Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
BACKGROUND
The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.


METHODS
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.


RESULTS
Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.


CONCLUSIONS
We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).
Washington University School of Medicine, Department of Neurology, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, USA. batemanr@wustl.edu
Randall J
RJ
Bateman
Chengjie
C
Xiong
Tammie L S
TL
Benzinger
Anne M
AM
Fagan
Alison
A
Goate
Nick C
NC
Fox
Daniel S
DS
Marcus
Nigel J
NJ
Cairns
Xianyun
X
Xie
Tyler M
TM
Blazey
David M
DM
Holtzman
Anna
A
Santacruz
Virginia
V
Buckles
Angela
A
Oliver
Krista
K
Moulder
Paul S
PS
Aisen
Bernardino
B
Ghetti
William E
WE
Klunk
Eric
E
McDade
Ralph N
RN
Martins
Colin L
CL
Masters
Richard
R
Mayeux
John M
JM
Ringman
Martin N
MN
Rossor
Peter R
PR
Schofield
Reisa A
RA
Sperling
Stephen
S
Salloway
John C
JC
Morris
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005260:Female; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D005947:Glucose