Memory impairment dues to normal aging? or mild cognitive impairment? or Alzheimer’s?

Memory insufficiency is a common complain among many especially among the elderly, but is every forgetfulness abnormal? or something more serious? It is important to differentiate them because if it is normal aging, definitely no treatment is required comparing to the later two. The question in mind is how to differentiate? are there any very reliable test? Unfortunately, there are no such test. Currently, in clinical practice, differentiating between these 3 is still by a carefully performed and detailed history taking and clinical assessment. Therefore it is important to know the test available and its’ accuracy before making a diagnosis.

Let’s begin with Alzheimer’s disease (AD), since this is the most serious among the three and a state that we are trying to prevent getting. In AD, the definite diagnosis according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), with clinical criteria for probable AD and histopathologic evidence obtained from either biopsy or autopsy (Fig.1)[ref1]. This shows that we would not reached a definite diagnosis when treatment is sought, until a biopsy or autopsy is done. Hence, probable AD is the ultimate diagnosis in clinical setting. In making diagnosis of probable AD, criteria for dementia is required to be met as shown in Fig 1. The mini-mental status exam (MMSE) is most commonly used to detect dementia but it lack sensitivity (71-85%) and only modest specificity (81-96%)[ref2]. Moreover, majority of person below the cutoff points of MMSE score would be false positive [ref1]. Another test Montreal cognitive assessment (MoCA) is used, which has higher sensitivity but lack specificity in detecting dementia [ref3].


In addition, by using NINCDS-ARDRA criteria in making diagnosis of probable AD, it only has sensitivity of 66-93% and specificity of 23-70%. Another set of criteria which is commonly used; the Diagnostic and Statistical Manual of Mental Disorders IV (DSMIV) has high positive predictive value (89-100%) but low negative predictive value (33-63%) [ref1]. However with the combination of Magnetic resonance imaging (MRI), the sensitivity and specificity increased [ref5]. With MRI detecting medial temporal lobe atrophy has sensitivity and specificity more than 90% [ref1]. Assessment of medial temporal atrophy on MRI is able to differentiate mild AD from normal aging with sensitivity and specificity more than 80% [ref4]. Dues to the fact the structural MRI is able to detect medial temporal lobe atrophy before the onset of AD, it can be used as a predictor of progression to AD, and a tool for detecting mild cognitive impairment [ref4] although more reviewing is required.

Therefore, by using definite AD criteria set by NINCDS-ADRDA as a standard, we have relatively high sensitivity but low specificity approach to diagnose AD, which can be increased with combination of neuroimaging. This come the next question, how to differentiate from Mild cognitive impairment (MCI) and normal aging?

MCI is an intermediate state of cognitive function between the changes seen in aging and those fulfilling the criteria for dementia and often Alzheimer’s disease [ref6]. If the presentation met the criteria of AD in either NINCDS-ADRDA or DSM, it is not MCI. One important criteria commonly used although not mentioned in NINCDS-ADRDA criteria is significant impairment in social and occupational functioning (mentioned in DSMiv-TR). MCI does not cause significant impairment, although ones tend to forget important information that relevant (previously easily remembered) to them such as appointment, and recent event that interest them; these exclude event that is subtle such as misplacing items and recalling words [ref6].

A set of criteria by Petersen et al. 1999 expanded in 2003 to diagnose MCI [ref7]. The 1999 version include:
1) Memory complaint, preferably corroborated by an informant
2) Memory impairment documented according to appropriate reference values
3) Essentially normal performance in nonmemory cognitive domains
4) Generally preserved activities of daily living
5) Not demented

For the revised 2003 version, please refer to [ref7]

In short, the 2003 version has removed non-memory cognitive domains has inclusion criteria and divided MCI into amnestic and non-amnestic subtype. However, impairment of social and personal living is an important differentiating factor between AD and MCI [ref6]. Dementia must not be present in diagnosing MCI; if dementia is present, according to NINCDS-ADRDA, it is AD or according to Petersen et al. 1999/2003 it is not MCI.Therefore, it is important to know the diagnostic criteria for dementia, one of it is by using MMSE. With the total score of 30, the conventional cutoff score is <;; 24/30 and it shows a sensitivity of 63% and a specificity of 96% [ref8]. However, MMSE scoring varies according to education level, and 27 cutoff point is recommended for more educated person [ref9]. Besides that, in 1 meta-analysis, MMSE has only modest accuracy, however with cutoff 29/30, it has great value in ruling out [ref2]. Another scale worth noting is Clinical Dementia Rating (CDR) scale. CDR is a rating scale ranging from normal (CDR 0) to questionable dementia (CDR 0.5) and mild (CDR 1), moderate (CDR 2) and severe (CDR 3)[ref10]. Some research studies have equated CDR 0.5 to MCI; however, it should be realised that the CDR is a severity rating scale and not a diagnostic instrument [ref10][ref11]. CDR is relatively reliable and stable[ref12] and may be modified in the future in helping to diagnose MCI. Montreal Cognitive Assessment (MoCA) has better sensitivity but lesser specificity comparing MMSE in detecting MCI [ref13]. We can say that we still does not has yet a perfect test to differentiate these three conditions.

