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Subjective cognitive decline: The first clinical manifestation of Alzheimer's disease?



Background: Mild cognitive impairment is considered as the first clinical manifestation of Alzheimer's disease (AD), when the individual exhibits below performance on standardized neuropsychological tests. However, some subjects before having a lower performance on cognitive assessments already have a subjective memory complaint. Objective: A review about subjective cognitive decline, the association with AD biomarkers and risk of conversion to dementia. Methods: We performed a comprehensive non-systematic review on PubMed. The keywords used in the search were terms related to subjective cognitive decline. Results: Subjective cognitive decline is characterized by self-experience of deterioration in cognitive performance not detected objectively through formal neuropsychological testing. However, various terms and definitions have been used in the literature and the lack of a widely accepted concept hampers comparison of studies. Epidemiological data have shown that individuals with subjective cognitive decline are at increased risk of progression to AD dementia. In addition, there is evidence that this group has a higher prevalence of positive biomarkers for amyloidosis and neurodegeneration. However, Alzheimer's disease is not the only cause of subjective cognitive decline and various other conditions can be associated with subjective memory complaints, such as psychiatric disorders or normal aging. The features suggestive of a neurodegenerative disorder are: onset of decline within the last five years, age at onset above 60 years, associated concerns about decline and confirmation by an informant. Conclusion: These findings support the idea that subjective cognitive complaints may be an early clinical marker that precedes mild cognitive impairment due to Alzheimer's disease.
Dement Neuropsychol 2016 September;10(3):170-177
170170 Subjective cognitive decline Studart Neto and Nitrini
Views & Reviews
Subjective cognitive decline
The first clinical manifestation of Alzheimer’s disease?
Adalberto Studart Neto1, Ricardo Nitrini1
ABSTRACT. Background: Mild cognitive impairment is considered as the first clinical manifestation of Alzheimer’s
disease (AD), when the individual exhibits below performance on standardized neuropsychological tests. However, some
subjects before having a lower performance on cognitive assessments already have a subjective memory complaint.
Objective: A review about subjective cognitive decline, the association with AD biomarkers and risk of conversion to
dementia. Methods: We performed a comprehensive non-systematic review on PubMed. The keywords used in the
search were terms related to subjective cognitive decline. Results: Subjective cognitive decline is characterized by
self-experience of deterioration in cognitive performance not detected objectively through formal neuropsychological
testing. However, various terms and definitions have been used in the literature and the lack of a widely accepted
concept hampers comparison of studies. Epidemiological data have shown that individuals with subjective cognitive
decline are at increased risk of progression to AD dementia. In addition, there is evidence that this group has a higher
prevalence of positive biomarkers for amyloidosis and neurodegeneration. However, Alzheimer’s disease is not the only
cause of subjective cognitive decline and various other conditions can be associated with subjective memory complaints,
such as psychiatric disorders or normal aging. The features suggestive of a neurodegenerative disorder are: onset of
decline within the last five years, age at onset above 60 years, associated concerns about decline and confirmation by
an informant. Conclusion: These findings support the idea that subjective cognitive complaints may be an early clinical
marker that precedes mild cognitive impairment due to Alzheimer’s disease.
Key words: subjective cognitive decline, dementia, Alzheimer’s disease, biomarkers.
