Norton DJ, Amariglio R, Protas H, Chen K, Aguirre-Acevedo DC, Pulsifer B, Castrillon G, Tirado V, Munoz C, Tariot P, Langbaum JB, Reiman EM, Lopera F, Sperling RA, Quiroz YT. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease. Neurology. 2017 Oct 3;89(14):1464-1470. Epub 2017 Sep 6 PubMed.

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  1. Due to inconsistent results, it is still under debate whether subjective cognitive decline (SCD) represents an early sign of Alzheimer’s disease. Previous evidence showed that SCD was associated with future objective cognitive decline and conversion from normal cognition to mild cognitive impairment. More recently, studies on SCD showed brain abnormalities related to AD, such as increased cerebral Aβ deposition, greater atrophy and glucose hypometabolism, and disrupted functional connectivity changes.

    The major issues that prevent the use of SCD as an early indicator of AD are related to the variability found in the literature and the lack of clear neurobiological mechanisms underlying SCD.

    In this JAMA Neurology paper, Buckley and colleagues take a step forward in understanding the neurobiological mechanisms underlying SCD by using PET flortaucipir F 18 to detect paired helical filaments of tau in the entorhinal cortex and the inferior temporal region, and Carbon 11–labeled Pittsburgh compound B to determine the global Aβ burden. Results from the linear regression model (controlling for age, sex, educational attainment, and Geriatric Depression Scale score) showed that greater SCD was associated with increasing entorhinal cortical tau burden and Aβ burden but not inferior temporal tau burden.

    The second study, by Norton and colleagues, investigated the frequencies of self-reported and partner-reported subjective memory complaints in individuals from a Colombian kindred with high prevalence of the presenilin-1 (PSEN-1) E280A mutation, and their association with age and hippocampal volume. Results revealed higher self-reported subjective memory complaints in carriers compared to noncarriers. Moreover, informant-reported subjective memory complaints and hippocampal volume significantly related to age, while self-reported subjective memory complaints did not. However, a previous study on the same population did not find any difference between cognitively unimpaired carriers and noncarriers, indicating that further studies should be conducted in order to clarify the role of subjective memory complaints in early onset AD.

    These manuscripts highlight new evidence on the genetic and pathophysiological bases of SCD. The definition of SCD is still evolving and the association between SCD and depressive symptoms is not clear yet. Moreover, it is not clear how the results found in these populations might be more related to depressive symptoms than to AD pathology. Finally, the impact of age in the neurodegeneration processes and its association with SCD is still under debate, as shown by the results of Norton and colleagues. Future studies investigating whether SCD might represent an early marker of AD should take into account depressive symptoms and age as independent factors, not exclusively as covariate, in order to understand exclusively the impact of SCD in relation to AD and to exclude neurodegeneration processes due to age or depressive symptoms. SCD might represent the early clinical expression of neurodegeneration during aging and depression.

    References:

    Mitchell AJ, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B. Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: meta-analysis. Acta Psychiatr Scand. 2014 Dec;130(6):439-51. Epub 2014 Sep 13 PubMed.

    Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stewart R, Uspenskaya O, Vellas B, Visser PJ, Wagner M, Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014 May 3; PubMed.

    La Joie R, Perrotin A, Egret S, Pasquier F, Tomadesso C, Mézenge F, Desgranges B, de La Sayette V, Chételat G. Qualitative and quantitative assessment of self-reported cognitive difficulties in nondemented elders: Association with medical help seeking, cognitive deficits, and β-amyloid imaging. Alzheimers Dement (Amst). 2016;5:23-34. Epub 2016 Dec 18 PubMed.

    Lista S, Molinuevo JL, Cavedo E, Rami L, Amouyel P, Teipel SJ, Garaci F, Toschi N, Habert MO, Blennow K, Zetterberg H, O'Bryant SE, Johnson L, Galluzzi S, Bokde AL, Broich K, Herholz K, Bakardjian H, Dubois B, Jessen F, Carrillo MC, Aisen PS, Hampel H. Evolving Evidence for the Value of Neuroimaging Methods and Biological Markers in Subjects Categorized with Subjective Cognitive Decline. J Alzheimers Dis. 2015 Sep 24;48 Suppl 1:S171-91. PubMed.

    Ossenkoppele R, Jagust WJ. The Complexity of Subjective Cognitive Decline. JAMA Neurol. 2017 Dec 1;74(12):1400-1402. PubMed.

    Buckley RF, Hanseeuw B, Schultz AP, Vannini P, Aghjayan SL, Properzi MJ, Jackson JD, Mormino EC, Rentz DM, Sperling RA, Johnson KA, Amariglio RE. Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden. JAMA Neurol. 2017 Dec 1;74(12):1455-1463. PubMed.

    Norton DJ, Amariglio R, Protas H, Chen K, Aguirre-Acevedo DC, Pulsifer B, Castrillon G, Tirado V, Munoz C, Tariot P, Langbaum JB, Reiman EM, Lopera F, Sperling RA, Quiroz YT. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease. Neurology. 2017 Oct 3;89(14):1464-1470. Epub 2017 Sep 6 PubMed.

    Lopera F, Ardilla A, Martínez A, Madrigal L, Arango-Viana JC, Lemere CA, Arango-Lasprilla JC, Hincapíe L, Arcos-Burgos M, Ossa JE, Behrens IM, Norton J, Lendon C, Goate AM, Ruiz-Linares A, Rosselli M, Kosik KS. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.

    View all comments by Harald Hampel

  2. The paper by Buckley et al. shows that higher subjective cognitive decline (SCD) scores are associated with higher tau burden in the brain in clinically healthy older adults. However, this finding does not yet justify considering SCD as an indicator for tauopathy in the brain, as we get no information about diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of SCD for the presence of tauopathy in the brain. In addition, higher tau levels in the brain are not necessarily pathological levels.

    Norton and colleagues demonstrate that cognitively normal carriers of the PSEN-1 E280A mutation show higher subjective memory complaint (SMC) scores than noncarriers. This indicates that increased SMC scores seem to be an early sign of autosomal-dominant Alzheimer`s disease (ADAD). However, the information about estimated years to symptom onset is missing, so it is not possible to say how early SMC scores are rising in the preclinical stage of ADAD.

    That both papers are using different terms (SCD versus SMC) and different quantitative measures for subjective memory problems demonstrates the urgent need to better standardize this research topic in the near future.

    View all comments by Christoph Laske

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