INTRODUCTION:Biomarkers for Alzheimer's disease neuropathologic change (ADNC) have been instrumental in developing effective disease-modifying therapeutics. However, to prevent/treat dementia effectively, we require biomarkers for non-AD neuropathologies; for this, neuropathologic examinations and annotated tissue samples are essential. METHODS:We conducted clinicopathologic correlation for the first 100 Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) cases. RESULTS:Clinical syndromes in this cohort showed 95% sensitivity and 79% specificity for predicting high/intermediate ADNC, a 21% false positive rate, and a ∼44% false negative rate. In addition, 60% with high/intermediate ADNC harbored additional potentially dementing co-pathologies. DISCUSSION:These results suggest that clinical presentation imperfectly predicts ADNC and that accurate prediction of high/intermediate ADNC does not exclude co-pathology that may modify presentation, biomarkers, and therapeutic responses. Therefore, new biomarkers are needed for non-AD neuropathologies. The ADNI NPC supports this mission with well-characterized tissue samples (available through ADNI and the National Institute on Aging) and "gold-standard" diagnostic information (soon to include digital histology). HIGHLIGHTS:The Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) brain donation cohort now exceeds 200 cases. ADNI NPC data in National Alzheimer's Coordinating Center format are available through the Laboratory of Neuro Imaging. Digitized slide files from the ADNI NPC will be available in 2025. Requests for ADNI brain tissue samples can be submitted online for ADNI/National Institute on Aging evaluation. Clinical diagnoses of Alzheimer's disease (AD)/AD and related dementias (ADRD) do not always predict post mortem neuropathology. Neuropathology is essential for the development of novel AD/ADRD biomarkers.

Objective To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS‐Aging) and age‐related diseases and to evaluate its contribution to cognitive impairment in the elderly. Methods Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University (St. Louis, MO). Relative neuron loss in the hippocampus of HS‐Aging was measured using unbiased stereological methods. Transactive response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy, a putative marker of HS‐Aging, was assessed. Clinical and cognitive data were analyzed using parametric statistical methods. Results Ninety‐three cases had HS‐Aging (6.8%), 8 cases had “pure” HS‐Aging, and 37 cases had comorbid intermediate or high Alzheimer's disease neuropathological change (i/h ADNC). Relative neuron loss (ratio of neuron number in hippocampal subfield CA1 to the neuron number in parahippocampal gyrus) was 0.15 for HS‐Aging; this was significantly lower than 0.64 for i/h ADNC and 0.66 for control cases (Kruskal‐Wallis test, p < 0.0001; p = 0.0003, respectively). TDP‐43 proteinopathy was present in 92.4% of HS‐Aging cases, higher than that in i/h ADNC (52%) and control (25%) cases. Pure HS‐Aging cases were more likely to have cognitive impairment in the memory domain. Interpretation Relative neuron loss in the hippocampus compared to the parahippocampus gyrus may be useful in distinguishing HS‐Aging in the context of comorbid ADNC. HS‐Aging contributes to cognitive impairment, which phenotypically resembles AD dementia. TDP proteinopathy is a frequent comorbidity in HS‐Aging and may contribute to cognitive impairment to a modest degree. Ann Neurol 2018;84:749–761

Longitudinal observational studies of autosomal dominant AD (ADAD) are attractive because the predicted age at onset is generally well known and biomarker trajectories can be ascertained. To determine the validity of ADAD as a model of the more frequent late-onset AD (LOAD) we have investigated the spectrum of genotypes and pathologies associated with ADAD and LOAD. The Neuropathology Cores of the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) represent a single laboratory to allow standardized neuropathologic assessments of all participants (n=55) who came to autopsy at ADNI sites (USA and Canada) and participants (n=14) and family members (n=15) at DIAN sites (Australia, Germany, UK, and USA). In fifteen brain areas, histology included hematoxylin and eosin; immunohistochemistry was performed to detect four frequent molecular pathologies: Aβ (10D5; Eli Lilly), phospho-tau (PHF1; gift of P. Davies), phospho-α-synuclein (Cell Applications), and phospho-TDP-43 (Cosmo Bio USA). Of 55 ADNI participants with AD dementia at expiration, 96% cases had AD neuropathologic change (ADNC); two cases had argyrophilic grain disease (AGD). All 29 DIAN cases (APP, PSEN1, and PSEN2) had florid ADNC at expiration. Seventeen of 24 (58.6%) DIAN cases had diffuse Lewy body disease or amygdala-predominant Lewy body disease. In the ADNI cohort, 49.1% had Lewy body disease. Other comorbidities in LOAD (ADNI cohort) included: TDP-43 proteinopathy (29.1%), AGD (16.4%), hippocampal sclerosis (7.3%), infarcts (7.3%), and aging-related tau astrogliopathy (10.9%). These comorbidities were absent from the ADAD (DIAN cohort) cases. APP, PSEN1, and PSEN2 mutations generate more florid ADNC than LOAD. Both ADAD and LOAD have significant alpha-synucleinopathy (Lewy bodies) comorbidity in up to one half of cases. LOAD cases are distinguished from ADAD by the presence of age-related pathology. Comorbid pathology may contribute to the variance in ADNI and DIAN biomarker data. The presence of additional age-related pathologies in LOAD may indicate that a more complex therapeutic approach is required in this group in comparison with ADAD. *For listing of ADNI and DIAN investigators see: http://www.adni-info.org/ and http://dian-info.org/.

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/.

INTRODUCTION:The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core (ADNI-NPC) facilitates brain donation, ensures standardized neuropathologic assessments, and maintains a tissue resource for research. METHODS:The ADNI-NPC coordinates with performance sites to promote autopsy consent, facilitate tissue collection and autopsy administration, and arrange sample delivery to the NPC, for assessment using National Institute on Aging-Alzheimer's Association neuropathologic diagnostic criteria. RESULTS:The ADNI-NPC has obtained 45 participant specimens, and neuropathologic assessments have been completed in 36 to date. Challenges in obtaining consent at some sites have limited the voluntary autopsy rate to 58%. Among assessed cases, clinical diagnostic accuracy for Alzheimer disease (AD) is 97%; however, 58% of cases show neuropathologic comorbidities. DISCUSSION:Challenges facing autopsy consent and coordination are largely resource related. The neuropathologic assessments indicate that ADNI's clinical diagnostic accuracy for AD is high; however, many AD cases have comorbidities that may impact the clinical presentation, course, and imaging and biomarker results. These neuropathologic data permit multimodal and genetic studies of these comorbidities to improve diagnosis and provide etiologic insights.

The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core (ADNI-NPC) facilitates brain donation, ensures standardized neuropathologic assessments, and maintains a tissue resource for research.The ADNI-NPC coordinates with performance sites to promote autopsy consent, facilitate tissue collection and autopsy administration, and arrange sample delivery to the NPC, for assessment using National Institute on Aging-Alzheimer's Association neuropathologic diagnostic criteria.The ADNI-NPC has obtained 45 participant specimens, and neuropathologic assessments have been completed in 36 to date. Challenges in obtaining consent at some sites have limited the voluntary autopsy rate to 58%. Among assessed cases, clinical diagnostic accuracy for Alzheimer disease (AD) is 97%; however, 58% of cases show neuropathologic comorbidities.Challenges facing autopsy consent and coordination are largely resource related. The neuropathologic assessments indicate that ADNI's clinical diagnostic accuracy for AD is high; however, many AD cases have comorbidities that may impact the clinical presentation, course, and imaging and biomarker results. These neuropathologic data permit multimodal and genetic studies of these comorbidities to improve diagnosis and provide etiologic insights.