O3‐04‐03: Age‐Related Neuropathology Helps Distinguish Autosomal Dominant from Late‐Onset Alzheimer's Disease

Although autosomal dominant Alzheimer disease (ADAD) accounts for a small proportion (approximately 1%) of cases of AD, there is evidence to suggest that it overlaps both clinically and neuropathologically with spofradic late-onset AD (LOAD). However, there have been few studies comparing the neuropathology of these two groups. The Neuropathology Core of the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) has undertaken standardized neuropathologic assessments of all participants (n=48) who came to autopsy at ADNI sites in the USA and Canada and participants (n=9) and family members (n=15) at DIAN sites in the USA and Australia. In fifteen brain areas, histology included hematoxylin and eosin and a modified Bielschowsky silver impregnation; immunohistochemistry was performed to detect four frequent molecular pathologies: Aβ (10D5; Eli Lilly, Indianapolis, IN, USA), phospho-tau (PHF1; gift of P. Davies, Feinstein Institute for Medical Research, Manhasset, NY, USA), phospho-α-synuclein (Phospho-α-synuclein (Ser129), Cell Applications, Inc., San Diego, CA, USA), and phospho-TDP-43 (pTDP-43, Cosmo Bio USA, Inc., Carlsbad, CA, USA). Of 48 ADNI participants with dementia of the Alzheimer type at expiration, 96% cases had AD neuropathologic change (ADNC); two cases had argyrophilic grain disease. All 24 DIAN cases had ADNC at expiration. Twelve of 24 DIAN cases had diffuse Lewy body disease or amygdala-predominant Lewy body disease. In the ADNI cohort, 42.4% had Lewy body disease. Other comorbidities in LOAD (ADNI cohort) included: TDP-43 proteinopathy (21.2%), AGD (18.2%), hippocampal sclerosis (6.1%), age-related tau astroglopathy (3%) and infarcts (3%). These comorbidities were absent from the ADAD (DIAN cohort) cases. Both ADAD and LOAD have significant α-synucleinopathy (Lewy bodies) in up to one half of cases. LOAD cases are distinguished from ADAD by additional age-related comorbidities including: TDP-43 proteinopathy, hippocampal sclerosis, AGD, age-related tau astrogliopathy, and small vessel disease with infarcts. Comorbid pathology may contribute to the variance in ADNI and DIAN biomarker data. These findings also suggest sophisticated diagnostic and therapeutic approaches for comorbid pathologies, in addition to ADNC, will be required to optimize treatment for dementing diseases. *For listing of ADNI and DIAN investigators see: http://www.adni-info.org/ and http://dian-info.org/.

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