dementing illnesses that have been referred to as “tangle-predominant senile dementia” (TPSD), “tangle-only dementia”, “preferential development of NFT without senile plaques”, and “senile dementia of the neurofibrillary tangle type” (SD-NFT), among other names. Here we explain the need for introducing this term, reviewing the relevant studies in the clinical and pathologic literature. We conclude with new proposed working guidelines for the neuropathological classification of subjects with PART.
The main reasons for proposing this new terminology are to provide a conceptual framework for studying PART, to facilitate communication among pathologists, clinicians, and researchers, and to draw attention to this entity, which is often overlooked. Another motivation, as with the recent National Institute on Aging-Alzheimer’s Association diagnostic criteria for Alzheimer’s disease (AD) [64, 102], is to “disentangle” pathologic classification from clinical diagnosis for a given patient. In the case of PART, the separation of clinical information from the pathological diagnosis is especially necessary, because the term “dementia”, as in “tangle-only dementia”, implies a multi-domain cognitive impairment with a profound decrease in the ability to perform activities of daily living, both of which are absent in the majority of persons with PART [65, 66, 107, 125, 142]. Practicing neuropathologists will benefit from the revised terminology because many are reluctant to apply the clinical term “dementia” to a pathologic diagnosis when dementia was not documented clinically or when knowledge of the clinical history is limited. Also, there have been recommendations to lessen the use of labels such as “dementia” and “senile” partly due to pejorative implications [139] and because the terms are considered to be imprecise [24].
Patients with mild-to-moderate AD-type neurofibrillary degeneration in the medial temporal lobe, but lacking Aβ plaques, have been described in European, Japanese, North and South American cohorts [2, 3, 14, 51, 52, 58, 69, 72, 79, 81, 82, 126, 142, 147, 149, 151]. NFTs are practically universal in older persons’ brains [22, 30, 108, 132], and are also observed in a more limited distribution in many younger individuals [30, 32, 42]. Cases at the more severe end of the pathologic spectrum (Braak stages III–IV) lacking Aβ plaques were observed in 2–10 % of brains in large autopsy series that included community-based sampling [89, 94, 107, 125]. These pathologic changes were more prevalent in a few autopsy series drawing from memory disorder clinics [128, 129]. The theoretical and practical implications of these findings remain controversial [9, 15, 29, 107]. Differences in nomenclature, study design (including cohort recruitment methods) variable sensitivity in detecting pathologic changes, and conceptual interpretations have fueled uncertainty. A more specific and ultimately useful term for neuropathologic diagnoses is required, drawing from an expanding research corpus.

Clinical features

Published data indicate that severe PART can be associated with memory loss in aging [66, 107]. However, the high prevalence of comorbid brain diseases in elderly individuals make clinicopathologic correlations challenging in this population [76, 80, 108, 109, 117, 125], and the entire clinicopathologic spectrum of PART has yet to be systematically characterized. Most relevant prior studies have either focused on the most severe cases with TPSD or have investigated the associations between medial temporal lobe or brainstem tau pathology related to AD [5, 6, 11, 12, 19, 48, 49, 55, 56, 79, 133, 134, 144]. A subset of patients with PART (previously referred to as SD-NFT, TPSD, etc.) displays marked clinical impairment in the absence of any other recognizable substrate for dementia [14, 21, 39, 60, 66, 72, 99, 142]. The average age of death is generally higher for these patients than those with AD pathology [37, 79, 107]. Whereas cognitively impaired subjects with PART often carry a clinical diagnosis of possible or probable AD [115], the coexistence of PART and AD in aging is an inevitable complicating factor [153]. A recent analysis of the National Alzheimer’s Coordinating Center (NACC) autopsy database [16] found that ~14 % of subjects clinically diagnosed with mild-to-moderate probable AD had no or sparse neuritic plaques [128]. Here we provide additional data from the NACC database that underscore characteristics of PART: the pathology is common and Braak stage “0” is relatively unusual in older individuals; there is an absence of an association between PART and APOE genotype; and, the more severe PART pathology is associated with a higher age of death and lower scores on cognitive tests (Table 1).
Table 1
Clinical features of primary age-related tauopathy (PART)
Amyloid plaque density
Braak stage
Number of subjects
 PART, definite
 PART, possible
Age at death (average)
 PART, definite
92.0*, **
 PART, possible
Final MMSE scores
 PART, definite
 PART, possible
18.8*, **
APOE ε4 positive (%)
 PART, definite
 PART, possible
56.6*, **
Patients from the National Alzheimer’s Disease Coordinating Center (NACC) Neuropathology Database who died after 2005, with Mini-Mental State Examination (MMSE) during life, but no evidence of severe AD, frontotemporal lobar degeneration, triplet repeat disorder, amyotrophic lateral sclerosis, or other known neurological syndrome at autopsy. A total of 434 individuals met inclusion criteria. Statistical comparisons versus Braak NFT stage 0 cases. Age and MMSE were assessed with one-way ANOVA; APOE was assessed with Fisher’s exact test
* p < 0.05 as individual test
** p < 0.05 after Bonferroni–Holm correction for multiple comparisons
*** Combining Braak III/IV comparing to Braak 0 leads to p = 0.003 (Student’s t test)
The application of imaging and CSF biomarkers has given a novel perspective on the prevalence and associated clinical features of neurodegenerative processes that undoubtedly include PART. Biomarker-based clinical research supports the claim, initially made based on the autopsy studies of putatively cognitively intact people [36, 88] and of persons with mild cognitive impairment (MCI) [83, 93, 113], that tauopathy in the absence of Aβ-type amyloidosis is common. Reported biomarkers include CSF Aβ(1–42) or positron emission tomography (PET) imaging for Aβ pathology and CSF tau or phospho-tau, structural MRI, and PET (including fluorodeoxyglucose PET) for neurodegeneration. The abnormalities of the neurodegeneration biomarkers have generally been defined relative to levels seen in AD. It appears that roughly a quarter of cognitively normal elderly individuals have abnormal neurodegeneration biomarkers in the absence of abnormal brain amyloidosis [86, 87, 143, 145]. This clinical cohort’s status has been termed “suspected non-Alzheimer pathophysiology” (SNAP) to distinguish it from persons with Aβ-type amyloidosis [75, 87]. In persons with amnestic MCI, remarkably, about the same proportion of SNAP cases is found [112, 114]. Although autopsy experience is limited so far in cases with biomarker-defined SNAP, the prominent involvement of the medial temporal lobe in reported SNAP cases suggests that PART-type pathologic changes may underlie at least a subset of persons with the SNAP biomarker profile in the broader population. A more specific diagnostic classification enables terminology that parallels the recently adopted nomenclature for AD, with a biomarker-positive presymptomatic stage and a symptomatic stage where both biomarkers and clinical phenotype are present [74]. There are ongoing and potential future clinical trials that target either Aβ- or tau-related pathogenic mechanisms. PART and AD may well respond differently to those therapeutic interventions [23], which underscore the importance of harmonizing clinical decisions with data that were previously obtained in high-quality autopsy series.

