The multi-morbid old brain

Abstract

in Alzheimer's disease (AD), lowers the threshold for the amount of AD pathology necessary to cause clinical dementia [1]. Kapasi and colleagues now try to clarify this assumption and review data from large community-based cohorts to evaluate the influence of multiple pathologies on the clinical phenotype [6].Despite recent advances in the development of biomarkers for neuropathological lesions, such as Aβ and tau by both imaging methods and cerebrospinal fluid assessment, cerebral multi-morbidity is not accurately reflected in clinical diagnoses. This has a detrimental impact on clinical cohort studies as cohorts are assumed to be homogenous, while they are in fact highly heterogenous; e.g., a clinical AD cohort will have patients with (i) Aβ and tau pathology only; (ii) Aβ, tau, and α-syn pathology (over 40%); and (iii) Aβ, tau, and TDP-43 pathology (over 50%). In addition, there will be a range of cerebrovascular pathologies present and likely combinations of (ii) and (iii). Therefore, the interpretation of clinical data will be highly biased and there is an urgent need for tools that allow for a more accurate cohort stratification based on the underlying pathologies. To date, this can only be achieved by neuropathological post-mortem examination as neuropathological data can be used to retrospectively stratify clinical cohorts and thereby facilitate the development of more accurate clinical biomarkers. The latter will in turn lead to an improvement in patients' diagnostics and therapy.Age-associated cerebral multi-morbidity challenges our current concept of classifying age-associated neurodegenerative diseases, which categorises cases according to the main underlying pathology, e.g., AD equals Aβ and tau pathology and dementia with Lewy bodies (DLB) equals α-syn pathology. Such a concept is actually based on the rather whimsical assumption that these diseases are mutually exclusive. However, it should not come as a surprise While it is well known that the "old" brain is characterised by the simultaneous presence of multiple neurodegenerative pathologies, rather than by the hallmark pathologies of one single age-associated neurodegenerative disease, comprehensive articles putting this multi-morbidity in context with clinical, neuropathological, genetic, and experimental data are lacking. Therefore, this issue of Acta Neuropathologica features two articles reviewing the various aspects and implications of age-associated cerebral multi-morbidity.Spires-Jones and colleagues inform the reader about the current evidence for interactions between different pathological proteins and provide data from both human brain tissue and experimental models [8]. The interaction between amyloid-β (Aβ) and tau is clearly the best documented one; while the "amyloid-hypothesis" in its strict sense, i.e., Aβ "causes" tau pathology, has been disproven, not least by the fact that tau pathology can develop in the complete absence of any Aβ (i.e., primary age-associated tauopathy (PART) [3]), we also know from human studies that severe...

Rate of Cognitive Decline in Alzheimer’s Disease Stratified by Age

“…It is likely that there are interactions of different pathological processes or proteins that seem to aggravate each other [28]. Neuropathological studies suggest older adults are more likely to have simultaneous presence of multiple pathologies in the brain which may accelerate disease progression [28][29][30]. However from our sample of older patients and similar to other studies [2,27], we found older adults had a slower rate of decline.…”

“…However from our sample of older patients and similar to other studies [2,27], we found older adults had a slower rate of decline. A possible explanation for this is that younger individuals have a more "pure" and greater degree of AD pathology, whereas the "older" brain often has mixed neuropathologies [29]. Younger onset of AD is associated with greater grey matter atrophy, increased glucose hypometabolism and greater tau deposition measured using neuroimaging [31]; neuropathologically more severe senile plaques, neurofibrillary tangles and synapse loss [8]; as well as greater deficits in the neurochemical acetylcholine and other neurotransmitters such as adrenaline [32].…”

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

“…Progranulin and β-amyloid have been shown to co-localize in plaques in DLB, suggesting a possible biological association between these two aggregated proteins [60]. However, there are often multiple concomitant pathologies that are identified in neurodegenerative disease, and so the observation of TDP-43 with Lewy and amyloid pathology could simply be coincidental multi-morbidity of simultaneous pathologies that coexist in the ageing brain [6]. After the identification of the GRN mutation, additional clinicopathological information was reviewed to assess this case.…”

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

“…Other similarities include the abnormal folding of endogenous protein into different strains via a template protein, transfer of misfolded proteins between cells, and pathology propagation in the brain [20,83,84]. Intriguingly, the heterogeneity of synucleinopathies and other neurodegenerative diseases is not usually attributed to an alternate hypothesis that arises from the neuropathological examination of the brain: The simultaneous presence of multiple types of pathologies which could, depending on the relative levels, explain the heterogeneity of the multi-morbid old brain [85].…”