Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample.
FADD (Fas-associated death domain) adaptor is a crucial protein involved in the induction of cell death but also mediates non-apoptotic actions via a phosphorylated form (p-Ser194-FADD). This study investigated the possible association of FADD forms with age-related neuropathologies, cognitive function, and the odds of dementia in an elderly community sample.



FADD forms were quantified by western blot analysis in dorsolateral prefrontal cortex (DLPFC) samples from a large cohort of participants in a community-based aging study (Memory and Aging Project, MAP), experiencing no-(NCI, n = 51) or mild-(MCI, n = 42) cognitive impairment, or dementia (n = 57).



Cortical FADD was lower in subjects with dementia and lower FADD was associated with a greater load of amyloid-β pathology, fewer presynaptic terminal markers, poorer cognitive function and increased odds of dementia. Together with the observations of FADD redistribution into tangles and dystrophic neurites within plaques in Alzheimer's disease brains, and its reduction in APP23 mouse cortex, the results suggest this multifunctional protein might participate in the mechanisms linking amyloid and tau pathologies during the course of the illness.



The present data suggests FADD as a putative biomarker for pathological processes associated with the course of clinical dementia.
BC Mental Health and Addictions Research Institute, Vancouver, Canada.|Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Alfredo
A
Ramos-Miguel
IUNICS, University of the Balearic Islands, Ctra. de Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.|Instituto de Investigación Sanitaria de Baleares, Palma de Mallorca, Spain.
Jesús A
JA
García-Sevilla
BC Mental Health and Addictions Research Institute, Vancouver, Canada.|Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Alasdair M
AM
Barr
Department of Psychiatry, University Medicine Goettingen, Goettingen, Germany.
Thomas A
TA
Bayer
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
Peter
P
Falkai
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, USA.
Sue E
SE
Leurgans
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, USA.
Julie A
JA
Schneider
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, USA.
David A
DA
Bennett
BC Mental Health and Addictions Research Institute, Vancouver, Canada.|Department of Psychiatry, University of British Columbia, Vancouver, Canada.
William G
WG
Honer
IUNICS, University of the Balearic Islands, Ctra. de Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain. j.garcia@uib.es.|Instituto de Investigación Sanitaria de Baleares, Palma de Mallorca, Spain. j.garcia@uib.es.
M Julia
MJ
García-Fuster
D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*
D015415:Biomarkers; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein
Aging; Alzheimer’s disease; Apoptosis; Neuroplasticity; Neurotoxicity