RESUMO. Introdução: O comprometimento cognitivo leve é considerado como a primeira manifestação clínica da doença
de Alzheimer, quando o indivíduo exibe um desempenho abaixo para idade e escolaridade em testes neuropsicológicos
padronizados. No entanto, alguns já apresentam uma queixa subjetiva de memória antes doprejuízo nas avaliações
cognitivas. Objetivo: Fazer uma revisão sobre o declínio cognitivo subjetivo, a associação com biomarcadores da doença
de Alzheimer e o risco de conversão para demência. Métodos: Realizou-se uma revisão não-sistemática no PubMed. As
palavras-chave utilizadas na busca foram relacionadas ao declínio cognitivo subjetivo. Resultados: O declínio cognitivo
subjetivo é caracterizada por uma autoexperiência da deterioração no desempenho cognitivo não detectado objetivamente
por meio de testes neuropsicológicos formais. Todavia, vários termos e definições são utilizados na literatura e a falta
de um conceito largamente aceito dificulta uma comparação. Os dados epidemiológicos mostram que indivíduos com
declínio cognitivo subjetivo estão em maior risco de progressão para demência. Além disso, há evidências de que este
grupo tem maior prevalência de biomarcadores positivos para amiloidose e neurodegeneração. Porém, a doença de
Alzheimer não é a única causa e várias outras condições podem estar associadas, tais como distúrbios psiquiátricos
ou o envelhecimento normal. As características sugestivas de uma doença neurodegenerativa são: início nos últimos
cinco anos, início acima de 60 anos, estar preocupado com declínio e confirmação por um informante. Conclusão: Estes
resultados suportam a ideia de que o declínio cognitivo subjetivo pode ser um marcador clínico precoce que precede
comprometimento cognitivo leve devido à doença de Alzheimer.
Palavras-chave: declínio cognitivo subjetivo, doença de Alzheimer, biomarcadores.
This study was conducted at the Department of Neurology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo SP, Brazil.
1Department of Neurology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo SP, Brazil.
Adalberto Studart Neto. Department of Neurology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – Av. Dr. Enéas de Carvalho
Aguiar, 255 – 05403-000 São Paulo SP – Brazil. E-mail:
Disclosure: The authors report no conflicts of interest.
Received June 11, 2016. Accepted in final form August 10, 2016.
doi: 10.1590/S1980-5764-2016DN1003002
Dement Neuropsychol 2016 September;10(3):170-177
171Studart Neto and Nitrini Subjective cognitive decline
Currently, the development of disease-modifying
treatments for Alzheimer’s disease (AD) targets
stages of the disease prior to the dementia syndrome,
in which neuronal damage is already irreversible. From
the development of biomarkers that allow the detection
of β-amyloid peptide, tau protein and neuronal injury,
it is known that the AD pathology precedes the onset
of dementia by many years.1,2 Consequently, identify-
ing the rst manifestation of AD with the aid of bio-
markers can enable early diagnosis and therapeutic
e working group of the National Institute on
Aging-Alzheimers Association (NIA-AA) has produced
new recommendations for the diagnosis of dementia
due to Alzheimer’s disease and proposed the concept
of AD stages based on the model of the “amyloid cas-
cade”.2 According to this model, the disease runs in a
continuous course from the preclinical phase (dened
as absence of cognitive decline and presence of positive
AD biomarkers) to the mild cognitive impairment stage
(decline in at least one cognitive or behavioral domain
without functional impairment and the presence of
positive biomarker) through to the dementia phase due
to Alzheimer’s disease (impairment in at least two cog-
nitive domains with functional decline).1,3,4 Also accord-
ing to the NIA-AA, the preclinical phase begins with the
cerebral amyloidosis stage (deposition of β-amyloid),
followed by amyloidosis with neurodegeneration, and
nally the subtle cognitive decline stage associated with
positive AD biomarkers.1
is subtle cognitive decline is characterized by a
self-experience of deterioration in cognitive perfor-
mance not detected objectively through formal neuro-
psychological testing.1,3,4 Traditionally, the consensus
considered mild cognitive impairment as the rst clini-
cal manifestation of the disease, when the individual
exhibits below-average age-, gender- and education-
adjusted performance on standardized neuropsycho-
logical tests.3,4 However, longitudinal studies, especially
those using biomarkers, have shown that before having
a lower performance on cognitive assessments, subjects
already have a subjective memory complaint. e term
“subjective cognitive decline” was created to describe
this stage prior to mild cognitive impairment.5,6 is
article entailed a non-systematic review on subjective
cognitive decline, the association with AD biomarkers
and risk of conversion to dementia. is knowledge is
critical to understanding the early stages of the disease
which can become targets of future earlier therapeutic
We performed a comprehensive literature non-system-
atic review on PubMed for references published between
January 1990 and July 2016. e keywords used in
the search were terms and words related to subjec-
tive cognitive decline: “subjective memory complaint”,
“self-reported memory complaint”, “subjective cogni-
tive impairment”, “subjective cognitive concerns” ,
“Alzheimer’s disease”, “Alzheimer’s biomarker”. e
search was restricted to articles written in English,
Spanish and Portuguese language.
