Possible Compensatory Events in Adult Down Syndrome Brain Prior to the Development of Alzheimer Disease Neuropathology: Targets for Nonpharmacological Intervention

Abstract

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

“…The study revealed that the number of amyloid-positive vessels reaches a top level in 61- to 72-year-old DS subjects. The increase in the numerical density of amyloid-positive vessels detected in each of four examined brain structures in 61- to 72-year-old DS subjects compared to 41- to 59-year-old DS subjects is consistent with the association between increasing CAA severity and age detected in amyloid precursor protein–overexpressing DS subjects [ 10 , 28 ].…”

Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

“…The study revealed that the number of amyloid-positive vessels reaches a top level in 61- to 72-year-old DS subjects. The increase in the numerical density of amyloid-positive vessels detected in each of four examined brain structures in 61- to 72-year-old DS subjects compared to 41- to 59-year-old DS subjects is consistent with the association between increasing CAA severity and age detected in amyloid precursor protein–overexpressing DS subjects [ 10 , 28 ].…”

Impact of Dementia‐derived Nonpharmacological Intervention Procedures on Cognition and Behavior in Older Adults With Intellectual Disabilities: A 3‐year Follow‐up Study

“…Recent in vivo imaging studies suggest molecular, cellular, and structural compensatory mechanisms in vulnerable brain regions of adults with DS prior to the development of DAT. This is consistent with the concept of a higher pathological threshold for function decline that allows neurons to function relatively normally despite extensive Alzheimer's pathology (Haier, Head, Head, & Lott, 2008; Head, Lott, Patterson, Doran, & Haier, 2007). Although dementia in adults with ID (other than DS) may not be exactly the same in origin or in sequence of progression as that which develops among adults with DS, similar compensation mechanisms for pathological brain aging might occur also in this group.…”

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal‐derived extracellular vesicles

“…Indeed, both Akt and P70S6K are known to phosphorylate BAD to promote anti‐apoptotic signals and, thus, cell survival 52,53 . This is the first observation of increased BAD inhibition in DS and is in agreement with the concept that compensatory events promote survival mechanisms prior to the development of AD pathology both in persons with DS and transgenic mice 54–56 . Moreover, we previously reported that pro‐apoptotic signals were significantly increased in persons with DS only after the development of AD pathology 57 …”

Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

“…The study revealed that the number of amyloid-positive vessels reaches a top level in 61- to 72-year-old DS subjects. The increase in the numerical density of amyloid-positive vessels detected in each of four examined brain structures in 61- to 72-year-old DS subjects compared to 41- to 59-year-old DS subjects is consistent with the association between increasing CAA severity and age detected in amyloid precursor protein–overexpressing DS subjects [ 10 , 28 ].…”

Impact of Dementia‐derived Nonpharmacological Intervention Procedures on Cognition and Behavior in Older Adults With Intellectual Disabilities: A 3‐year Follow‐up Study

“…Recent in vivo imaging studies suggest molecular, cellular, and structural compensatory mechanisms in vulnerable brain regions of adults with DS prior to the development of DAT. This is consistent with the concept of a higher pathological threshold for function decline that allows neurons to function relatively normally despite extensive Alzheimer's pathology (Haier, Head, Head, & Lott, 2008; Head, Lott, Patterson, Doran, & Haier, 2007). Although dementia in adults with ID (other than DS) may not be exactly the same in origin or in sequence of progression as that which develops among adults with DS, similar compensation mechanisms for pathological brain aging might occur also in this group.…”

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal‐derived extracellular vesicles

“…Indeed, both Akt and P70S6K are known to phosphorylate BAD to promote anti‐apoptotic signals and, thus, cell survival 52,53 . This is the first observation of increased BAD inhibition in DS and is in agreement with the concept that compensatory events promote survival mechanisms prior to the development of AD pathology both in persons with DS and transgenic mice 54–56 . Moreover, we previously reported that pro‐apoptotic signals were significantly increased in persons with DS only after the development of AD pathology 57 …”

Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

“…The study revealed that the number of amyloid-positive vessels reaches a top level in 61- to 72-year-old DS subjects. The increase in the numerical density of amyloid-positive vessels detected in each of four examined brain structures in 61- to 72-year-old DS subjects compared to 41- to 59-year-old DS subjects is consistent with the association between increasing CAA severity and age detected in amyloid precursor protein–overexpressing DS subjects [ 10 , 28 ].…”

Impact of Dementia‐derived Nonpharmacological Intervention Procedures on Cognition and Behavior in Older Adults With Intellectual Disabilities: A 3‐year Follow‐up Study

“…Recent in vivo imaging studies suggest molecular, cellular, and structural compensatory mechanisms in vulnerable brain regions of adults with DS prior to the development of DAT. This is consistent with the concept of a higher pathological threshold for function decline that allows neurons to function relatively normally despite extensive Alzheimer's pathology (Haier, Head, Head, & Lott, 2008; Head, Lott, Patterson, Doran, & Haier, 2007). Although dementia in adults with ID (other than DS) may not be exactly the same in origin or in sequence of progression as that which develops among adults with DS, similar compensation mechanisms for pathological brain aging might occur also in this group.…”

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal‐derived extracellular vesicles

“…Indeed, both Akt and P70S6K are known to phosphorylate BAD to promote anti‐apoptotic signals and, thus, cell survival 52,53 . This is the first observation of increased BAD inhibition in DS and is in agreement with the concept that compensatory events promote survival mechanisms prior to the development of AD pathology both in persons with DS and transgenic mice 54–56 . Moreover, we previously reported that pro‐apoptotic signals were significantly increased in persons with DS only after the development of AD pathology 57 …”