Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin–1 gene

Abstract

It is now 10 years since the first report of mutations in the presenilin genes that were deterministic for familial autosomal dominant Alzheimer's disease. The most common of these mutations occurs in the presenilin-1 gene (PSEN1) located on chromosome 14. In the ensuing decade, more than 100 PSEN1 mutations have been described. The emphasis of these reports has largely been on the novelty of the mutations and their potential pathogenic consequences rather than detailed clinical, neuropsychological, neuroimaging and neuropathological accounts of patients with the mutation. This article reviews the clinical phenotypes of reported PSEN1 mutations, emphasizing their heterogeneity, and suggesting that other factors, both genetic and epigenetic,must contribute to disease phenotype.

P2‐203: Phenotypic Similarities between Late‐Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single‐Family Case‐Control Study

“…Hallucinations and delusions were reported more frequently in PSEN1 A79V MCs from this family, as has been noted previously in individuals with ADAD. 44,45 These findings demonstrate that the clinical phenotypes of late-onset ADAD and LOAD can overlap, and suggest that previously reported clinical (e.g., seizures, early myoclonus, spastic paraparesis, dysarthria, and rapid decline [9][10][11][12][13][14][15][16][17][18] ) and neuropathological differences (e.g., altered cerebral Aβ 42 and neurofibrillary tangle deposition, increased prevalence of cerebral amyloid angiopathy, and formation of "cotton wool" plaques 6,12,16,[19][20][21][22][23][24][25][26][27] ) may reflect age-or mutation-dependent effects.…”

“…46 The limited secondary effects on cellular calcium homeostasis associated with the PSEN1 A79V mutation may contribute to the later AAO reported in this cohort and others. 16,33 Additionally, variability may reflect alterations in the metabolism of other known PSEN1 cleavage substrates, including Notch, a transmembrane receptor involved in neuronal development and function. 47 PSEN1 A79V mutations have been shown to alter Aβ 42 levels and Aβ 42/40 ratio in cell culture, and MCs from the family described herein were previously found to have high CSF Aβ 42 and Aβ 42/40 ratios: findings that suggest gamma-secretase function may be altered in PSEN1 A79V MCs within this family.…”

“…7,8 Also, ADAD may be characterized by clinical features that are unusual in LOAD, including pyramidal signs, hypo/hyperkinetic movement disorders, ataxia, and early myoclonus and seizures. [9][10][11][12][13][14][15][16][17][18] Additional differences in the pattern of cerebral Aβ 42 deposition are reported in some ADAD cases, including 6,16,19,20 higher Aβ 42 burden and greater densities of neurofibrillary tangles; [21][22][23] increased Aβ 42 deposition within the cerebellum [24][25][26] and basal ganglia; 19,20 ; and higher prevalence of cerebral amyloid angiopathy and large diffuse so-called "cotton wool" plaques. 12,22,24,27 Such clinical and pathological differences may challenge whether findings from studies of early-onset ADAD, including current trials of anti-amyloid therapies, 28 can be extrapolated to the understanding of the far more common LOAD.…”

“…11,32,33 PSEN1 knockout cells transfected with the A79V mutant PSEN1 showed significantly increased Aβ 42 secretion, confirming the amyloidogenic potential of this mutation. 31 Reports of individuals with late-onset ADAD are rare 16,33,34 but offer the opportunity to mitigate the confound of age in comparisons with LOAD. Because dysregulation of Aβ 42 metabolism appears central to both ADAD and LOAD, 29,30,35 we hypothesized that the clinical characteristics of our cohort of PSEN1 A79V mutation carriers (MCs) with late-onset ADAD would overlap with those of LOAD.…”

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

“…Two of the most consistent cellular changes associated with both PS1 and PS2 FAD-associated mutations include ion channel dysfunction, such as defects in capacitative Ca 2ϩ entry (CCE) (16,17) and membrane trafficking defects, including diminished cell surface delivery of APP (15,(19)(20)(21). These A␤42-independent cellular changes may also contribute to the onset and/or neuropathological characteristics of presenilindependent FAD (22). Interestingly, certain pathogenic mutations in PS1 cause frontotemporal dementia with profound neurofibrillary tangle pathology in the absence of amyloid plaques (23).…”