Neuropathologic changes

Gross examination of the brain of subjects with PART may show no obvious differences from those deemed “normal for age”. In other individuals with PART, there may be mild-to-moderate diffuse atrophy of the neocortex, and medial temporal lobe atrophy may be pronounced in persons with dementia (Fig. 1) [110, 122]. Immunohistochemistry reveals telencephalic NFTs emerging most consistently in the medial temporal lobe, particularly the hippocampal formation and adjacent regions (Fig. 1b–d). Abnormal tau-immunoreactive inclusions are most prominent in neurons (Fig. 2). Subcortical NFTs can be observed even in teenage years in the locus coeruleus [9, 30, 41, 42, 131], so this process is not necessarily limited to individuals of advanced age. NFTs may also be seen in the amygdala, nucleus basalis of Meynert, nucleus accumbens, hypothalamus, thalamus, olfactory system (bulb and cortex), dorsal raphé nucleus, and medulla oblongata [7, 8, 53, 107, 141]. While NFTs at all stages of evolution can be seen in PART, individuals with cognitive impairment often have abundant extracellular, so-called “ghost”, tangles [110, 122].
Fig. 1
Primary age-related tauopathy (PART): gross pathology and low-power photomicrographs. a A formalin-fixed left hemisphere from a 103-year-old woman reveals enlargement of the inferior horn of lateral ventricle and severe medial temporal atrophy. Only mild neocortical atrophy is present. b A Luxol fast blue-counterstained hematoxylin–eosin section (LHE) shows atrophy of the medial temporal lobe. c Phospho-tau (p-tau; AT8)-immunolabeled sections highlight marked tauopathic changes predominantly in the hippocampus and entorhinal cortex. d For comparison, a case with advanced AD demonstrates a more severe tauopathy extending into the temporal neocortex
Fig. 2
Primary age-related tauopathy (PART): histopathology. The neuropathology corresponds to Braak stages I–IV, with involvement of the hippocampal formation (ac are nearly serial sections from the hippocampus of the same patient) as shown with Luxol fast blue-counterstained hematoxylin–eosin (LHE) (a), and p-tau (AT8) immunohistochemistry (b). However, unlike cases with AD, Aβ immunohistochemistry (c) shows minimal or no staining. Gallyas silver impregnation reveals many “ghost tangles” in the hippocampal formation (d), here without amyloid plaques. A key difference between AD and PART pathology is that, by definition, advanced AD (e) shows extensive hyperphosphorylated tau (p-tau) in neocortical areas such as the prefrontal cortex (Brodmann area 9), whereas PART pathology spares the neocortex (f). Scale bar in a 1 mm for (ac), scale bar in d 100 µm, and scale bar in e 5 mm for (e, f). CA1-4 denote the hippocampal subfields, DG dentate gyrus
The only existing grading system that applies to PART is Braak neurofibrillary staging [26, 28, 32]. The pathologic continuum of PART includes pretangle or cortical pretangle (up to Stage Ib), entorhinal (I–II), or limbic (III–IV) Braak stages [25, 27, 28]. Theoretically, given experimental findings that tau pathology might be propagated trans-synaptically [34, 35, 38, 46, 47, 57, 91], it is notable that PART-type pathology generally does not progress to the isocortical Braak stages (i.e., V–VI), remaining relatively restricted neuroanatomically even in the oldest-old subjects with limited extension beyond the temporal neocortex to other neocortical regions [73, 148].
The neurofibrillary changes in PART resemble those in AD brains (Fig. 3). Immunohistochemical and biochemical studies have found that NFTs in PART, as in AD, contains accumulation of both 3-repeat (3R) and 4-repeat (4R) tau isoforms (Fig. 3a–c) [70, 79, 122, 130]. In AD NFTs, electron microscopy has revealed predominantly paired helical filaments (PHFs), which are considered a disease hallmark [85, 119, 146]. The tau fibrils in brains with PART pathology also display a typical PHF morphology (Fig. 3d) [67, 72, 122]. These observations are not unique to PART and the pathologic overlap requires further consideration.
