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Tijms BM, Vromen EM, Mjaavatten O, Holstege H, Reus LM, vanderLee SJ, Wesenhagen K, Lorenzini L, Vermunt L, Venkatraghavan V, Tesi N, Tomassen J, denBraber A, Goossens J, Vanmechelen E, Barkhof F, Pijnenburg YA, vanderFlier WM, Teunissen CE, Berven F, Visser PJ. Large-scale cerebrospinal fluid proteomic analysis in Alzheimer's disease patients reveals five molecular subtypes with distinct genetic risk profiles. 2023 May 11 10.1101/2023.05.10.23289793 (version 1) medRxiv.
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Weill College Medicine, New York
This is undoubtedly a step forward in the molecular characterization of AD, which, in concert with pathological and imaging studies, indicates that the molecular drivers are diverse, even though amyloid and tau may be frequent downstream offenders. The findings have critical therapeutic implications because they support the concept that a “one-size-fits-all” therapy may no longer be tenable, and that treatment approaches for AD need to be guided by the underlying molecular drivers on a patient-by-patient basis.
As in similar studies, the mechanisms suggested by proteomic analysis need to be independently validated at the functional level. In this regard, it would be desirable to have blood proteomics at the time of CSF collection. This would have provided some insight into the source of the proteins differentially represented in AD patients compared to controls. This issue is particularly relevant to the proteins observed in the group with presumed BBB dysfunction, in which some proteins were assumed to have crossed the BBB and reached the CSF, but the possibility of endogenous synthesis cannot be excluded.
The statement about amyloid clearance and CAA also needs to be independently validated by imaging/pathological approaches. It would also have been valuable to examine which of the different AD subgroups has coexisting macro- and micro-vascular pathology. Intracranial atherosclerosis has been linked to RNA processing dysfunction and neuroplasticity (Wingo et al., 2020), while white-matter lesions may hint at BBB dysfunction (Rudilosso et al., 2023; Shirzadi et al., 2023). Despite these considerations the study is a step in the right direction in expanding the pathobiology of AD beyond Aβ and tau, and in suggesting new therapeutic strategies and targets. The findings implicating the choroid plexus are particularly intriguing, and provide support to imaging studies implicating alterations of this poorly understood structure in AD. Whether these proteomic alterations are a cause or an effect of the pathology remains to be established, but the finding will undoubtedly enhance the interest of the AD scientific community in the choroid plexus.
I also find the link between AD subtype and survival very interesting, as it provides insight into the aggressiveness of the pathology, being greatest for the RNA dysfunction subtype. These associations between AD proteomic subtype and disease duration are also relevant to the management of AD patients, at both the prognostic and therapeutic levels.
Overall, the findings support the usefulness of CSF proteomics in the phenotypic characterization of patients with AD. Whether this approach will remain a valuable research tool, or will be transferable to community health care, remains to be seen.
References:
Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y, Harerimana NV, White B, Thambisetty M, Troncoso JC, Kim N, Schneider JA, Hajjar IM, Lah JJ, Bennett DA, Seyfried NT, Levey AI, Wingo TS. Shared proteomic effects of cerebral atherosclerosis and Alzheimer's disease on the human brain. Nat Neurosci. 2020 Jun;23(6):696-700. Epub 2020 May 18 PubMed. Correction.
Rudilosso S, Stringer MS, Thrippleton M, Chappell F, Blair GW, Jaime Garcia D, Doubal F, Hamilton I, Janssen E, Kopczak A, Ingrisch M, Kerkhofs D, Backes WH, Staals J, Duering M, Dichgans M, Wardlaw JM, SVDs@target consortium. Blood-brain barrier leakage hotspots collocating with brain lesions due to sporadic and monogenic small vessel disease. J Cereb Blood Flow Metab. 2023 Sep;43(9):1490-1502. Epub 2023 May 3 PubMed.
Shirzadi Z, Schultz SA, Yau WW, Joseph-Mathurin N, Fitzpatrick CD, Levin R, Kantarci K, Preboske GM, Jack CR Jr, Farlow MR, Hassenstab J, Jucker M, Morris JC, Xiong C, Karch CM, Levey AI, Gordon BA, Schofield PR, Salloway SP, Perrin RJ, McDade E, Levin J, Cruchaga C, Allegri RF, Fox NC, Goate A, Day GS, Koeppe R, Chui HC, Berman S, Mori H, Sanchez-Valle R, Lee JH, Rosa-Neto P, Ruthirakuhan M, Wu CY, Swardfager W, Benzinger TL, Sohrabi HR, Martins RN, Bateman RJ, Johnson KA, Sperling RA, Greenberg SM, Schultz AP, Chhatwal JP, Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging Initiative. Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease. JAMA Neurol. 2023 Dec 1;80(12):1353-1363. PubMed.
View all comments by Costantino IadecolaUniversity of Southern California
University of Southern California
USC
Alzheimer’s disease is molecularly highly heterogeneous, involving many different pathophysiological processes. This heterogeneity may also contribute to the limited effects observed in current clinical Alzheimer’s disease (AD) trials, highlighting the need for personalized treatment. Defining those molecular AD subtypes may be possible through analyzing cerebral spinal fluid (CSF), as CSF has been shown to carry a multifaceted AD signature that goes beyond Aβ and tau (Johnson et al., 2023; Del Campo et al., 2022).