Subjective cognitive decline: what is it and what is the risk?
Various terms and denitions have been used in the
literature, such as “subjective memory complaint”, “self-
reported memory complaint”, “subjective cognitive
impairment” and “subjective cognitive concerns”.5-12
Consequently, the lack of a widely accepted concept, a
“gold standard”, makes it dicult to compare studies.5,6
A multicenter international working group (Subjective
Cognitive Decline Initiative, SCD-I) was created with
the objective to standardize terminology for studies
and clinical trials.5 is group proposes the use of
the term “subjective cognitive decline”. “Subjective”
because it refers to individual self-experience, regard-
less of objective performance on neuropsychological
tests. e term “cognitive” rather than “memory”
because the rst symptoms of Alzheimer’s disease are
not restricted only to the memory domain. And nally,
“decline” refers to the idea of progressive deterioration
or a change from the previous level of functioning and
not just an isolated complaint.5,7 us, the proposed
criteria are: [1] self-experienced persistent decline in
cognitive abilities compared with previously normal
status and not related to an acute event; and [2] normal
performance on standardized cognitive tests (for age,
gender and education); while exclusion criteria are: [1]
mild cognitive impairment or dementia diagnosis; and
[2] decline explained by psychiatric disorders, neuro-
logical diseases (except Alzheimer’s disease), other
medical disorders, medication or other substance use.5
Several epidemiological studies have shown an
increased risk of progression to AD dementia among
individuals with subjective cognitive decline.6-12 How-
ever, these epidemiological studies dier in the method
of evaluation of subjective complaints. While some stud-
ies were based on testimonies of participants, other
applied standardized questionnaires (as discussed in
the following section). Consequently, this dierence of
methodology impairs in part the comparison between
Dement Neuropsychol 2016 September;10(3):170-177
172 Subjective cognitive decline Studart Neto and Nitrini
these studies. Sixteen studies included in a systematic
review showed a conversion risk to dementia or mild
cognitive impairment that was 1.5-3 times higher in
older age individuals with subjective cognitive com-
plaints.6 Jessen et al., during a follow-up of six years,
compared progression to dementia among normal
controls, a subjective cognitive impairment group and
another with mild cognitive impairment.8 e incidence
of AD dementia in the group with subjective complaints
was 1.5 times higher than in the control group. And
when the subjects with memory complaints were con-
cerned with their cognitive decline, the conversion rate
to dementia was 2.44 times higher than in the control
group, a value similar to that found in early mild cogni-
tive impairment (dened as a performance on delayed
recall between 1.5 SD and 1.0 SD below the normative
mean).8 In another study involving the same cohort, the
relationship between subjective cognitive decline and
longitudinal performance on objective tests was exam-
ined over an 8-year period. e presence of subjective
cognitive impairment at baseline predicted a more accel-
erated decline on episodic memory tests (immediate and
delayed verbal recall) and more pronounced decline in
the group of individuals with associated concerns.9
Reisberg et al. followed 213 individuals for about
seven years and found that 54.2% of the group with sub-
jective cognitive impairment declined to mild cognitive
impairment or dementia, compared to 14.9% among
normal controls (hazard ratio 4.5).10 Furthermore, sub-
jects with complaints evolved more quickly to dementia
