title: Differential clinicopathologic and genetic features of late-onset amnestic dementias.
abstract: Hippocampal sclerosis of the elderly (HpScl) and Alzheimer's disease (AD), especially the limbic-predominant subtype (LP-AD), are amnestic syndromes that can be difficult to distinguish. To complicate matters, a subset has concomitant HpScl and AD (HpScl-AD). We examined a large cohort of autopsy-confirmed cases of HpScl, HpScl-AD, LP-AD, and typical AD to identify distinct clinical, genetic, and pathologic characteristics. HpScl cases were significantly older at death and had a substantially slower rate of cognitive decline than the AD subtypes. Genetic analysis revealed that the AD groups (AD, LP-AD, and HpScl-AD) were more likely to be APOE ε4 carriers. In contrast, the HpScl groups (HpScl and HpScl-AD) were more likely to exhibit genetic variants in GRN and TMEM106B that are associated with frontotemporal lobar degeneration. The HpScl groups had a high frequency of TDP-43 pathology that was most often Type A morphology and distribution, while typical AD and LP-AD had a significantly lower frequency of TDP-43 pathology that was most often Type B. These results suggest that HpScl and AD are pathologically and genetically distinct and non-synergistic neurodegenerative processes that present with amnestic dementia. Pure HpScl and HpScl with concomitant AD occur most often in elderly individuals.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Liesinger
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Ranjan
authors.initials: R
authors.lastname: Duara
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000473:pathology; D000544:Alzheimer Disease / Q000145:classification / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000473:pathology; D009483:Neuropsychological Tests; D058225:Plaque, Amyloid / Q000473:pathology; D000077153:Progranulins; D012598:Sclerosis / Q000473:pathology; D018709:Statistics, Nonparametric
chemical_list: D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; C556915:TMEM106B protein, human