Ferreira, Daniel

AbstractIntroductionHarboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described.MethodsMulticenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3).ResultsCarrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging.DiscussionIn addition to the known resistance against amyloid‐β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD‐related cognitive decline.

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous disease. Recent neuropathology and neuroimaging studies have sought to formalize this heterogeneity by defining AD subtypes based on the distribution of tau neurofibrillary tangle pathology and regional brain atrophy. These studies consistently revealed the existence of four subtypes: typical, limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD. We will give an overview on the current state‐of‐the‐art, leveraging on the first systematic review and meta‐analysis on subtype studies based on neuropathological and neuroimaging data, recently published by our group (Ferreira et al. 2020 Neurology). We will also present a conceptual framework to guide subtype studies in the future. Our ultimate goal was to advance our current understanding of mechanisms driving heterogeneity in AD dementia and its pre‐dementia stages.MethodThe EMBASE, PubMed and Web of Science databases were consulted for AD subtype studies based on neuropathological or neuroimaging data. We calculated meta‐analytical estimates on key demographic, clinical, and CSF biomarker measures. Prevalence values for the subtypes were also calculated. We summarized and integrated all the data on a hypothetical conceptual framework.ResultOur meta‐analytical analysis shows that typical AD displays tau neurofibrillary tangle 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 two core dimensions of heterogeneity: “typicality” and “severity”. We propose that these two dimensions determine individuals’ belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and comorbid non‐AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, results interpretation, and understanding mechanisms in future subtype studies. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease‐modifying drugs for AD.