than controls by an average of 3.5 years. Similar results
were found in a Swedish study, a prospective follow-up
for a median of ten years of a sample of 2043 individu-
als without dementia, which showed an incidence of
dementia two to three times higher in the group with
subjective cognitive impairment.11 In another study
with a very long follow-up, 1107 older women (mean
age: 70 years) were evaluated 18 years after the rst visit
where 52.8% of participants with subjective complaints
progressed to dementia or mild cognitive impairment,
while in the group without complaints the rate was
38%.12 Epidemiological studies have also used post-mor-
tem pathological ndings as an outcome. In one such
study, subjective complaints were associated with higher
amounts of neuritic amyloid plaques (but not neuro-
brillary tangles) in the medial and neocortical regions of
the temporal lobe in samples from autopsies.13
Some authors question whether the complaint of the
individual would itself be sucient to increase the risk
of progression to dementia. is questioning arises from
two observations: memory complaints are very preva-
lent in the elderly (and therefore can be nonspecic) and
a high prevalence of lack of insight among patients with
dementia exists. Consequently, some studies analyzed
whether conrmation of cognitive decline by an infor-
mant increases the specicity and risk for progression to
dementia.14,15,16 Giord et al. observed that the isolated
complaint from a patient had a conversion rate of 2.1;
similar to the risk of progression when only the infor-
mant reports the complaint. On the other hand, if both
the individual and informant report cognitive decline,
the risk rises to 4.2.14
However, akin to individuals with mild cognitive
impairment, many with subjective complaints may
remain stable or even show improvement in cognition.
Alzheimer’s disease is not the only cause of subjective
cognitive decline and various other conditions can be
associated with subjective memory complaints, such as
normal aging, personality traits, psychiatric disorders
and use of psychiatric drugs.5,7 Within this heteroge-
neous group, how can individuals who will progress to
mild cognitive impairment or dementia be identied?
And what are the features of subjective cognitive com-
plaint that aggregate this risk of cognitive decline? In
other words, how can we determine whether an elderly
individual with subjective cognitive decline presents
an underlying preclinical Alzheimer’s disease and not
another cause, such as a depressive disorder?
Subjective cognitive decline: how can it be identified?
Although several studies have evaluated subjec-
tive cognitive decline and its risk of progression to
dementia, there is no standard on how the evaluation
should be carried out. Ideally, the assessment of subjec-
tive cognitive decline in any study must provide balance
and not be too sensitive (with high false positive rates)
or very specic (and therefore too restrictive).5,17 How
can we objectively evaluate a subjective complaint?
Several questionnaires and scales have been devel-
oped and applied in clinical and epidemiological stud-
ies. e most frequent self-reported measures include:
Questionnaire AgeCoDe Study,18 Everyday Cognition
scale (E-cog),19 Memory Functioning Questionnaire
(MFQ),20 Subjective memory decline scale (SMDS),21
Memory complaint questionnaire (MAC-Q),22 Memory
failures everyday - 30 (MFE - 30),23 Structured Tele-
phone Interview for Dementia Assessment (STIDA),24
Informant Questionnaire on Cognitive Decline in the
Elderly (IQCODE)25 and Subjective Memory Complaints
(SMC).26 ese dier in mode of administration, num-
ber of items, timeframe referenced by items, cognitive
domains reported as complaints and degree of severity.
