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Examining early‐onset Alzheimer’s disease (EOAD) and late‐onset Alzheimer’s disease to understand the neuropathological substract of typical and atypical AD
Author(s) -
Grinberg Lea Tenenholz,
Petersen Cathrine,
Nolan Amber L.,
Resende Elisa de Paula França,
Miller Zachary A.,
Spina Salvatore,
Miller Bruce L.,
Rabinovici Gil D.,
Seeley William W.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041616
Subject(s) - disease , early onset alzheimer's disease , dementia , neuropathology , cognitive decline , psychology , posterior cortical atrophy , medicine , neuroscience , pathology
Background Pathologically 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. Method We 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. Result From 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. Conclusion Other 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.