Fig. 3
The NFTs of PART resemble those of AD by immunohistochemistry, biochemistry, and ultrastructure. a, b NFTs in PART reveal immunoreactivity with both 3R and 4R anti-tau monoclonal antisera (RD3 and RD4, respectively). Scale bar 200 μm for a, b. c Immunoblot using polyclonal antisera targeting total tau (tau C) shows a banding pattern similar to that in AD (from Ref. [122] with permission). d The tau fibrils (paired helical filaments) in PART show similar ultrastructural features and periodicity as in AD. Scale bar 100 nm

Differentiating PART from other neurodegenerative diseases

A synthesis of previously reported observations exposes an apparent paradox: the NFT is one of the two defining pathological hallmarks of AD, the other is the Aβ plaque. However, AD-type NFTs are almost ubiquitously observed in older persons’ brains, even in the absence of Aβ plaques or features of other classifiable tauopathies. Because there are pathologic features in common with AD, some investigators may consider PART a subset of AD or an early stage of AD. Indeed, NFTs in the brainstem of younger adults show features in common with the pathological processes of AD [31]. Yet clinically and pathologically salient features may differ despite the overlap in pathologies. In comparison to AD, current data suggest that PART typically has a far more limited impact on cognition and develops in persons without Aβ plaques or biochemical evidence of elevated Aβ [122]. A diagnosis of AD neuropathologic changes requires at least a minimum threshold level of Aβ deposition [64, 102]. This criterion is supported by extensive genetic and clinicopathologic observations [108]. There is an accumulating body of evidence suggesting that medial temporal lobe NFTs are involved in at least two common processes, an AD-related process, and a non-AD aging-related process [103, 107]. Supportive evidence comes from genetic studies that show an association between PART and the microtubule-associated protein tau gene (MAPT) H1 haplotype [76, 122], whereas there is an absence of an association between PART and the strongest risk factor for AD, the APOE ε4 allele [13, 67, 70, 122, 150, 151].
PART cases have likely been reported in autopsy series of SD-NFT, TPSD, tangle-predominant dementia or tangle-only dementia [10, 14, 17, 43, 79, 98, 106, 110, 122]. These proposed pathologic entities may have included some cases that would now be considered frontotemporal lobar degeneration (FTLD). TPSD has previously been grouped among FTLD subtypes [33] and there are presumably FTLD-tau subtypes that may overlap with the spectrum of PART even if the pathogenesis is distinct. For example, individuals with germline MAPT R406W mutation may present as a temporal lobe predominant tauopathy with similar features to TPSD [63], but the presence of NFTs in the globus pallidus, subthalamic nucleus, substantia nigra, and pons in such cases is reminiscent of PSP. The pattern of tau isoform accumulation associated with PART pathology can also be seen in other tauopathies, including amyotrophic lateral sclerosis/Parkinsonism dementia complex of Guam [61, 111, 123, 124], which, like AD, may also show α-synuclein and TDP-43 pathology [50, 140]. By contrast, PSP and CBD display a predominance of 4-repeat tau isoforms, and Pick disease shows predominantly 3-repeat tau isoforms [4, 44, 79, 90, 138, 152]. Also commonly seen in brains from individuals of advanced age are tau-immunoreactive argyrophilic grains. However, argyrophilic grain disease is a 4R tauopathy featuring CA2 pretangles and dentate granule cell involvement, all acetylated tau-negative, and none of these features are seen in AD/PART [54, 71, 84, 107, 120, 136, 138].

Future studies and unanswered questions

Additional studies are necessary to refine our understanding of PART in the complicated context of the aged human brain. Most fundamentally, the exact clinicopathologic spectrum of PART remains to be definitively characterized. Additional topical questions relate to the “boundary zone” between PART and other tauopathies, especially AD. The precise threshold of Aβ deposition below which a diagnosis of definite PART is appropriate, and the relative importance of diffuse amyloid and neuritic plaques, require further study. In addition, there is a growing appreciation, not yet incorporated into consensus-based guidelines, that the neuropathology of AD is heterogeneous [2, 18, 20, 59, 62, 7678, 92, 104, 105, 118, 151]. It is possible that brains with hypothesized hippocampal “localized” [100, 101] or “limbic-predominant” [76, 104, 105, 151] AD subtypes are along a common continuum with PART [76, 79, 105]. The rationale for including extracortical tau pathology in PART is that the pathologies commonly coexist and that brainstem NFTs, if they represent the same process, appear to occur even earlier in human aging [3032, 53]. In this context, it is also not known whether spinal cord tauopathy is related to PART [40]. More studies will be needed to determine whether there are distinct subtypes of extracortical tauopathy and how these changes relate to AD as well as PART. There are other conditions besides AD that overlap pathologically with PART. For example, it is notable that chronic traumatic encephalopathy generally presents pathologically as a non-Aβ tauopathy with features that overlap pathologically with PART [95], and in the future markers may be developed to better discriminate between disorders in which NFTs develop in similar brain areas. Tau-immunoreactive glial pathology is also frequently seen in advanced old age [1, 44, 65, 68, 89, 90, 127]. It is unknown whether the age-related glial tauopathy is associated with mechanisms that also cause PART pathology, but PART appears to be a predominantly neuronal pathology. To enable future studies aimed at addressing the extant unresolved questions, a working diagnostic guideline is required.

Neuropathologic criteria

New criteria are proposed to classify patients with PART for research and potential future clinical purposes (Table 2). PART is defined by AD-type neurofibrillary changes without, or with few, Aβ plaques as described below. PART can be designated as “Definite” or “Possible” depending on the presence of coexisting neuropathology and many cases will not be gradable due to comorbid pathology. Specifically, neurofibrillary changes may correspond to subcortical pretangle or cortical pretangle (up to Ib), entorhinal (I–II), or limbic (III–IV) Braak stages [25, 27, 28]. In keeping with the current guidelines for AD [64, 102], mild Aβ plaques defined using the Thal grading system [116, 135, 137], consistent with low AD neuropathologic changes, preclude the diagnosis of “Definite” PART. Some pathologists may prefer the CERAD system for grading neuritic plaque density [96], but the method used must be indicated as it would alter the classification of some subjects. Possible wording for the pathologic diagnoses is provided (Table 2). If both early AD pathology and “Possible” PART pathology are observed, both may be reported diagnostically. The presence of few or moderate argyrophilic grains as assessed with established staging methods [45, 121] does not rule out PART. We emphasize that a pathologic diagnosis of PART does not necessarily indicate that a functional deficit was detected clinically. We also note that Braak stage IV pathology without Aβ plaques is unusual and in these cases the possibility of a FTLD-tau condition should be considered.