Dement Neuropsychol 2016 September;10(3):170-177
173Studart Neto and Nitrini Subjective cognitive decline
Some self-reported measures explore only memory com-
plaints, while others evaluate decline in other cognitive
abilities. Even among the scales that include memory
complaints only, some are generic issues while other
measures evaluate specic everyday situations. Another
dierence is a large variability among questionnaires
in relation to response timeframe and subjective per-
ception.. Some of these instruments compare current
cognitive performance with a few weeks or months ago,
while others compare with several years ago or even
when younger.17
As previously mentioned, not all subjective memory
complaint is due to pre-clinical Alzheimer’s disease. Of
other causes, mental disorders are among the most
often associated and therefore the evaluation of patients
with subjective memory complaint must include a
neuropsychiatric inventory. However, even excluding
patients who meet criteria for a major psychiatric dis-
order, symptoms of depression and anxiety or morbid
personality traits are fairly frequently observed in epi-
demiological studies.8,12,15 us, in clinical practice, how
can it be distinguished whether a cognitive complaint
is due to a mental disorder or Alzheimer’s disease in
the preclinical stage? For this purpose, some authors
have coined the term “subjective cognitive decline plus”
whose features increase the likelihood of an underlying
neurodegenerative disorder.5,6 For example, a decline
noticed by the patient within a ve-year interval
increases the probability of preclinical AD. In contrast,
complaints in a patient with a history of many years
most likely have causes other than AD. Age of onset is
also an important feature to distinguish neurological
and psychiatric causes. It is more likely for an elderly
person than a young adult to have subjective decline
due to Alzheimer’s disease. As discussed in the studies
cited above, associated concerns with complaint and
conrmation of decline by an informant are features
that suggest a neurodegenerative cause. In summary,
elderly with increased risk of conversion to dementia
are those with progressive memory complaint within
the last ve years, concerns about decline, and whose
family members conrm this decline.
Although subjective cognitive decline is dened as a
complaint without detectable impairment by standard-
ized neuropsychological tests, a new generation of epi-
sodic memory tests has shown utility for the diagnosis
of Alzheimer’s preclinical disease with a good correla-
tion with subjective complaint.27-29 For example, a task
of Short-Term Memory Binding (STMB) has recently
been validated and shown to be more sensitive than
traditional neuropsychological evaluations in individu-
als with subjective cognitive decline for diagnosing the
pre-clinical stage of Alzheimer’s disease.27 Other tests
developed, which have also shown good correlation with
subjective cognitive impairment, were the Name Face
Associative Memory Exam (FNAME)28 and evaluation of
prospective memory.29 erefore, these are useful tools
in the clinical evaluation of patients with subjective
cognitive decline, which increases the specicity of the
complaint as a marker of preclinical Alzheimer’s disease.
Subjective cognitive decline studies in the Brazilian popula-
tion. Although an increasingly discussed topic in Cogni-
tive Neurology, there are few studies involving the
Brazilian population.30-35 Moreover, to date, there are
no published Brazilian studies involving AD biomarkers
in patients with subjective cognitive decline.
In a community-based study, seventy-one healthy
older adults were asked if they had memory complaints,
lled out the Memory Complaint Questionnaire (MAC-
Q) and underwent a formal test of episodic memory
(Rey Auditory Verbal Learning Test - RAVLT). Spontane-
ous complaints were associated with poor performance
on the RAVLT, but not on the MAC-Q.33 Another study
analyzed the presence of memory complaint in 163 sub-
jects without dementia in a forest reserve in the Brazil-
ian Amazon. e study volunteers were submitted to
the Mini-Mental State Examination (MMSE), delayed
recall from the Brief Cognitive Battery and a question-
naire assessing psychiatric symptoms. Results revealed
a positive correlation between the presence of psychiat-
ric symptoms and lower MMSE scores but not delayed
recall test scores.34
On the other hand, some studies have shown no cor-
relation between worse performance on cognitive tests
and the presence of subjective decline.35,36 In one investi-
gation, two groups were compared: one formed by com-
munity elders with complaints and another consisting of
institutionalized elderly without complaints. No dier-
ences were observed between the groups in performance
