A systematic review and meta-analysis

Objective To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data. Methods EMBASE, PubMed, and Web of Science databases were consulted until July 2019. Results Neuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbicpredominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE e4 genotype, and CSF biomarker levels. Conclusion We identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals’ belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD. From the Division of Clinical Geriatrics (D.F., A.N., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; Theme Aging (A.N.), Karolinska University Hospital, Huddinge, Sweden; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Swedish Research Council. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 436 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Alzheimer disease (AD) is a heterogeneous disease. Variability in age at onset and clinical presentation is known since the very first reports. Extensive research showed marked differences between early-onset and late-onset AD, mostly with early-onset AD showing more pronounced pathologic findings such as more tau-related pathology and brain atrophy. Regarding variation in the clinical presentation, different clinical subtypes have extensively been investigated, showing that the amnestic presentation is more common than nonamnestic presentations such as posterior cortical atrophy (PCA), logopenic primary progressive aphasia (LPPA), and the frontal variant of AD. Of interest, an association between age at onset and clinical presentation exists, with nonamnestic subtypes having earlier onset. Recent progress in biomarker research and wider availability of postmortem data has intensified the study of biologically defined subtypes of AD (based on neuropathologic and neuroimaging data). Several studies have been published including subtypes based on postmortem data, MRI data, and recently, tau-PET data. With the new definition of AD as a biological disease, it is now timely and unprecedented to review the literature on biologically defined subtypes of AD. We conducted a systematic review on the topic and calculated meta-analytical estimates aiming at characterizing the AD subtypes across key demographic and clinical measures. Our ultimate goal was to advance in our understanding of mechanisms driving heterogeneity in AD, hopefully contributing to guide the search for subtype-specific therapies within the current efforts of precision medicine.