Table 2
Primary age-related tauopathy (PART): working classification
1. Requires
 NFTs present with Braak stage ≤IV (usually III or lower)
2. Then subclassify as follows
Thal Aβ Phasea
Other disease associated with NFTb
 Primary age-related tauopathy (PART), Definite, Braak stage II
 Primary age-related tauopathy (PART), Possible, Braak stage III, Thal Aβ phase 2
3. Ancillary studies (not required)
 Immunohistochemistry: 3R and 4R tau-positive
 Electron microscopy: paired helical filaments present
 Genetics: absence of pathogenic FTLD-tau mutation
aSee [116, 135]. Laboratories using the CERAD neuritic plaque density score [96, 97] may classify subjects with neuritic plaque frequency of “None” as “Definite” and “Sparse” as “Possible”
bFor example, “progressive supranuclear palsy”, “corticobasal degeneration”, “Pick’s disease”, “frontotemporal lobar degeneration with MAPT mutation”, and “chronic traumatic encephalopathy”


PART is a common brain pathology relevant to researchers, clinicians, and the broader public. Despite the high prevalence in published brain autopsy series, PART has been difficult to categorize because of the absence of a well-accepted nosology. We expect that the study of tau biomarkers will broaden the recognition of PART, and improve our understanding of a condition currently known mostly from neuropathologic studies. More studies are needed to better understand the pathogenesis of PART, its relation to other neurodegenerative disorders, and the full clinical spectrum of this common brain disease of aging.
We are extremely grateful to the patients, clinicians, and fellow researchers that made this effort possible. We also acknowledge the following funding sources: the Society for Supporting Research in Experimental Neurology, Vienna, Austria, National Institutes of Health Grants P50AG08702, R01 AG037212, P01AG07232, P30 AG028383, P50 AG005138, P50 AG016574, U01 AG006786, R01 AG041851, R01 AG011378, P30 AG028383, P50 AG016574, P01 AG003949, P30 AG012300, P50 AG005146, P50 AG005136, P50 AG025688, P50 AG005138, P01 AG002219, P50 AG005133, P50 AG005681, P01 AG003991, R01 AG038651, P30 AG019610, P30 AG013854, P30 AG036453, P30 AG010124, AG005131, AG184440, AG008051, Medical Research Council (MRC, G0400074), National Institute for Health Research (NIHR, R:CH/ML/0712), the Dunhill Medical Trust (R173/1110), Alzheimer’s Research UK (ARUK), and the Alzheimer’s Society (AS-PG-2013-011), Louis V. Gerstner, Jr., Foundation, Alzheimer’s Association (NIRG-11-204450), FP7 EU Project Develage (No. 278486), Comprehensive brain research network, Grant-in-Aid for Scientific Research (C; 26430060), and Daiwa Health Science Foundation, BrightFocus Foundation, Alzheimer’s Association NIRGD-12-242642, Alzheimer Forschung Initiative (AFI # 13803) (DRT); German Ministry for Research and Education (BMBF) FTLD-Net, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation.
Ahmed Z, Bigio EH, Budka H et al (2013) Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126:537–544. doi:10.​1007/​s00401-013-1171-0PubMedCentralPubMed
Alafuzoff I (2013) Alzheimer’s disease-related lesions. J Alzheimers Dis 33(Suppl 1):S173–S179. doi:10.​3233/​JAD-2012-129024PubMed
Andrade-Moraes CH, Oliveira-Pinto AV, Castro-Fonseca E et al (2013) Cell number changes in Alzheimer’s disease relate to dementia, not to plaques and tangles. Brain 136:3738–3752. doi:10.​1093/​brain/​awt273PubMed
Arai T, Ikeda K, Akiyama H et al (2001) Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 101:167–173PubMed
Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1:103–116PubMed
Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–1688PubMed
Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25:265–271PubMed
Attems J, Lintner F, Jellinger KA (2005) Olfactory involvement in aging and Alzheimer’s disease: an autopsy study. J Alzheimers Dis 7:149–157 (discussion 173–180)PubMed
Attems J, Thal DR, Jellinger KA (2012) The relationship between subcortical tau pathology and Alzheimer’s disease. Biochem Soc Trans 40:711–715. doi:10.​1042/​BST20120034PubMed
Baborie A, Griffiths TD, Jaros E et al (2012) Frontotemporal dementia in elderly individuals. Arch Neurol 69:1052–1060. doi:10.​1001/​archneurol.​2011.​3323PubMed
Ball MJ (1978) Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients. A quantitative study. Acta Neuropathol 42:73–80PubMed
Ball MJ, Nuttall K (1981) Topography of neurofibrillary tangles and granulovacuoles in hippocampi of patients with Down’s syndrome: quantitative comparison with normal ageing and Alzheimer’s disease. Neuropathol Appl Neurobiol 7:13–20PubMed
Bancher C, Egensperger R, Kosel S, Jellinger K, Graeber MB (1997) Low prevalence of apolipoprotein E epsilon 4 allele in the neurofibrillary tangle predominant form of senile dementia. Acta Neuropathol 94:403–409PubMed
Bancher C, Jellinger KA (1994) Neurofibrillary tangle predominant form of senile dementia of Alzheimer type: a rare subtype in very old subjects. Acta Neuropathol 88:565–570PubMed
Bancher C, Paulus W, Paukner K, Jellinger K (1997) Neuropathologic diagnosis of Alzheimer disease: consensus between practicing neuropathologists? Alzheimer Dis Assoc Disord 11:207–219PubMed
Beekly DL, Ramos EM, Lee WW et al (2007) The National Alzheimer’s Coordinating Center (NACC) database: the uniform data set. Alzheimer Dis Assoc Disord 21:249–258. doi:10.​1097/​WAD.​0b013e318142774e​PubMed