on neuropsychological assessment.35 Similar ndings
were also obtained in a sample of normal elderly (care-
givers of patients with dementia), where there was no
statistically signicant correlation between subjective
complaints and objective cognitive assessment.36
Alzheimer’s disease biomarkers in subjective cognitive
decline. In recent years, several studies (such as the
“Alzheimer’s Disease Neuroimaging Initiative - ADNI”
and “Australian Imaging Biomarkers and Lifestyle study
- AIBL”) have been investigating the correlation in vivo
of pathologic ndings (using biomarkers) with clinical
Dement Neuropsychol 2016 September;10(3):170-177
174 Subjective cognitive decline Studart Neto and Nitrini
manifestations of Alzheimer’s disease.1,7,38,39 Patholo-
gical processes most widely investigated through
biomarkers are: brain amyloidosis (by decreased
β-amyloid peptide in cerebrospinal uid and PET-CT
with positive ligands for β-amyloid - for example Pitts-
burgh compound B, PiB) and neurodegeneration (by
elevated total tau and phosphorylated tau proteins in
the cerebrospinal uid, cortical atrophy on structural
magnetic resonance imaging, MRI, and decreased g lyco-
lytic metabolism in 18F-uorodeoxyglucose PET-CT).1,2
While there are studies with evidence of increased
frequency of amyloidosis and neurodegeneration asso-
ciated with aging in cognitively normal patients,39-42
the presence of amyloidosis in normal elderly is associ-
ated with higher rates of progression to mild cognitive
impairment and dementia.39,42-45 Consequently, the use
of biomarkers attempts to resolve the above question
by identifying which individuals with subjective cogni-
tive decline have a higher risk of progressing to an AD
dementia stage. Structural MRI, PET-CT with positive
ligands for β-amyloid and 18F-uorodeoxyglucose
PET-CT (FDG-PET), are methods that both determine
the stage of progression of the disease as well as eluci-
date the anatomical extent of the disease.46-51
Perrotin et al. compared two groups of normal
elderly, one with positive PiB PET-CT and another with
negative PiB PET-CT, for subjective cognition and per-
formance on a neuropsychological evaluation.47 e
positive PiB group had a higher frequency of subjective
cognitive complaints and worse performance in episodic
memory tests. In addition, some anatomical regions of
interest showed a positive correlation between increased
uptake of radiotracer for amyloid and subjective decline
(right medial frontal/anterior cingulate cortex and right
precuneus/posterior cingulate cortex).47 Amariglio et al.
applied three subjective cognition questionnaires and a
neuropsychological battery in a group of 130 elderly who
underwent a PiB-PET. A positive correlation between
memory complaints and cortical PiB binding was found.
On the other hand, performance on tests of episodic
memory and executive functions and cortical PiB bind-
ing did not show a statistically signicant correlation.48
e same research group also used PiB-PET, FDG-PET
and structural MRI, classifying normal elderly patients
into four groups according to status of biomarkers for
amyloidosis (Aβ) and neurodegeneration (ND): nega-
tive biomarker (Aβ– / ND–), amyloidosis alone (Aβ β+ /
ND–), amyloidosis plus neurodegeneration (Aβ+ / NA+)
and suspected non-Alzheimer disease pathophysiology
(Aβ– / ND+).35 Participants lled out a questionnaire for
subjective cognitive complaints and the presence of bio-
markers correlated with more complaints, especially in
the groups with positive Aβ.49 Similar results were found
in a recent longitudinal study.50 Fifty-eight normal
older adults with positive β-amyloid-PET answered a
questionnaire of subjective memory decline and under-
went neuropsychological assessment. After a follow-up
of three years, it was found that individuals with com-
plaints had a higher rate of progression to mild cognitive
impairment or dementia (hazard ratio of 5.1) compared
to those without complaints. However, two groups did
not dier in decline on formal tests of episodic mem-
ory. Moreover, the group with complaints had a higher
incidence of depressive symptoms and lower left hip-
pocampus volume.50 However, some studies have failed
to demonstrate the relationship between the presence of
biomarkers and subjective decline. A prospective study
of 289 healthy elderly found no dierences between
PiB-PET status and presence of subjective memory com-
plaint, although a group with positive PiB-PET showed
a moderate decline in working memory and learning.51
Recently, the development of a PET tracer with high
anity for tau protein has allowed to understand the
distribution of tau aggregates in vivo.52,53 However, there
are still no published studies of tau imaging in normal
individuals with subjective memory complaints.
Evidence also points to a correlation between subjec-
tive cognitive decline and cortical atrophy on structural
MRI, especially in commonly vulnerable regions for
Alzheimer disease.54-57 In one such study, two hundred
and sixty-one healthy middle-age adults were asked
whether they had a memory problem. e group with
cognitive complaints had signicant cortical thinning
in the entorhinal, fusiform, posterior cingulate and
posterior parietal cortices, as well as reduced amygdala
volume.54 Additionally, this same group showed worse
performance on memory tests, even within the normal
range. A pattern of gray matter atrophy, similar to that
found in Alzheimer’s disease, has been found in a group
of 226 subjects with subjective memory disorders in a
German study.55 A cross-sectional study compared hip-
pocampal volume in 47 healthy elderly with memory
complaints and 48 normal controls and measured the
plasma levels of beta amyloid. ose with subjective
complaints showed lower volume in CA1, CA2, dentate
gyrus and the molecular layer and had higher levels of
beta amyloid.56 Other neuroimaging methods have also
been exploited by several studies on subjective cognitive
decline, such as functional magnetic resonance imaging
(fMRI) and MRI with diusion tensor imaging (DTI).58,59
In one fMRI study, there was less activation of the right
hippocampus in patients with subjective decline during
Dement Neuropsychol 2016 September;10(3):170-177
175Studart Neto and Nitrini Subjective cognitive decline
the course of episodic memory testing, despite the fact
that test performance was within the normal range.58
And a Japanese study examined the association of
white matter connectivity (by performing MRI-DTI)
and amyloid deposition (PiB-PET) and compared two
groups (one with subjective cognitive impairment and
another without complaint). In the end, it was found
that individuals with subjective cognitive impairment
had reduced functional connectivity between retrosple-
nial cortex and anterior medial cortical structures.59
Similarly to imaging methods, studies of β-amyloid
peptide, total tau and phosphorylated tau proteins in
cerebrospinal uid (CSF) are widely used in investiga-
tions of subjective cognitive decline.60-64 In a multi-
center cohort, the frequency of individuals with subjec-
tive complaint and positive AD biomarkers in CSF was
superior to the control group (52% vs. 31%).60 A Span-
ish longitudinal study followed 149 subjects without
dementia (but with subjective cognitive decline or mild
cognitive impairment) for ve years and found that only
15% of those with pathological CSF remained free of
AD dementia. e odds ratio for conversion to demen-
tia was 27.1, demonstrating that an abnormal AD CSF
biomarker prole is a powerful predictor for cognitive
and functional decline.61 In a Dutch longitudinal study,
a sample of 127 volunteers with subjective decline was
followed by two years after collection of CSF biomark-
ers. e study found that a decrease in Aβ CSF was the
strongest predictor of progression to mild cognitive
impairment and dementia (odds ratio 16).61
In addition to the biomarkers, AD has many other
risk factors, but none is better established than the e4
allele of apolipoprotein E (APOE). ere is ample evi-
dence that individuals with subjective cognitive decline
have a greater frequency of expression of the allele, espe-
cially among those with positive biomarkers.65,66 Sam-
ieri et al. compared subjective cognitive decline among
APOE e4 carriers and non-carriers for over six years. e
authors concluded that APOE e4 carriers evolved with
faster memory decline.65 In a more recent study, normal
elderly with memory complaints were also grouped into
APOE e4 carriers and non-carriers and underwent amy-
loid PET, FDG PET, structural MRI and CSF biomarker
testing. e APOE e4 carriers had changes in amyloid
PET and CSF biomarkers. erefore, these results indi-
cate an association between the APOE e4 allele and AD
biomarkers in older adults with memory complaints.66
Several studies have shown that individuals with subjec-
tive cognitive decline are at increased risk of progres-
sion to AD dementia. According to epidemiological data,
the features which increase the likelihood of conversion
are: onset of decline within the last ve years, age at
onset above 60 years, associated concerns about decline
and conrmation by an informant. In addition, there is
evidence that this group has a higher prevalence of posi-
tive biomarkers for amyloidosis and neurodegenera-
tion. Consequently, these ndings support the idea that
subjective cognitive complaints may be an early clinical
marker of pathology and help further understanding
on the natural history of Alzheimer’s disease from pre-
dementia stages. However, due to lack of consensus on
how to dene and assess subjective cognitive decline, it
is still unclear which characteristics of subjective cogni-
tive decline suggest the preclinical AD stage.
