Fifty-eight autopsies of patients with
primary progressive aphasia are reported. Twenty-three of these were previously described (Mesulam et al., 2008) but had their neuropathological diagnoses updated to fit current criteria. Thirty-five of the cases are new. Their clinical classification was guided as closely as possible by the 2011 consensus guidelines (Gorno-Tempini et al., 2011). Tissue diagnoses included
Alzheimer's disease in 45% and
frontotemporal lobar degeneration (
FTLD) in the others, with an approximately equal split between TAR
DNA binding protein 43
proteinopathies and
tauopathies. The most common and distinctive feature for all pathologies associated with
primary progressive aphasia was the asymmetric prominence of
atrophy, neuronal loss, and disease-specific
proteinopathy in the language-dominant (mostly left) hemisphere. The
Alzheimer's disease pathology in
primary progressive aphasia displayed multiple atypical features. Males tended to predominate, the neurofibrillary pathology was more intense in the language-dominant hemisphere, the Braak pattern of hippocampo-entorhinal prominence was tilted in favour of the neocortex, and the
APOE e4 allele was not a risk factor. Mean onset age was under 65 in the
FTLD as well as
Alzheimer's disease groups. The
FTLD-TAR
DNA binding protein 43 group had the youngest onset and fastest progression whereas the
Alzheimer's disease and
FTLD-tau groups did not differ from each other in either onset age or progression rate. Each cellular pathology type had a preferred but not invariant clinical presentation. The most common aphasic manifestation was of the logopenic type for Alzheimer pathology and of the agrammatic type for
FTLD-tau. The
progressive supranuclear palsy subtype of
FTLD-tau consistently caused prominent speech abnormality together with
agrammatism whereas
FTLD-TAR
DNA binding protein 43 of type C consistently led to semantic
primary progressive aphasia. The presence of
agrammatism made
Alzheimer's disease pathology very unlikely whereas the presence of a logopenic
aphasia or word comprehension impairment made
FTLD-tau unlikely. The association of logopenic
primary progressive aphasia with
Alzheimer's disease pathology was much more modest than has been implied by results of in vivo
amyloid imaging studies. Individual features of the
aphasia, such as
agrammatism and comprehension impairment, were as informative of underlying pathology as more laborious subtype diagnoses. At the single patient level, no clinical pattern was pathognomonic of a specific neuropathology type, highlighting the critical role of
biomarkers for diagnosing the underlying disease. During clinical subtyping, some patients were unclassifiable by the 2011 guidelines whereas others simultaneously fit two subtypes. Revisions of criteria for logopenic
primary progressive aphasia are proposed to address these challenges.