Berg L, McKeel DW Jr, Miller JP et al (1998) Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55:326–335PubMed
Bondareff W, Mountjoy CQ, Roth M et al (1987) Age and histopathologic heterogeneity in Alzheimer’s disease. Evidence for subtypes. Arch Gen Psychiatry 44:412–417PubMed
Bondareff W, Mountjoy CQ, Roth M et al (1987) Neuronal degeneration in locus coeruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord 1:256–262PubMed
Bondareff W, Mountjoy CQ, Wischik CM et al (1993) Evidence of subtypes of Alzheimer’s disease and implications for etiology. Arch Gen Psychiatry 50:350–356PubMed
Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex 4:138–150PubMed
Bouras C, Hof PR, Morrison JH (1993) Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett 153:131–135PubMed
Boutajangout A, Wisniewski T (2014) Tau-based therapeutic approaches for Alzheimer’s disease—a mini-review. Gerontology 60(5):381–385. doi:10.​1159/​000358875PubMed
Bowler JV, Hachinski V (1995) Vascular cognitive impairment: a new approach to vascular dementia. Bailliere’s Clin Neurol 4:357–376
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. doi:10.​1007/​s00401-006-0127-zPubMedCentralPubMed
Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMed
Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278 (discussion 278–284)PubMed
Braak H, Braak E, Bohl J (1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33:403–408PubMed
Braak H, Del Tredici K (2004) Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-beta formation. Neurobiol Aging 25:713–718. doi:10.​1016/​j.​neurobiolaging.​2003.​12.​015 (discussion 743–716)PubMed
Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181. doi:10.​1007/​s00401-010-0789-4PubMed
Braak H, Del Tredici K (2012) Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 25:708–714. doi:10.​1097/​WCO.​0b013e32835a3432​PubMed
Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. doi:10.​1097/​NEN.​0b013e318232a379​PubMed
Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol (Berl) 114:5–22
Clavaguera F, Akatsu H, Fraser G et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540. doi:10.​1073/​pnas.​1301175110PubMedCentralPubMed
Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913. doi:10.​1038/​ncb1901PubMedCentralPubMed
Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388PubMed
Dawe RJ, Bennett DA, Schneider JA, Arfanakis K (2011) Neuropathologic correlates of hippocampal atrophy in the elderly: a clinical, pathologic, postmortem MRI study. PLoS One 6:e26286. doi:10.​1371/​journal.​pone.​0026286PubMedCentralPubMed
de Calignon A, Polydoro M, Suarez-Calvet M et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697. doi:10.​1016/​j.​neuron.​2011.​11.​033PubMedCentralPubMed
Dickson DW, Kouri N, Murray ME, Josephs KA (2011) Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J Mol Neurosci 45(3):384–389. doi:10.​1007/​s12031-011-9589-0PubMedCentralPubMed
Dugger BN, Hidalgo JA, Chiarolanza G et al (2013) The distribution of phosphorylated tau in spinal cords of Alzheimer’s disease and non-demented individuals. J Alzheimers Dis 34:529–536. doi:10.​3233/​JAD-121864PubMedCentralPubMed
Dugger BN, Tu M, Murray ME, Dickson DW (2011) Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer’s disease and progressive supranuclear palsy. Neurosci Lett 491(2):122–126. doi:10.​1016/​j.​neulet.​2011.​01.​020PubMedCentralPubMed
Elobeid A, Soininen H, Alafuzoff I (2012) Hyperphosphorylated tau in young and middle-aged subjects. Acta Neuropathol 123:97–104. doi:10.​1007/​s00401-011-0906-zPubMedCentralPubMed
Feany MB, Dickson DW (1996) Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol 40:139–148. doi:10.​1002/​ana.​410400204PubMed
Ferrer I, Lopez-Gonzalez I, Carmona M et al (2014) Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol 73:81–97. doi:10.​1097/​NEN.​0000000000000030​PubMed
Ferrer I, Santpere G, van Leeuwen FW (2008) Argyrophilic grain disease. Brain 131:1416–1432. doi:10.​1093/​brain/​awm305PubMed
Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11:155–159. doi:10.​1038/​nrn2786PubMedCentralPubMed
Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852. doi:10.​1074/​jbc.​M808759200PubMedCentralPubMed
Fukutani Y, Kobayashi K, Nakamura I et al (1995) Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer’s disease. Neurosci Lett 200:57–60 (0304-3940(95)12083-G [pii])PubMed
Garcia-Sierra F, Hauw JJ, Duyckaerts C et al (2000) The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol 100:29–35PubMed
Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145. doi:10.​1007/​s00401-007-0257-yPubMed
Giannakopoulos P, Hof PR, Mottier S, Michel JP, Bouras C (1994) Neuropathological changes in the cerebral cortex of 1258 cases from a geriatric hospital: retrospective clinicopathological evaluation of a 10-year autopsy population. Acta Neuropathol 87:456–468PubMed
Goodman L (1953) Alzheimer’s disease: a clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis. J Nerv Ment Dis 117:97–130
Grinberg LT, Rub U, Ferretti RE et al (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol 35:406–416. doi:10.​1111/​j.​1365-2990.​2009.​00997.​xPubMed
Grinberg LT, Wang X, Wang C et al (2013) Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125:581–593. doi:10.​1007/​s00401-013-1080-2PubMedCentralPubMed
Grudzien A, Shaw P, Weintraub S et al (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335. doi:10.​1016/​j.​neurobiolaging.​2006.​02.​007PubMed
Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736PubMed
Guo JL, Lee VM (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286(17):15317–15331. doi:10.​1074/​jbc.​M110.​209296PubMedCentralPubMed
Hauw JJ, Vignolo P, Duyckaerts C et al (1986) Neuropathological study of 12 centenarians: the incidence of Alzheimer type senile dementia is not particularly increased in this group of very old patients. Rev Neurol 142:107–115PubMed
Hof PR, Archin N, Osmand AP et al (1993) Posterior cortical atrophy in Alzheimer’s disease: analysis of a new case and re-evaluation of a historical report. Acta Neuropathol 86:215–223PubMed
Hof PR, Bouras C, Buée L et al (1992) Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer’s disease cases. Acta Neuropathol 85:23–30PubMed
Hof PR, Perl DP, Loerzel AJ, Morrison JH (1991) Neurofibrillary tangle distribution in the cerebral cortex of parkinsonism-dementia cases from Guam: differences with Alzheimer’s disease. Brain Res 564:306–313 (0006-8993(91)91467-F [pii])PubMed
Hof PR, Vogt BA, Bouras C, Morrison JH (1997) Atypical form of Alzheimer’s disease with prominent posterior cortical atrophy: a review of lesion distribution and circuit disconnection in cortical visual pathways. Vision Res 37:3609–3625. doi:10.​1016/​S0042-6989(96)00240-4PubMed
Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. doi:10.​1038/​31508PubMed
Hyman BT, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.​1016/​j.​jalz.​2011.​10.​007PubMedCentralPubMed
Ikeda K, Akiyama H, Arai T, Nishimura T (1998) Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. Neurobiol Aging 19:S85–S91PubMed
Ikeda K, Akiyama H, Arai T et al (1999) Clinical aspects of ‘senile dementia of the tangle type’—a subset of dementia in the senium separable from late-onset Alzheimer’s disease. Dement Geriatr Cogn Disord 10:6–11PubMed
Ikeda K, Akiyama H, Arai T et al (1997) A subset of senile dementia with high incidence of the apolipoprotein E epsilon2 allele. Ann Neurol 41:693–695. doi:10.​1002/​ana.​410410522PubMed
Ikeda K, Akiyama H, Kondo H et al (1995) Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles. Acta Neuropathol 90:620–625PubMed
Ikeda K, Kondo H, Fujishima T, Kase K, Mizutani Y (1993) A case of atypical senile dementia of Alzheimer type. No To Shinkei 45:455–460PubMed
Iseki E, Tsunoda S, Suzuki K et al (2002) Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer’s disease and limbic NFT dementia. Neuropathology 22:34–39PubMed
Ishizawa T, Ko LW, Cookson N et al (2002) Selective neurofibrillary degeneration of the hippocampal CA2 sector is associated with four-repeat tauopathies. J Neuropathol Exp Neurol 61:1040–1047PubMed
Itoh Yamada M, Yoshida R et al (1996) Dementia characterized by abundant neurofibrillary tangles and scarce senile plaques: a quantitative pathological study. Eur Neurol 36:94–97PubMed
Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E (1998) An immunohistochemical study of centenarian brains: a comparison. J Neurol Sci 157:73–81PubMed
Jack CR Jr, Albert MS, Knopman DS et al (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:257–262. doi:10.​1016/​j.​jalz.​2011.​03.​004PubMedCentralPubMed
Jack CR Jr, Knopman DS, Weigand SD et al (2012) An operational approach to National Institute on Aging-Alzheimer’s Association criteria for preclinical Alzheimer disease. Ann Neurol 71:765–775. doi:10.​1002/​ana.​22628PubMedCentralPubMed
Janocko NJ, Brodersen KA, Soto-Ortolaza AI et al (2012) Neuropathologically defined subtypes of Alzheimer’s disease differ significantly from neurofibrillary tangle-predominant dementia. Acta Neuropathol 124:681–692. doi:10.​1007/​s00401-012-1044-yPubMedCentralPubMed
Jellinger KA (2013) Challenges in the neuropathological diagnosis of dementias. Int J Neuropathol 1:44
Jellinger KA (2012) Neuropathological subtypes of Alzheimer’s disease. Acta Neuropathol 123:153–154. doi:10.​1007/​s00401-011-0889-9PubMed
Jellinger KA, Attems J (2007) Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol 113:107–117. doi:10.​1007/​s00401-006-0156-7PubMed
Jellinger KA, Attems J (2010) Prevalence and pathology of vascular dementia in the oldest-old. J Alzheimers Dis 21:1283–1293PubMed
Jellinger KA, Bancher C (1998) Senile dementia with tangles (tangle predominant form of senile dementia). Brain Pathol 8:367–376PubMed
Jicha GA, Abner EL, Schmitt FA, et al. (2012) Preclinical AD Workgroup staging: pathological correlates and potential challenges. Neurobiol Aging. 33:622 e621–622 e616. doi:10.​1016/​j.​neurobiolaging.​2011.​02.​018
Jicha GA, Parisi JE, Dickson DW et al (2006) Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 63:674–681PubMed
Josephs KA, Whitwell JL, Parisi JE et al (2008) Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging 29:566–573. doi:10.​1016/​j.​neurobiolaging.​2006.​10.​032PubMedCentralPubMed
Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193PubMed
Knopman DS, Caselli RJ (2012) Appraisal of cognition in preclinical Alzheimer’s disease: a conceptual review. Neurodegener Dis Manag 2:183–195. doi:10.​2217/​NMT.​12.​5PubMedCentralPubMed
Knopman DS, Jack CR Jr, Wiste HJ et al (2013) Brain injury biomarkers are not dependent on beta-amyloid in normal elderly. Ann Neurol 73:472–480. doi:10.​1002/​ana.​23816PubMedCentralPubMed
Knopman DS, Parisi JE, Salviati A et al (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095PubMed
