TY - JOUR
T1 - Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer’s Disease
AU - Haberman, Rebecca P.
AU - Branch, Audrey
AU - Gallagher, Michela
N1 - Funding Information:
This work was supported by National Institute on Aging/National Institutes of Health program project grant P01-AG009973-22, Postdoctoral Training grant T32 AG027668, and RO1 AG048349. We would like thank Ming Teng Koh for his contribution and assistance with the figures.
Publisher Copyright:
© 2017, The Author(s).
PY - 2017/7/1
Y1 - 2017/7/1
N2 - Sporadic late-onset Alzheimer’s disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.
AB - Sporadic late-onset Alzheimer’s disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.
KW - Amnestic mild cognitive impairment (aMCI)
KW - Cognitive aging
KW - Hippocampal CA3
KW - Late-onset Alzheimer’s disease
KW - Levetiracetam (Keppra)
UR - http://www.scopus.com/inward/record.url?scp=85019675868&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019675868&partnerID=8YFLogxK
U2 - 10.1007/s13311-017-0541-z
DO - 10.1007/s13311-017-0541-z
M3 - Review article
C2 - 28560709
AN - SCOPUS:85019675868
SN - 1933-7213
VL - 14
SP - 662
EP - 676
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 3
ER -