We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (i) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (ii) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (iii) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

The current consensus criteria for the neuropathologic diagnosis of Alzheimer’s disease (AD), known as the National Institute on Aging/Reagan Institute of the Alzheimer Association Consensus Recommendations for the Postmortem Diagnosis of AD or NIA-Reagan Criteria [1], were published in 1997 (hereafter referred to as “1997 Criteria”). Knowledge of AD and the tools used for clinical investigation of cognitive impairment and dementia have advanced substantially since then and have prompted this update on the neuropathologic assessment of AD.

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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 (NFT) 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 NFT 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.

Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: L imbic-predominant A ge-related T DP-43 E ncephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes.