A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer’s disease
Open accessAbstract
Presenilin-1 (PSEN1) mutations cause familial Alzheimer’s disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aβ) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype–phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aβ, there were no relevant differences between groups in generation and deposition of Aβ. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin–proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aβ accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aβ pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD.
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Aβ pathology distribution showed an expected fronto-temporal predominant pattern.
“In contrast, Aβ pathology distribution showed an expected [6, 32] fronto-temporal predominant pattern (Fig. 2A–C, Supp. Figure 2, online resource).”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [32]
The Results section, Fig. 2 caption (page unavailable), reports Aβ staining and plaque-load measurements in the frontal, temporal, parietal, and occipital cortices. Our copy does not state that pathology was predominantly fronto-temporal or compare those regions in a way that establishes that pattern. (LLM, conf=0.78)
Experimental — accuracy not yet measuredOur findings provide evidence supporting tau pathology as the main driver of cognitive decline in PSEN E280A ADAD.
“Our findings provide evidence supporting tau pathology as the main driver of cognitive decline in PSEN E280A ADAD, as suggested by other previous findings in this population [31, 32]”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [32]
The Results report lower tau pathology in late-onset PSEN1 E280A patients. The Discussion proposes phosphorylated tau pathology as the main determinant of age of onset and says factors affecting tau phosphorylation can accelerate cognitive decline. It does not establish tau pathology as the main driver of cognitive decline; it also describes Aβ accumulation as a prerequisite for dementia. (LLM, conf=0.83)
Experimental — accuracy not yet measuredOther genetic variants identified as modifiers or protective against familial Alzheimer's disease (FAD) delay Alzheimer's disease (AD) onset and are related to astrocyte genes, ubiquitin-proteasome function, and p-tau degradation.
“Other genetic variants that have also been identified as modifiers or protective against FAD, delay AD‐onset and are related to astrocyte genes, ubiquitin‐proteasome function, and p‐tau degradation [61, 126, 129]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [129]
The Results and Discussion link genetic variants in PSEN1 E280A familial Alzheimer’s disease to age of onset, ubiquitin–proteasome function, and p-tau degradation. Our copy does not link the identified variants to astrocyte genes, so that part of the sentence is not supported by this source. The passages provided have no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome cases in a large kindred carrying the PSEN1 E280A mutation have shown delayed onset, suggesting possible mechanisms of disease modulation.
“Nevertheless, some cases belonging to a large kindred carrying the presenilin-1 (PSEN1) E280A mutation have shown delayed onset, suggesting possible mechanisms of disease modulation [31, 32].”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [32]
AD protected cases showed decreased tau cortical pathology, with the exception of the occipital cortex which showed the same degree of tau pathology regardless of age of onset.
“Similar to our current findings, AD protected cases showed decreased tau cortical pathology, with the exception of the occipital cortex which showed the same degree of tau pathology regardless of age of onset [32].”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [32]
We previously reported the impact of tau pathology as a disease onset modifier and disease progression marker in vivo in this ADAD population.
“We previously reported the impact of tau pathology as a disease onset modifier [32] and disease progression marker in vivo [31] in this ADAD population.”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [32]
The observation that characteristics of soluble tau correlate with aggressiveness of clinical phenotype has been replicated in two other clinical populations.
“This observation—that the characteristics of soluble tau correlate with how aggressive the clinical phenotype is—has already been replicated in two other clinical populations (68, 69).”
From All the Tau We Cannot See (2023) · cites this paper as [69]
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Exosomal mRNA Signatures as Predictive Biomarkers for Risk and Age of Onset in Alzheimer’s Disease
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Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders
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- Authors
- Sepulveda-Falla, D., Chavez-Gutierrez, L., Portelius, E., Vélez, J. I., Dujardin, S., Barrera-Ocampo, A., Dinkel, F., Hagel, C., Puig, B., Mastronardi, C., Lopera, F., Hyman, B. T., Blennow, K., Arcos-Burgos, M., de Strooper, B., & Glatzel, M.
- Affiliations
- Sahlgrenska University Hospital (SE)
- Harvard University (US)
- University Medical Center Hamburg-Eppendorf (DE)
- Australian National University (AU)
- Universidad de Antioquia (CO)
- Corresponding author
- Glatzel, Markus
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2020-12-14
- Volume
- 141
- Issue
- 2
- Pages
- 217-233
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC7847436
- OpenAlex
- W3112685614
- Cited by
- 54
- References
- 65
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 11 · 2023: 10 · 2022: 10 · 2021: 9
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (publishedVersion, other-oa)
- Lirias (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- ANU Open Research (Australian National University) (submittedVersion, cc-by)
- Greater South Information System
- Funders
- Hamburg Landesforschungsförderung (Molekularemechanismen der netzwerkmodifizierung)
- Bundesministerium für Bildung und Forschung (UndoAD)
- Fonds Wetenschappelijk Onderzoek
- Vlaams Initiatief voor Netwerken voor Dementie Onderzoek (135043)
- Stiftelsen Gamla Tjänarinnor
- Eccles Scholarship in Medical Sciences
- Deutscher Akademischer Austauschdienst
- Colciencias, Ministerio de Ciencia y Tecnología (1115 657 41185)
- Swedish Alzheimer Foundation (AF-553101)
- John Curtin School of Medical Research
- Alzheimer's Association (2018-AARF-591935)
- National Institutes of Health (RF1AG059789, R56AG061196)
- Universitätsklinikum Hamburg-Eppendorf (UKE)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- familial Alzheimer's disease, presenilin 1, PSEN1 E280A mutation, amyloid-beta, tau hyperphosphorylation, tau aggregation, proteasome activity, ubiquitin-proteasome system, genotype-phenotype correlation, gamma-secretase, sporadic Alzheimer's disease
- MeSH terms
- Exome Sequencing, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Genotype, Heterozygote, Humans, Male, Middle Aged, Models, Neurological, Phenotype, Phosphorylation, Amyloid beta-Protein Precursor, tau Proteins, Age of Onset, Proteasome Endopeptidase Complex, Presenilin-1, Ubiquitination
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