Kovacs GG, Milenkovic I, Wohrer A et al (2013) Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol 126:365–384. doi:10.​1007/​s00401-013-1157-yPubMed
Kovacs GG, Molnar K, Laszlo L et al (2011) A peculiar constellation of tau pathology defines a subset of dementia in the elderly. Acta Neuropathol 122:205–222. doi:10.​1007/​s00401-011-0819-xPubMed
Liu L, Drouet V, Wu JW et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302. doi:10.​1371/​journal.​pone.​0031302PubMedCentralPubMed
Malkani RG, Dickson DW, Simuni T (2012) Hippocampal-sparing Alzheimer’s disease presenting as corticobasal syndrome. Parkinsonism Relat Disord 18:683–685. doi:10.​1016/​j.​parkreldis.​2011.​11.​022PubMed
Markesbery WR, Schmitt FA, Kryscio RJ et al (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46PubMed
Matsui Y, Tanizaki Y, Arima H et al (2009) Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol Neurosurg Psychiatry 80:366–370. doi:10.​1136/​jnnp.​2008.​155481PubMed
McKee AC, Cantu RC, Nowinski CJ et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735. doi:10.​1097/​NEN.​0b013e3181a9d503​PubMedCentralPubMed
Mirra SS (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging 18:S91–S94PubMed
Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMed
Mitchell TW, Mufson EJ, Schneider JA et al (2002) Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer’s disease. Ann Neurol 51:182–189PubMed
Mizutani T, Kasahara M, Yamada S, Mukai M, Amano N (1993) Study on the neuropathological diagnosis of senile dementia of the Alzheimer type. No To Shinkei 45:333–342PubMed
Mizutani T, Shimada H (1992) Neuropathological background of twenty-seven centenarian brains. J Neurol Sci 108:168–177PubMed
Mizutani T, Shimada H (1991) Quantitative study of neurofibrillary tangles in subdivisions of the hippocampus. CA2 as a special area in normal aging and senile dementia of the Alzheimer type. Acta Pathol Jpn 41:597–603PubMed
Montine TJ, Phelps CH, Beach TG et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. doi:10.​1007/​s00401-011-0910-3PubMedCentralPubMed
Mungas D, Tractenberg R, Schneider JA, Crane PK, Bennett DA (2014) A 2-process model for neuropathology of Alzheimer’s disease. Neurobiol Aging 35:301–308. doi:10.​1016/​j.​neurobiolaging.​2013.​08.​007PubMed
Murray ME, Cannon A, Graff-Radford NR et al (2014) Differential clinicopathologic and genetic features of late-onset amnestic dementias. Acta Neuropathol. doi:10.​1007/​s00401-014-1302-2
Murray ME, Graff-Radford NR, Ross OA et al (2011) Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol 10:785–796. doi:10.​1016/​S1474-4422(11)70156-9PubMedCentralPubMed
Nakaya H, Miki T, Seino S et al (2003) Molecular and functional diversity of ATP-sensitive K+ channels: the pathophysiological roles and potential drug targets. Nihon Yakurigaku Zasshi 122:243–250PubMed
Nelson PT, Abner EL, Schmitt FA et al (2009) Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 68:774–784. doi:10.​1097/​NEN.​0b013e3181aacbe9​PubMedCentralPubMed
Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. doi:10.​1097/​NEN.​0b013e31825018f7​PubMedCentralPubMed
Nelson PT, Jicha GA, Schmitt FA et al (2007) Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol 66:1136–1146PubMedCentralPubMed
Noda K, Sasaki K, Fujimi K et al (2006) Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle-only dementia): the Hisayama Study. Neuropathology 26:508–518PubMed
Perl DP, Hof PR, Purohit DP, Loerzel AJ, Kakulas BA (2003) Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction. J Neuropathol Exp Neurol 62:381–388PubMed
Petersen RC, Aisen P, Boeve BF et al (2013) Criteria for mild cognitive impairment due to alzheimer’s disease in the community. Ann Neurol. doi:10.​1002/​ana.​23931
Petersen RC, Parisi JE, Dickson DW et al (2006) Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63:665–672. doi:10.​1001/​archneur.​63.​5.​665PubMed
Prestia A, Caroli A, van der Flier WM et al (2013) Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease. Neurology 80:1048–1056. doi:10.​1212/​WNL.​0b013e3182872830​PubMed
Ranginwala NA, Hynan LS, Weiner MF, White CL 3rd (2008) Clinical criteria for the diagnosis of Alzheimer disease: still good after all these years. Am J Geriatr Psychiatry 16:384–388. doi:10.​1097/​JGP.​0b013e3181629971​PubMed
Rijal Upadhaya A, Kosterin I, Kumar S et al (2014) Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain 137:887–903. doi:10.​1093/​brain/​awt362PubMed
Robinson JL, Geser F, Corrada MM et al (2011) Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain 134:3708–3715. doi:10.​1093/​brain/​awr308PubMed
Rohrer JD, Schott JM (2011) Primary progressive aphasia—defining genetic and pathological subtypes. Curr Alzheimer Res 8:266–272 (BSP/CAR/0119 [pii])PubMed
Ruben GC, Wang JZ, Iqbal K, Grundke-Iqbal I (2005) Paired helical filaments (PHFs) are a family of single filament structures with a common helical turn period: negatively stained PHF imaged by TEM and measured before and after sonication, deglycosylation, and dephosphorylation. Microsc Res Tech 67:175–195. doi:10.​1002/​jemt.​20197PubMed
Sabbagh MN, Sandhu SS, Farlow MR et al (2009) Correlation of clinical features with argyrophilic grains at autopsy. Alzheimer Dis Assoc Disord 23:229–233. doi:10.​1097/​WAD.​0b013e318199d833​PubMedCentralPubMed
Saito Y, Ruberu NN, Sawabe M et al (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918PubMed
