The Genetics of Alzheimer Disease

Abstract

Four genes involved in the development of Alzheimer disease have been identified. Three fully penetrant (deterministic) genes lead to the development of Alzheimer disease in patients younger than 60 years: the amyloid beta-protein precursor on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1. Together, they account for about half of this early-onset form of the disease. One genetic risk factor--apolipoprotein E-4--is associated with late-onset Alzheimer disease. It accounts for a substantial fraction of disease burden but seems to act primarily to lower the age of disease onset. In general, none of these genes can be easily adapted for use as a diagnostic or predictive test for Alzheimer disease. Research activity includes searching for additional genes, especially for late-onset disease, and elucidating the mechanism of action of all identified genes as part of a long-term effort to develop more effective therapeutic and preventive strategies.

Reduced Expression of the Inhibitory Synapse Scaffolding Protein Gephyrin in Alzheimer's Disease

“…No significant difference in gephyrin expression was found when AD subjects were divided by APOE geno-type [37]. Other AD susceptibility genes included APOC1 [14], TNFA-850 [23] and -308 [1], and A2M [4], but none showed an association with the levels of gephyrin within groups or as a whole.…”

Reduced Expression of the Inhibitory Synapse Scaffolding Protein Gephyrin in Alzheimer's Disease

“…No significant difference in gephyrin expression was found when AD subjects were divided by APOE geno-type [37]. Other AD susceptibility genes included APOC1 [14], TNFA-850 [23] and -308 [1], and A2M [4], but none showed an association with the levels of gephyrin within groups or as a whole.…”

Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer's Disease

“…2). Within the group of APOE-4 non-carriers, there was a significant main effect of family history (F [2,23] = 4.0, p = 0.03), which on post-hoc examination was due to the MH group having lower COX compared to NH and to PH (32% and 35%, respectively, p ≤ 0.02). Likewise, MH 2.…”

“…Similar results were obtained using the ratio of COX to CS. There was a significant main effect of family history on COX/CS (F [2,33] = 5.4, p = 0.009), which on post-hoc examination was due to the MH group having lower COX/CS compared to NH and to PH (34% and 26%, respectively, p ≤ 0.03; Table 2). There were no differences between PH and NH.…”

“…COX measures by family history groups are found in Table 2. There was a significant main effect of family history on total protein-referenced COX Vmax activity (F [2,33] = 7.0, p = 0.003). On post-hoc examination, COX Vmax activity was reduced in the MH group as ).…”

Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

“…However, the relationship between amyloid and tau in the pathophysiology of LOAD remains unclear. It is known that tangles deposition is associated with cognitive decline, 68,69 while mutations in the APP cause familial AD 70 . The current literature suggests that plaques and tangles may act synergistically as both are necessary for cognitive decline and glucose hypometabolism.…”

Reduced Expression of the Inhibitory Synapse Scaffolding Protein Gephyrin in Alzheimer's Disease

“…No significant difference in gephyrin expression was found when AD subjects were divided by APOE geno-type [37]. Other AD susceptibility genes included APOC1 [14], TNFA-850 [23] and -308 [1], and A2M [4], but none showed an association with the levels of gephyrin within groups or as a whole.…”

Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer's Disease

“…2). Within the group of APOE-4 non-carriers, there was a significant main effect of family history (F [2,23] = 4.0, p = 0.03), which on post-hoc examination was due to the MH group having lower COX compared to NH and to PH (32% and 35%, respectively, p ≤ 0.02). Likewise, MH 2.…”

“…Similar results were obtained using the ratio of COX to CS. There was a significant main effect of family history on COX/CS (F [2,33] = 5.4, p = 0.009), which on post-hoc examination was due to the MH group having lower COX/CS compared to NH and to PH (34% and 26%, respectively, p ≤ 0.03; Table 2). There were no differences between PH and NH.…”

“…COX measures by family history groups are found in Table 2. There was a significant main effect of family history on total protein-referenced COX Vmax activity (F [2,33] = 7.0, p = 0.003). On post-hoc examination, COX Vmax activity was reduced in the MH group as ).…”

Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

“…However, the relationship between amyloid and tau in the pathophysiology of LOAD remains unclear. It is known that tangles deposition is associated with cognitive decline, 68,69 while mutations in the APP cause familial AD 70 . The current literature suggests that plaques and tangles may act synergistically as both are necessary for cognitive decline and glucose hypometabolism.…”

Reduced Expression of the Inhibitory Synapse Scaffolding Protein Gephyrin in Alzheimer's Disease

“…No significant difference in gephyrin expression was found when AD subjects were divided by APOE geno-type [37]. Other AD susceptibility genes included APOC1 [14], TNFA-850 [23] and -308 [1], and A2M [4], but none showed an association with the levels of gephyrin within groups or as a whole.…”

Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer's Disease

“…2). Within the group of APOE-4 non-carriers, there was a significant main effect of family history (F [2,23] = 4.0, p = 0.03), which on post-hoc examination was due to the MH group having lower COX compared to NH and to PH (32% and 35%, respectively, p ≤ 0.02). Likewise, MH 2.…”

“…Similar results were obtained using the ratio of COX to CS. There was a significant main effect of family history on COX/CS (F [2,33] = 5.4, p = 0.009), which on post-hoc examination was due to the MH group having lower COX/CS compared to NH and to PH (34% and 26%, respectively, p ≤ 0.03; Table 2). There were no differences between PH and NH.…”

“…COX measures by family history groups are found in Table 2. There was a significant main effect of family history on total protein-referenced COX Vmax activity (F [2,33] = 7.0, p = 0.003). On post-hoc examination, COX Vmax activity was reduced in the MH group as ).…”

Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

“…However, the relationship between amyloid and tau in the pathophysiology of LOAD remains unclear. It is known that tangles deposition is associated with cognitive decline, 68,69 while mutations in the APP cause familial AD 70 . The current literature suggests that plaques and tangles may act synergistically as both are necessary for cognitive decline and glucose hypometabolism.…”