Paper
- Alzforum Recommends
Krell-Roesch J, Rakusa M, Syrjanen JA, van Harten AC, Lowe VJ, Jack CR Jr, Kremers WK, Knopman DS, Stokin GB, Petersen RC, Vassilaki M, Geda YE. Association between CSF biomarkers of Alzheimer's disease and neuropsychiatric symptoms: Mayo Clinic Study of Aging. Alzheimers Dement. 2022 Feb 9; PubMed.
Recommends
Please login to recommend the paper.
Comments
Mercer University School of Medicine and Gateway BHS
The Krell-Roesch et al. study presents a rich set of results on the value of biomarkers and behavioral indices on depression and anxiety in a group of normal and MCI subjects. The study contributes to this body of research by providing preliminary evidence that lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42, are associated with depression and anxiety as measured in different ways by scales. Increased odds of presence of some behaviors, especially apathy and altered nighttime behavior, were also noteworthy.
The authors used a large sample of community-dwelling older adults free of dementia, detailed assessment of neuropsychiatric symptoms using both self-reported BDI-II and BAI, as well as informant-observed NPI-Q. The study did allude to mild behavioral impairment (MBI) as being associated with AD biomarker abnormalities.
The neuropsych battery used here is solid and representative of the cognitive domains. The behaviors were evaluated by the NPI and via an informant. I believe the MBI may be a better marker that the NPI, as this measure is discrete. Clearly one can consider depression and anxiety measured by scales as behaviors. In this case, the study “validated” the need for behaviors in the assessment.
Now I believe the question becomes what is the best set of behaviors to be assessed and how to assess them? The MBI has 10 or so studies on the issue of neurodegeneration and is a more promising index to assess early signs/symptoms of this problem. The NPI assesses more severe markers of neurodegeneration. It is examiner-based, which can be an advantage or a problem, subject to the strengths/weaknesses of an interviewer versus a self-report measure. Additionally, the MBI has more than 30 questions assessing five more relevant behaviors in the earlier stages of a decline process. It can also be rated by a significant other.
View all comments by Lee HyerLund University
Clinical Memory Research Unit
This paper makes a very important contribution to the literature by investigating the cross-sectional associations between core AD-related biomarkers in CSF and neuropsychiatric symptoms (NPS) in a large cohort of non-demented people.
The research field of NPS in AD struggles with diverse methodologies and conflicting findings. The straightforward methodology in this paper is therefore much welcomed and open for easier comparisons with other studies. Their key findings, including associations between Aβ pathology and certain NPS, such as anxiety and apathy, are relatively consistent with the overall literature. For example, we have previously demonstrated that anxiety and apathy are associated with Aβ deposition by PET imaging in non-demented individuals (Johansson et al, 2020).
However, the literature on depression is less conclusive. This probably reflects the polythetic concept of depression, which is captured somewhat differently between various rating scales. This is clearly illustrated by the opposing findings in this study when using the BDI-II or the NPI subdomain “dysphoria.” Therefore, it is a strength of this study that it studied associations with “clinical depression” obtained by dichotomization of the BDI-II according to a clinical cut-off. This probably increases the likelihood of having addressed “depression” and not NPS with overlapping symptomatology such as apathy or anxiety. In line with the use of the continuous BDI-II total rating score, clinical depression was related to lower levels of CSF Aβ42, as well as higher levels of the ratios of P-tau/Aβ42, and T-tau/Aβ42, respectively.
The interplay between NPS, cognition, and AD pathologies is complex. As the authors comment, the causal direction of the demonstrated associations cannot be displayed due to the study’s cross-sectional nature. Interestingly, the stratified analyses according to cognitive status show more robust associations between NPS and CSF Aβ42 among the MCI than the CU subjects, which indicates that cognitive dysfunction could play a role in NPS evolution.
Accordingly, studies exploring the effect of AD pathologies should control for cognitive dysfunction in order to reduce confounding.
In a recent paper, we demonstrated that the effect of CSF Aβ42 status on longitudinal change in NPS was mainly independent of cognitive decline (Johansson et al, 2022). However, additional longitudinal studies in this area are needed.
References:
Johansson M, Stomrud E, Lindberg O, Westman E, Johansson PM, van Westen D, Mattsson N, Hansson O. Apathy and anxiety are early markers of Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:74-82. Epub 2019 Oct 19 PubMed.
Johansson M, Stomrud E, Johansson PM, Svenningsson A, Palmqvist S, Janelidze S, Westen D, Mattsson-Carlgren N, Hansson O. Development of apathy, anxiety, and depression in cognitively unimpaired older adults: effects of Alzheimer’s disease pathology and cognitive decline. Biological Psychiatry, 31 January 2022
View all comments by Maurits JohanssonStanford / VA Aging Clinical Research Center
There is a well-established relationship between Alzheimer’s disease and depression (Ashford, 2018).
Below are the “risk factors” for Alzheimer’s disease, citations below; depression is listed: APOE-e4 genotype - 1 allele x 4; 2 alleles x 16
There is even some thought that there is a genetic link between depression and AD (Lutz et al., 2020). The focus on genetic factors is interesting but does not tell the whole story.
Two changes characteristic of very early Alzheimer’s disease are, first, loss of norepinephrine neurons in the locus coeruleus of the dorsal pons in the brainstem and, second, loss of serotonin neurons in the midbrain raphe system. Both norepinephrine and serotonin are thought to be related to depression since all of the anti-depressant medications work through one or both of these neurotransmitter systems (Ashford, 2018). And the norepinephrine and serotonin neurons are also involved in memory mechanisms (Ashford and Larvik, 1985).
The problem of the Alzheimer's and depression relationship in the elderly, not young individuals, is that both are likely related to similar underlying damage of the norepinephrine and serotonin neurons. The damage in the brainstem is likely the initial factor, which leads to both depression and Alzheimer's disease. Norepinephrine and serotonin synapses in the cortex, releasing their neurotransmitters in response to operant conditioning and classical conditioning signals respectively, activate the α-secretase (ADAM-10) to cleave the amyloid-protein precursor and stimulate the formation of new synapses. When an activated neuron does not get activation of the α-secretase, the default β-secretase pathway leads to removal of the local synapse, which is destroyed by the γ-secretase product Aβ, while the synaptic spine is withdrawn by the complement component by activating phosphorylation of the microtubule-associated protein-TAU. This careful balance leads to a turnover of synapses in the brain at a rate of about 5 trillion synapses (made and destroyed) per day.
Depression has been related to underactivity of norephinephrine and/or sertonin neurons. In depression, when it is an early symptom of Alzheimer's disease, the damaged projections of these neurons to the frontal lobes fail to activate the α-secretase to cleave the amyloid pre-protein, leading to excess of the default β-secretase and formation of excess amyloid, which is seen as deposits in early phases of Alzheimer's disease predominantly in the frontal lobes, though without dementia, but unrecognized cognitive changes likely do occur. However, the actual deposition of amyloid is probably not relevant, with the depression related to failure of frontal lobe processing of new information related to the decrease of α-secretase action and the excess loss of synapses due to the actions of the default β pathway.
Dementia occurs later, with more severe impairment of the norepinephrine and serotonin pathways. The failure of norepinephrine and serotonin activation in the regions of cortex with heavy memory activity and neuroplasticity, the hippocampus and amygdala and posterior temporal and inferior parietal cortices, leads to lack of processing of incoming information and memory dysfunction. These regions appear to be affected at a later age and predominantly show the signs of excess Tau phosphorylation, and these regions manifest less amyloid deposition, likely due to their adaptation for heavy amounts of neuroplasticity.
In any case, the amyloid protein precursor appears to be important, as overexpression of the gene encoding this protein is responsible for the dementia of Down’s syndrome, and the predisposition to amyloid deposition is closely related to APOE genotype, as evidenced by the age of onset of amyloid deposition and decades later by the age of onset of dementia. But neither of these points proves that amyloid deposition is related either to depression or dementia. In fact, while CSF amyloid goes down in relationship to APOE-e4 genotype, it is not related to dementia severity. Alternatively, CSF TAU increases in relationship to dementia severity but is not related to APOE genotype. It is more likely the amyloid deposition is serving as a scar caused by the underlying neurochemical process, which causes the underproduction of synapses and their over-destruction.
This view suggests that there is no role for amyloid removal as a treatment for Alzheimer's disease or its symptoms. The important questions are why the norepinephrine and serotonin neurons deteriorate, and how to alleviate that degeneration. The current best answers are healthy behaviors, though precision application according to genotype needs extensive study.
References:
Ashford JW. The Dichotomy of Alzheimer's Disease Pathology: Amyloid-β and Tau. J Alzheimers Dis. 2019;68(1):77-83. PubMed.
Lutz MW, Sprague D, Barrera J, Chiba-Falek O. Shared genetic etiology underlying Alzheimer's disease and major depressive disorder. Transl Psychiatry. 2020 Mar 9;10(1):88. PubMed.
Ashford JW, Jarvik L. Alzheimer's disease: does neuron plasticity predispose to axonal neurofibrillary degeneration?. N Engl J Med. 1985 Aug 8;313(6):388-9. PubMed.
Rocca WA. Frequency, distribution, and risk factors for Alzheimer's disease. Nurs Clin North Am. 1994 Mar;29(1):101-11. PubMed.
in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001 Nov 22;345(21):1515-21. PubMed.
Breitner JC, Jarvik GP, Plassman BL, Saunders AM, Welsh KA. Risk of Alzheimer disease with the epsilon4 allele for apolipoprotein E in a population-based study of men aged 62-73 years. Alzheimer Dis Assoc Disord. 1998 Mar;12(1):40-4. PubMed.
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. PubMed.
View all comments by John (Wes) AshfordMake a Comment
To make a comment you must login or register.