Santa-Maria I, Haggiagi A, Liu X et al (2012) The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathol 124:693–704. doi:10.​1007/​s00401-012-1017-1PubMedCentralPubMed
Schmidt ML, Garruto R, Chen J, Lee VM, Trojanowski JQ (2000) Tau epitopes in spinal cord neurofibrillary lesions in Chamorros of Guam. Neuroreport 11:3427–3430PubMed
Schmidt ML, Zhukareva V, Perl DP et al (2001) Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism-dementia complex. J Neuropathol Exp Neurol 60:1075–1086PubMed
Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 18:691–701. doi:10.​3233/​JAD-2009-1227PubMedCentralPubMed
Schnitzler JG (1911) Zur Abgrenzung der sogenannten Alzheimerschen Erkrankung. Z ges Neurol Psychiat. 7:34–57
Schultz C, Ghebremedhin E, Del Tredici K, Rüb U, Braak H (2004) High prevalence of thorn-shaped astrocytes in the aged human medial temporal lobe. Neurobiol Aging 25:397–405. doi:10.​1016/​S0197-4580(03)00113-1PubMed
Serrano-Pozo A, Qian J, Monsell SE et al (2014) Mild to moderate Alzheimer dementia with insufficient neuropathological changes. Ann Neurol 75:597–601. doi:10.​1002/​ana.​24125PubMedCentralPubMed
Serrano-Pozo A, Qian J, Monsell SE et al (2013) Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the National Alzheimer Coordinating Center. J Neuropathol Exp Neurol 72:1182–1192. doi:10.​1097/​NEN.​0000000000000016​PubMed
Shiarli AM, Jennings R, Shi J et al (2006) Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer’s disease. Neuropathol Appl Neurobiol 32:374–387. doi:10.​1111/​j.​1365-2990.​2006.​00736.​xPubMed
Simic G, Stanic G, Mladinov M et al (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol Appl Neurobiol 35:532–554. doi:10.​1111/​j.​1365-2990.​2009.​01038.​xPubMedCentralPubMed
Sonnen JA, Santa Cruz K, Hemmy LS et al (2011) Ecology of the aging human brain. Arch Neurol 68:1049–1056. doi:10.​1001/​archneurol.​2011.​157PubMedCentralPubMed
Syed A, Chatfield M, Matthews F et al (2005) Depression in the elderly: pathological study of raphe and locus ceruleus. Neuropathol Appl Neurobiol 31:405–413. doi:10.​1111/​j.​1365-2990.​2005.​00662.​xPubMed
Takahashi J, Shibata T, Sasaki M, et al (2014) Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer’s disease: high-resolution fast spin-echo T1-weighted imaging. Geriatr Gerontol Int. doi:10.​1111/​ggi.​12280
Thal DR, Capetillo-Zarate E, Del Tredici K, Braak H (2006) The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowl Environ 2006:re1. doi:10.​1126/​sageke.​2006.​6.​re1
Thal DR, Schultz C, Botez G et al (2005) The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer’s disease-related pathology. Neuropathol Appl Neurobiol 31:270–279. doi:10.​1111/​j.​1365-2990.​2005.​00635.​xPubMed
Thal DR, von Arnim C, Griffin WS et al (2013) Pathology of clinical and preclinical Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 263(Suppl 2):S137–S145. doi:10.​1007/​s00406-013-0449-5PubMed
Togo T, Sahara N, Yen SH et al (2002) Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 61:547–556PubMed
Trachtenberg DI, Trojanowski JQ (2008) Dementia: a word to be forgotten. Arch Neurol 65:593–595. doi:10.​1001/​archneur.​65.​5.​593PubMed
Trojanowski JQ, Ishihara T, Higuchi M et al (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11PubMed
Tsuboi Y, Wszolek ZK, Graff-Radford NR, Cookson N, Dickson DW (2003) Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. Neuropathol Appl Neurobiol 29:503–510PubMed
Ulrich J, Spillantini MG, Goedert M, Dukas L, Staehelin HB (1992) Abundant neurofibrillary tangles without senile plaques in a subset of patients with senile dementia. Neurodegeneration 1:257–284
Vos SJ, Xiong C, Visser PJ et al (2013) Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol 12:957–965. doi:10.​1016/​S1474-4422(13)70194-7PubMedCentralPubMed
West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772PubMed
Wirth M, Villeneuve S, Haase CM et al (2013) Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol 70:1512–1519. doi:10.​1001/​jamaneurol.​2013.​4013PubMed
Wisniewski HM, Narang HK, Terry RD (1976) Neurofibrillary tangles of paired helical filaments. J Neurol Sci 27:173–181PubMed
Yamada M (2003) Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis. Neuropathology 23:311–317PubMed
Yamada M, Itoh Y, Sodeyama N et al (1998) Aging of the human limbic system: observations of centenarian brains and analyses of genetic risk factors for senile changes. Neuropathology 18:228–234
Yamada M, Itoh Y, Sodeyama N et al (2001) Senile dementia of the neurofibrillary tangle type: a comparison with Alzheimer’s disease. Dement Geriatr Cogn Disord 12:117–126. doi:10.​1159/​000051245PubMed
Yamada M, Itoh Y, Suematsu N, Otomo E, Matsushita M (1996) Apolipoprotein E genotype in elderly nondemented subjects without senile changes in the brain. Ann Neurol 40:243–245. doi:10.​1002/​ana.​410400217PubMed
Yamada M, Itoh Y, Yohinori I et al (1996) Dementia of the Alzheimer type and related dementias in the aged: DAT subgroups and senile dementia of the neurofibrillary tangle type. Neuropathology 16:89–98
Yoshida M (2006) Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies. Neuropathology 26:457–470PubMed
Yu L, Boyle PA, Leurgans S, Schneider JA, Bennett DA (2014) Disentangling the effects of age and APOE on neuropathology and late life cognitive decline. Neurobiol Aging 35:819–826. doi:10.​1016/​j.​neurobiolaging.​2013.​10.​074PubMed