Abstract
ObjectiveTo 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.MethodsEMBASE, PubMed, and Web of Science databases were consulted until July 2019.ResultsNeuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, 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 ε4 genotype, and CSF biomarker levels.ConclusionWe 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.
Highlights
We propose that these 2 dimensions determine individuals’ belonging to one of the Alzheimer disease (AD) subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies
Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively
We identified 3 dimensions that are major drivers of the heterogeneity within AD: (1) risk factors, including sex, APOE, and age; (2) protective factors, including aspects such as cognitive reserve, brain resilience, and brain resistance; and (3) concomitant non-AD pathologies that together with amyloid (A) and tau-related pathology (T) may contribute to the neurodegeneration (N) seen in AD, which are formulated under the A/T/N framework for AD.[35]
Summary
Search strategy and selection criteria This study followed the PRISMA statement. We conducted a systematic review using EMBASE, PubMed, and Web of Science in July 2019 without any limits in publication dates. The search strategy combined the following medical subject heading and free-text terms (data available from Dryad, table e-1, doi.org.10.5061/dryad.h70rxwdf3): “Alzheimer,” “AD,” “subtype,” “heterogeneity,” “atrophy,” “patterns,” “subtypes,” “MRI,” “Magnetic Resonance,” “PET,” “postmortem,” “neurofibrillary tangle,” and “neuropathological”. Selection criteria for the meta-analysis included (1) casecontrol studies reporting summary estimates on subgroups of patients with AD based on grouping strategies applied on MRI, PET, or postmortem data; (2) availability of data on subtypes frequency and key demographic and clinical measures; and (3) studies published in English. When data were missing for a variable, the larger study was included (data available from Dryad, table e-2, doi.org.10.5061/dryad.h70rxwdf[3])
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