Common genetic signatures of Alzheimer’s disease in Down Syndrome

Abstract

Background: People with Down Syndrome (DS) are born with an extra copy of Chromosome (Chr) 21 and many of these individuals develop Alzheimer’s Disease (AD) when they age. This is due at least in part to the extra copy of the APP gene located on Chr 21. By 40 years, most people with DS have amyloid plaques which disrupt brain cell function and increase their risk for AD. About half of the people with DS develop AD and the associated dementia around 50 to 60 years of age, which is about the age at which the hereditary form of AD, early onset AD, manifests. In the absence of Chr 21 trisomy, duplication of APP alone is a cause of early onset Alzheimer’s disease, making it likely that having three copies of APP is important in the development of AD and in DS. In individuals with both DS and AD, early behavior and cognition-related symptoms may include a reduction in social behavior, decreased enthusiasm, diminished ability to pay attention, sadness, fearfulness or anxiety, irritability, uncooperativeness or aggression, seizures that begin in adulthood, and changes in coordination and walking. Methods: We investigate the relationship between AD and DS through integrative analysis of genesets derived from a MeSH query of AD and DS associated beta amyloid peptides, Chr 21, GWAS identified AD risk factor genes, and differentially expressed genes in DS individuals. Results: Unique and shared aspects of each geneset were evaluated based on functional enrichment analysis, transcription factor profile and network analyses. Genes that may be important to both disorders: ACSM1, APBA2, APLP1, BACE2, BCL2L, COL18A1, DYRK1A, IK, KLK6, METTL2B, MTOR, NFE2L2, NFKB1, PRSS1, QTRT1, RCAN1, RUNX1, SAP18 SOD1, SYNJ1, S100B. Conclusions: Our findings indicate that oxidative stress, apoptosis, and inflammation/immune system processes likely underlie the pathogenesis of AD and DS.

Towards a Consensus on Alzheimer’s Disease Comorbidity?

“…Notably, the term depression also refers to a systematic decline, a financial recession, or a hollow impression, and multiple citations refer to meanings other than psychiatric depression. Finally, Down’s syndrome, is also highly associated with AD, and trisomy 21 carriers of amyloid precursor protein develop early onset AD [ 56 ]. However, these associations are trivial, and may be discarded as insignificant.…”

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

“…TDP43 was particularly linked to ongoing brain injury since its elevation has been observed in traumatic brain injury, post-cardiac arrest states, strokes, and dementia [ 38 , 45 , 107 , 110 , 111 ]. Similarly, KLK6 is seen in several neurodegeneration disorders [ 48 , 55 , 112 , 113 , 114 , 115 ]. Sustained elevations in TDP43, YKL40, and KLK6 may suggest potential links to delirium, increased psychoactive disorders, and atypical dementias in the wake of COVID-19.…”

Alzheimer's Disease in Individuals with Down Syndrome

“…2 It is thought the APP gene, amyloid precursor protein, is present on chromosome 21, and trisomy of the chromosome leads to overexpression of the APP gene and increases the development of amyloid plaques. 3 Other than memory, language, executive function, and motor coordination problems, cognitive impairment can also develop in people with DS. The presentation may vary significantly due to advanced age or other risk factors that lead to increased development of dementia.…”

“…Some early behavioral changes and cognition-related symptoms in individuals with DS and AD include sadness, anxiety, low enthusiasm, aggressiveness, irritability, uncooperativeness, and inattentiveness. 3 Due to the dramatic increase of life expectancy in the DS population, from 12 years in 1942 to 60 years in 2003, revealing early-onset dementia proved necessary to prevent cognitive deterioration. 5 This is supported later by the finding that dementia is more likely to be found in DS individuals more than 50 years old compared to the general population of the same age.…”

“…19 This results in overproduction of APP intermediate product, amyloid β (Aβ), leading to increased accumulation in the brain. 3 This overproduction also accelerates downstream neurodegeneration, disturbs synapses signal, causes nerve cell death, tissue damage, and brain mass reduction at the end. The increased synthesis of amyloid beta (Aβ)…”