Authors: Lea Tenenholz Grinberg, Cathrine Petersen, Amber L. Nolan, Elisa de Paula França Resende, Zachary A. Miller, Salvatore Spina, Bruce L. Miller, Gil D. Rabinovici, William W. Seeley
Published: 2020-12-07
DOI: 10.1002/alz.041616
Source: Full article
AbstractBackgroundPathologically proven Alzheimer’s disease (AD) manifest clinically with a broad spectrum of cognitive presentations beyond the classic progressive amnestic‐predominant syndrome pointing to different patterns of selective vulnerability to AD pathology. As atypical clinical variants of AD tend to show a younger age of onset, EOAD cohorts present the best opportunity to understanding differences in the neuropathological substrate of typical vs. atypical AD presentation. Such studies may unveil mechanisms of selective neural vulnerability to AD and inform on novel modifiable pathogenic pathways. To reveal the features and mechanisms underlying the differences between typical and atypical AD, we investigated a sizeable clinicopathological series of sporadic EOAD. We hypothesized that a higher rate of comorbid pathology would explain an atypical AD clinical presentation.MethodWe used the UCSF/Neurodegenerative Disease Brain Bank (NDBB), which is a LEADS neuropathological hub. Neuropathological diagnosis follows internationally accepted research standards. We also employed quantitative neuropathological analysis in a subset for measuring p‐tau burden in neurons and astroglia. Definition of AD pathology required an ADNC ABC score ≥ A2B2C2. Sporadic EOAD cases manifested symptoms when < 65 years and lacked a AD‐associated autosomal dominant mutation.ResultFrom 2009 to 2019, the NDBB performed 113 autopsies with a primary neuropathological diagnosis of EOAD. Of those, (41%) showed an atypical presentation (Figure 1). Typical and atypical EOAD were similar in age and disease duration, but atypical cases were more likely to be female and have less comorbid Lewy body disease (Table 1). In brain areas associated with the most affected cognitive domain, atypical cases demonstrated a higher proportion of neurofibrillary (Table 2), but not of amyloid plaques or age‐related tau astrogliosis.ConclusionOther than greater regional tau burden, no other frequent neurodegenerative changes underlie atypical presentation. LEADS will enable increasing the EOAD neuropathological cohorts to leverage investigation on the factors underlying an atypical AD presentation.