This new, large-scale, CSF quantitative proteomic analysis from 609 individuals (AD: 419, CTRL: 187) identified a total of 3,863 proteins, of which approximately one-third was observed across all individuals. Proteins were further quantitated using 16 plex tandem mass tags (TMT), fractionated, and analyzed by state-of-the-art LC-MS/MS with FAIMS, and data dependent acquisition. Cluster analysis in AD individuals revealed three previously identified subtypes characterized by 1) neuronal hyperplasticity, 2) innate immune activation, and 3) BBB dysfunction, and two new subtypes: 4) RNA dysregulation and 5) choroid plexus dysfunction, all associated with distinct AD genetic risk factors.
The CSF proteomics for classifying AD subtypes may be a valuable resource in developing specific future treatments. For instance, patients exhibiting pronounced innate immune activation might respond more effectively to immune modulators. Conversely, those showing signs of neuronal hyperplasticity could potentially benefit from treatments that activate TREM2. Individuals with predominant vascular dysfunction and a subtype of AD with blood-brain barrier (BBB) breakdown that can predict cognitive decline might benefit from treatments preventing the BBB leaks into the brain and stabilizing the BBB integrity.
Future clinical studies will reveal whether the classified AD subtypes show different responses to particular treatments, or whether the classification can be used to select suitable subjects for upcoming clinical trials. Ideally, the presented AD subtype classification could be complemented by future studies with blood-based tests, addressing a broader AD population and facilitating earlier detection and therapeutic intervention in the disease process.
References:
Johnson EC, Bian S, Haque RU, Carter EK, Watson CM, Gordon BA, Ping L, Duong DM, Epstein MP, McDade E, Barthélemy NR, Karch CM, Xiong C, Cruchaga C, Perrin RJ, Wingo AP, Wingo TS, Chhatwal JP, Day GS, Noble JM, Berman SB, Martins R, Graff-Radford NR, Schofield PR, Ikeuchi T, Mori H, Levin J, Farlow M, Lah JJ, Haass C, Jucker M, Morris JC, Benzinger TL, Roberts BR, Bateman RJ, Fagan AM, Seyfried NT, Levey AI, Dominantly Inherited Alzheimer Network. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease. Nat Med. 2023 Aug;29(8):1979-1988. Epub 2023 Aug 7 PubMed.
Del Campo M, Peeters CF, Johnson EC, Vermunt L, Hok-A-Hin YS, van Nee M, Chen-Plotkin A, Irwin DJ, Hu WT, Lah JJ, Seyfried NT, Dammer EB, Herradon G, Meeter LH, van Swieten J, Alcolea D, Lleó A, Levey AI, Lemstra AW, Pijnenburg YA, Visser PJ, Tijms BM, van der Flier WM, Teunissen CE. CSF proteome profiling across the Alzheimer's disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels. Nat Aging. 2022 Nov;2(11):1040-1053. Epub 2022 Nov 10 PubMed.
View all comments by Marcelo CobaEmory University
This study employs unbiased clustering of over 400 CSF proteomic profiles to categorize or subtype distinct groups of individuals clinically diagnosed with AD. This type of unbiased classification is important because, despite displaying indications of dementia, or positivity for amyloid and/or tau biomarkers, individuals do not follow the same disease course. The authors identified five distinct subtypes of AD characterized by their CSF proteomic profiles and investigated their relationships with genetic risk and clinicopathologic phenotypes. These groups were classified based on biological ontologies that effectively differentiated them from one another. This classification included neuronal hyperplasticity, innate immunity, RNA dysregulation, choroid plexus dysfunction, and blood-brain barrier (BBB) dysfunction. Notably, some of the subtypes differed in their rate of progression from MCI to dementia and in brain atrophy.
It was intriguing that individuals within two of these subtypes, choroid plexus and BBB dysfunction, comprising approximately one-third of the cohort, displayed lower levels of tau and p-tau compared to the other three subtypes. This implies that mechanisms beyond tau may be influencing their cognitive decline, or alternatively, that tau is not an optimal biomarker for these subclasses. Genetic profiles were linked to subtypes, also, revealing an association with genetic risk, particularly in the hyperplasticity subtype, which is enriched with TREM2 variant carriers. The authors propose that individuals with this subtype may respond to treatments targeting TREM2, even if they do not carry the TREM2 R47H variant. It was also interesting that APOE4 carriers were enriched, albeit not statistically, in the BBB subtype compared to other subtypes, because APOE4 carriers are known to have increased cerebrovascular dysfunction compared to noncarriers.
One outstanding question is whether individuals within specific subtypes are more or less responsive to particular drug treatments. The authors propose that additional studies should aim to analyze or even retrospectively reanalyze CSF in clinical trials by proteomics. This would allow the assessment of whether specific treatments have effects that are specific to only certain subtypes. If this proves to be the case, it could pave the way for personalized medicine approaches in the treatment of AD.
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