Neuropathology of Dementia Disorders

This article provides an overview of the neuropathology of common age-related dementing disorders, focusing on the pathologies that underlie Alzheimer disease (AD) and related dementias, including Lewy body dementias, frontotemporal dementia, vascular dementia, limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), and mixed-etiology dementias. This article also discusses the underlying proteinopathies of neurodegenerative diseases (eg, amyloid-β, paired helical filament tau, α-synuclein, and TDP-43 pathology) and vascular pathologies, including tissue injury (eg, infarcts, hemorrhages) with or without vessel disease.

New criteria for AD pathologic diagnosis highlight amyloid-β as the sine qua non of AD; they require molecular markers of amyloid and establish a minimum threshold of Braak neurofibrillary tangle stage 3. Pathologic diagnosis is separated from clinical disease (ie, pathologic diagnosis no longer requires dementia). TDP-43 pathology, a major pathology in a frontotemporal dementia subtype, was found as a central pathology in LATE, a newly named amnestic disorder. Multiple pathologies (often co-occurring with AD) contribute to dementia and add complexity to the clinical picture. Conversely, Lewy body, LATE, and vascular dementias often have accompanying AD pathology. Pathology and biomarker studies highlight subclinical pathologies in older people without cognitive impairment. This resilience to brain pathology is common and is known as cognitive reserve.

The pathologies of dementia in aging are most commonly amyloid, tangles, Lewy bodies, TDP-43, hippocampal sclerosis, and vascular pathologies. These pathologies often co-occur (mixed pathologies), which may make specific clinical diagnoses difficult. In addition, dementia-related pathologies are often subclinical, suggesting varying levels of resilience in older people.