In conclusion, in differentiating normal aging, MCI, and AD (probable AD) largely depend on clinical assessment. MMSE, DSM, and MoCA is commonly used in detecting dementia; if dementia is identified, it is not MCI or aging. The significance of social or occupational is another importance clue toward the differentiating AD and MCI; if significant impairment of living function is found, it is most likely AD (provided other type of dementia is ruled out). The more challenging part is differentiating normal aging and MCI; if memory impairment is subtle and has normal MMSE, it is more likely to be normal aging. Hence, MCI fall between normal aging and AD, with memory impairment and affected objective memory assessment (MMSE, MoCA, ect) but does not met the criteria of dementia. Criteria set by Petersen et al. 1999 or the 2003 revised version is commonly and perhaps the best test used in detecting MCI.


1. Elizabeth Finger, Kirk R. Daffner. Cognitive and Behavioral Neurology. In: Burneo, Jorge G; Demaerschalk, Bart M.; Jenkins, Mary E. eds. Neurology: an evidence-based approach. New York, NY: Springer; 2012:161-174

2. Mitchell AJ. (2009). A meta-analysis of the accuracy of the mini-mental state examination in the detection of dementia and mild cognitive impairment. J Psychiatr Res. 2009;43:411–31.

3. Anne M Damian, Sandra A Jacobson, Joseph G Hentz, et al. (2011), The Montreal Cognitive Assessment and the Mini-Mental State Examination as Screening Instruments for Cognitive Impairment: Item Analyses and Threshold Scores. Dement Geriatr Cogn Disord 2011;31:126-131. doi: 10.1159/000323867

4. Johnson KA, Fox NC, Sperling RA, Klunk WE. (2012), Brain imaging in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2012 Apr;2(4):a006213. doi: 10.1101/cshperspect.a006213

5. Yawu Liu, Teemu Paajanen, Yi Zhang, et al. [2011], Combination analysis of neuropsychological tests and structural MRI measures in differentiating AD, MCI and control groups—The AddNeuroMed study, Neurobiology of Aging, Volume 32, Issue 7, July 2011, Pages 1198-1206, ISSN 0197-4580, 10.1016/j.neurobiolaging.2009.07.008.

6. Ronald C. Petersen, M.D., Ph.D. (2011), Mild Cognitive Impairment. New England Journal of Medicine, 364:2227-2234. doi: 10.1056/NEJMcp0910237

7. Petersen RC, Roberts RO, Knopman DS, et al. (2009), Mild cognitive impairment: Ten years later. Arch Neurol. 2009;66(12):1447-1455. doi:10.1001/archneurol.2009.266.

8. W.A. Kukull, E.B. Larson, L. Teri, J. Bowen, W. McCormick, M.L. Pfanschmidt, The mini-mental state examination score and the clinical diagnosis of dementia, Journal of Clinical Epidemiology, Volume 47, Issue 9, September 1994, Pages 1061-1067, ISSN 0895-4356, 10.1016/0895-4356(94)90122-8.

9. O’Bryant SE, Humphreys JD, Smith GE, et al. Detecting Dementia With the Mini-Mental State Examination in Highly Educated Individuals. Arch Neurol. 2008;65(7):963-967. doi:10.1001/archneur.65.7.963.

10. R. C. Petersen (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine. 2004; 256(3):183-194. doi:10.1111/j.1365-2796.2004.01388.x

11. Morris JC, Storandt M, Miller J, et al. Mild Cognitive Impairment Represents Early-Stage Alzheimer Disease. Arch Neurol.2001;58(3):397-405. doi:10.1001/archneur.58.3.397.

12. Williams MM, Roe CM, Morris JC. Stability of the Clinical Dementia Rating, 1979-2007.Arch Neurol. 2009;66(6):773-777. doi:10.1001/archneurol.2009.69.

13. Nasreddine, Z. S., Phillips, N. A., Bédirian, V., Charbonneau, S., Whitehead, V., Collin, I., Cummings, J. L. and Chertkow, H. (2005), The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment. Journal of the American Geriatrics Society, 53: 695–699. doi: 10.1111/j.1532-5415.2005.53221.x


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