Defining and describing the pre-dementia stages of familial Alzheimer's disease

With the prospect of prevention trials for familial Alzheimer's disease on the horizon, understanding the natural history of the illness has never been so important. Earlier this year in The Lancet Neurology, Acosta-Baena and colleagues published the results of the largest and longest retrospective study of pre-dementia clinical stages in familial Alzheimer's disease to date. By reviewing serial neuropsychological assessments of individuals from a large Colombian kindred affected by the E280A mutation in the Presenilin 1 gene, they defined three stages of pre-dementia cognitive impairment. Using survival analyses, the authors estimated the median age at onset and rate of progression through each of these stages towards dementia and ultimately death. Their study provides valuable insights into the time course of cognitive decline associated with this mutation. Furthermore, the study highlights some of the challenges of defining pre-dementia clinical stages in familial Alzheimer's disease and the need for the field to develop a consistent terminology.

It is now well established that symptoms of Alzheimer's disease (AD) dementia are preceded by a long period of gradual accumulation of pathological changes [1]. Th e growing view that disease-modifying therapies may only be eff ective if used relatively early in this process has shifted attention towards the pre-dementia phases of the disease. Th is shift in focus has been accompanied by increasing recognition of the importance of familial AD. Th e study of individuals carrying rare, autosomal dominantly inherited mutations in the amyloid precursor protein (APP), Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2) genes provides unique opportunities to observe the earliest manifestations of the pathological process. With the design of prevention trials for these individuals already underway [2,3], there is an urgent need to better understand and defi ne the pre-dementia stages of familial AD.
Acosta-Baena and colleagues recently reported the results from their 15-year study of a Colombian kindred aff ected by the E280A PSEN1 mutation [4]. Of 1,784 family members enrolled, 1,181 were genotyped yielding 459 carriers and 722 noncarriers. Of the carriers, 449 had undergone neuropsychological testing; 140 (31%) were assessed only once, whilst the remainder had serial assessments (average 3.2 assessments, range 1 to 12) at intervals ranging from 1 to 11 years (mean 2.1 years). Th e neuropsychological data from 499 of the noncarriers were used to generate normal parameters for the Colombian population under the age of 50, which were grouped according to age and education.
Th e authors defi ned fi ve clinical states: healthy, dementia, and three intermediate stages of pre-dementia cognitive impairment [4]. Pre-dementia cognitive impairment was defi ned as a score 2 standard deviations away from the noncarrier mean, adjusted for age and education, on at least one cognitive test. Th ose patients with pre-dementia cognitive impairment but no memory complaints were defi ned as asymptomatic pre-mild cogni tive impairment (pre-MCI). Th ose patients with memory complaints and a score higher than the noncarrier mean on a subjective memory complaints checklist, but with little or no impairment of complex activities of daily living (ADL), were defi ned as MCI. In between, a stage of symptomatic pre-MCI defi ned those individuals who had some memory complaints but did not score higher than the noncarrier mean on the subjective memory complaints checklist, with preserved ADL. Individuals with memory complaints interfering with complex and basic ADL were defi ned as demented.
Using survival analyses to model progression, the authors described a typical trajectory from healthy to asymptomatic pre-MCI (median age at onset 35 years), to sym pto matic pre-MCI (median age 38 years), to MCI (median age 44 years), to dementia (median age 49 years) and ultimately to death (median age 59 years). Th e cognitive

