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While the typical amnestic presentation of Alzheimer\u2019s disease may have limited specificity due to coexisting age-related pathologies, atypical presentations such as logopenic variant primary progressive aphasia (lvPPA) or posterior cortical atrophy (PCA) are often associated with ADNC. This study evaluated how well clinical diagnoses of amnestic and atypical Alzheimer\u2019s disease predict ADNC and how co-pathologies contribute to clinical-pathological discordance. To evaluate how clinical diagnosis predicts ADNC, we calculated positive predictive values (PPVs) and negative predictive values (NPVs) for clinical diagnoses of PCA, lvPPA, amnestic Alzheimer\u2019s disease or non-Alzheimer\u2019s disease dementia for ADNC, using four neuropathological thresholds defined by combinations of the Consortium to Establish a Registry for Alzheimer\u2019s disease (CERAD) neuritic plaque frequency (moderate or frequent) and Braak stage (III\u2013VI or V\u2013VI). Analyses were replicated in vivo using amyloid- and tau-PET positivity (A+T+) as a surrogate for Alzheimer\u2019s disease pathology. We also quantified the frequency of co-pathologies and assessed their contribution to false-positive Alzheimer\u2019s disease diagnoses. This study included 6363 autopsy-confirmed cases from the National Alzheimer\u2019s Coordinating Center (NACC) database (mean age: 80.0 \u00b1 11.4 years; 46.0% female) and 76 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (mean age: 67.9 \u00b1 9.94 years; 55.3% female). The PPV of probable Alzheimer\u2019s disease dementia ranged from 58 to 80%, while PCA and lvPPA showed higher PPVs (81\u201396% and 80\u201392%, respectively) for ADNC. The NPV of probable Alzheimer\u2019s disease dementia ranged from 66 to 83%, compared with 38\u201358% for PCA and lvPPA. In TRIAD, individuals with PCA or lvPPA had 100% PPV for Alzheimer\u2019s disease biomarker abnormality, whereas amnestic Alzheimer\u2019s disease dementia showed a PPV of 78.1%. Among Alzheimer\u2019s disease dementia cases, 20.2% were ADNC-negative, with a higher frequency of false-positive diagnoses in late-onset compared with early-onset cases (23.8% versus 6.9%). Among ADNC-negative Alzheimer\u2019s disease dementia cases, vascular pathology was the most common pathology (early-onset: 93%; late-onset: 98%). In the late-onset group, limbic-predominant age-related TDP-43 encephalopathy occurred in 31% of the cases, followed by Lewy body pathology (28.8%) and primary age-related tauopathy (24.3%). Visuospatial and language variants of clinical Alzheimer\u2019s disease offer excellent predictive value for underlying Alzheimer\u2019s disease pathology, both in vivo and at autopsy, outperforming the amnestic presentation classically associated with Alzheimer\u2019s disease. Clinical-pathological discordance in amnestic Alzheimer\u2019s disease dementia is frequently associated with coexisting age-related and vascular pathologies, highlighting the complexity of interpreting clinical Alzheimer\u2019s disease diagnoses in the absence of ADNC.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag304","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:45:08Z","timestamp":1785930308000},"source":"Crossref","is-referenced-by-count":0,"title":["Posterior cortical atrophy and logopenic variant primary progressive aphasia are more specific for Alzheimer\u2019s disease pathology than probable Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5593-7717","authenticated-orcid":false,"given":"Lydia","family":"Trudel","sequence":"first","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur C","family":"Macedo","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine","family":"Rahmouni","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Paul","family":"Soucy","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"PET Unit, McConnell Brain Imaging Centre , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8953-1542","authenticated-orcid":false,"given":"Paolo","family":"Vitali","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Guiot","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Montreal Neurological Institute, McGill University , Montreal, QC H3A 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili-Naz","family":"Hazrati","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Montreal Neurological Institute, McGill University , Montreal, QC H3A 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-1376","authenticated-orcid":false,"given":"Pedro","family":"Rosa-Neto","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montr\u00e9al, QC H3A 1A1 ,","place":["Canada"]},{"name":"McGill University Research Centre for Studies in Aging, Douglas Hospital Research Centre - Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et services sociaux de l\u2019Ouest-de-l\u2019\u00cele-de-Montr\u00e9al , Verdun, Qu\u00e9bec H4H 1R3 ,","place":["Canada"]},{"name":"Peter O\u2019Donnell Jr. Brain Institute (OBI), University of Texas Southwestern Medical Centre (UTSW) , Dallas, TX 75390 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"issue":"4","key":"2026081103371675600_fcag304-B1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1097\/NEN.0b013e31824b211b","article-title":"Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer disease centers, 2005\u20132010","volume":"71","author":"Beach","year":"2012","journal-title":"J Neuropathol Exp 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