Biological subtypes of Alzheimer disease: A systematic review and meta-analysis.

Publication date: Feb 11, 2020

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.

EMBASE, PubMed, and Web of Science databases were consulted until July 2019.

Neuropathology 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 ?4 genotype, and CSF biomarker levels.

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.

Open Access PDF

Ferreira, D., Nordberg, A., and Westman, E. Biological subtypes of Alzheimer disease: A systematic review and meta-analysis. 06319. 2020 Neurology.

Concepts Keywords
Alzheimer Cerebral atrophy
Atrophy Aphasias
Biomarker Psychiatric diagnosis
Biomarkers Dementia
Brain Cognitive disorders
Cognitive Clinical medicine
Cortex Medicine
EMBASE Branches of biology
Frequency Successful disease
Genotype Subtypes Alzheimer disease
Heterogeneity Alzheimer’s disease
Hippocampal Hippocampus
Hippocampus Meta-analysis
Limbic Genotype
Meta Analysis


Type Source Name
disease MESH Alzheimer disease
pathway KEGG Alzheimer disease
disease MESH pathology
disease MESH atrophy
disease MESH factors risk
drug DRUGBANK Etodolac
disease MESH Aging
disease MESH primary progressive aphasia
drug DRUGBANK Acetylsalicylic acid


Original Article

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