Abstract
With the prospect of prevention trials for familial Alzheimer's disease on the horizon, understanding the natural history of the illness has never been so important. Earlier this year in The Lancet Neurology, Acosta-Baena and colleagues published the results of the largest and longest retrospective study of pre-dementia clinical stages in familial Alzheimer's disease to date. By reviewing serial neuropsychological assessments of individuals from a large Colombian kindred aff ected by the E280A mutation in the Presenilin 1 gene, they defi ned three stages of predementia cognitive impairment. Using survival analyses, the authors estimated the median age at onset and rate of progression through each of these stages towards dementia and ultimately death. Their study provides valuable insights into the time course of cognitive decline associated with this mutation. Furthermore, the study highlights some of the challenges of defi ning pre-dementia clinical stages in familial Alzheimer's disease and the need for the fi eld to develop a consistent terminology.
profi le was predominantly amnestic, with some transient recovery noted in the symptomatic pre-MCI stage, followed by a continuous decline in multiple cognitive domains.
Given the phenotypic heterogeneity observed between diff erent genetic mutations associated with familial AD [5], Acosta-Baena and colleagues' study of such a large number of individuals with the same mutation is a valuable addition to the literature. Th eir framework for characterising the pre-dementia stages of familial AD does raise certain issues, however, which question how applicable it may be to other populations with familial AD and highlight the diffi culties of defi ning pre-dementia clinical stages.
As the authors discuss, the concept of MCI was not widespread when they started their study and debate continues regarding how MCI may best be defi ned. Th eir MCI defi nition resembles the Petersen criteria, which require the presence of memory complaints with preserved basic ADL and no or minimal impairment of complex ADL [6]. While the Petersen criterion for cognitive impairment is a score 1.5 standard deviations away from normal values on neuropsychological tests, however, Acosta-Baena and colleagues defi ned impair ment as 2 standard deviations away. Th ey chose this more stringent cut-off value to reduce the possibility of false positives; a valid justifi cation, although it limits how comparable their results are with studies employing the Petersen criteria.
Comparability within the fi eld is further limited by the fact that many other studies do not incorporate neuropsychological results into their classifi cation of MCI, instead defi ning it as a score of 0.5 on the clinical dementia rating scale; a structured interview with the participant and a close informant [7]. As the fi eld moves forward and prevention trials for familial AD are launched, it will be crucial that diff erent studies share a common construct of MCI if the effi cacies of diff erent therapies are to be compared.
Th e situation is more complex regarding the term pre-MCI, which is conventionally used to describe subjective memory complaints without evidence of neuropsychological defi cit [8]. Acosta-Baena and colleagues, however, use the term pre-MCI for individuals with objective cognitive impairment who are either asymptomatic or symptomatic with a score on the subjective memory complaints checklist lower than the noncarrier mean. In some centres this symptomatic pre-MCI group would have been classifi ed as MCI, and the fi ndings by the authors of some transient recovery in the symptomatic pre-MCI group may be akin to the subset of MCI patients in other studies whose symptoms revert.
Th e authors speculate that cognitive reserve is the source of the transient recovery in these individuals; although an alternative explanation may be that anxiety or depression was the cause of the initial symptoms. It is not unusual for individuals at risk of familial AD to experience considerable anxiety about the possibility of developing memory problems, which understandably accentuates as they grow close to the age at which their parent developed symptoms. Th e authors' reference to the subjective memory complaints scores in the noncarriers provided one way of addressing this issue, but it would have also been interesting to know how the individuals with symptomatic pre-MCI who improved scored on the geriatric depression scale.
It is notable that all of the symptomatic participants in Acosta-Baena and colleagues' study had objective cognitive defi cits by the time they manifested symptoms. In our experience, not all individuals who develop familial AD follow the same trajectory. Whilst objective cognitive defi cits do manifest several years prior to symp toms in many patients [9], others may develop memory complaints without objective impairment initially, and would conform to the conventional defi nition of pre-MCI. Anxiety may play a role in these symptoms, or it may be that standard neuropsychological tests are not sensitive enough to detect the earliest defi cits in highly educated participants. Th e low education level in the current study (>50% had <6 years of education) may limit the generalisa bility of the results to other populations aff ected by familial AD. One must also be wary of practice eff ects in individuals who have been participat ing in natural history studies for many years. All of these factors should be considered as limitations when using neuro psychological tests as the basis for defi ning stages of disease.
Much progress has been made to refi ne and incorporate biomarkers into defi nitions of pre-dementia stages in sporadic AD [10][11][12]. Understanding the sequence of biomarker changes in familial AD may, in time, contribute to the characterisation of stages of disease. However, as biomarker abnormalities are already present in presymptomatic familial AD [13][14][15], the interpretation of their signifi cance itself requires correlation with clinical stage. How these stages are defi ned will be infl uenced by the meaning that symptoms have for an individual, their family and sociocultural environment. Variability in these factors across diff erent geographical locations brings challenges, but the rarity of familial AD means that eff orts to prevent it must take a global perspective and start by establishing a common frame work for defi ning the stages of disease.