Author contribution. Adalberto Studart Neto contributed
to study concept and design, acquisition of data, anal-
ysis and interpretation of data, drafting of the manu-
script and critical revision of the manuscript for impor-
tant intellectual content. Ricardo Nitrini contributed
drafting of the manuscript and critical revision of the
manuscript for important intellectual content.
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... Mild cognitive impairment is often considered an intermediate stage of cognitive progression from subjective cognitive decline to dementia. However, subjective cognitive decline and mild cognitive impairment do not always lead to dementia [114,138]. Dementia is an umbrella term for conditions which cause changes in cognitive, motor, and sensory functioning beyond what might be expected from "normal ageing" [141]. Dementia is typically described in terms of cognitive decline, affecting domains such as memory, thinking, comprehension, learning capacity, language, judgment, and ability to perform everyday tasks [141]. ...
Clinical researchers have identified sensory changes people with age-related cognitive changes, such as dementia and mild cognitive impairment, experience that are different from typical age-related sensory changes. Technology designers and researchers do not yet have an understanding of how these unique sensory changes affect technology use. This work begins to bridge the gap between the clinical knowledge of sensory changes and technology research and design through interviews with people with mild to moderate dementia, mild cognitive impairment, subjective cognitive decline, and healthcare professionals. This extended version of our ASSETS conference paper includes people with a range of age-related cognitive changes describing changes in vision, hearing, speech, dexterity, proprioception, and smell. We discuss each of these sensory changes and ways to leverage optimal modes of sensory interaction for accessible technology use with existing and emerging technologies. Finally, we discuss how accessible sensory stimulation may change across the spectrum of age-related cognitive changes.
... Moreover, subjective cognitive decline (SCD), characterized by the self-expression/awareness/concern of a deterioration in cognitive performance and seen as a subtle decline (Jessen et al., 2020;Si et al., 2020;Studart & Nitrini, 2016), is a potential antecedent stage to cognitive decline due to MCI or AD. SCD can significantly overlap with depression. ...
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Mild cognitive impairment (MCI) is a prevalent condition with major implications for both society as a whole and on an individual level. The progression from MCI to dementia as part of the Alzheimer’s continuum has been widely studied. This progression is considered as an intermediate clinical stage from normal aging for many individuals before meeting full criteria for dementia. The identification of predictive factors continues to be studied with evidence suggesting that early prevention, rather than treatment per se, is the current most productive focus of research. However, comorbid old-age related conditions (e.g., vestibular dysfunction) and neuropsychiatric conditions such as depression can significantly confound identification of MCI in the absence of biomarkers and can also increase the risk of progression to dementia. Additionally, subjective cognitive decline (SCD) can be present in depression, which can complicate and obfuscate differential diagnosis. Notably, in the context of forensic psychological assessment, whether cognitive change is due to brain injury resulting from progressive multifaceted neurodegenerative condition or not has medico-legal implications. Moreover, the validity and reliability of collateral information also play a significant role in forensic settings. Hence, the neuropsychological assessment is uniquely placed to appropriately assess cognitive and psychological changes that can occur in the individual and impair functioning. Consequently, recommendations for best practice in the assessment of MCI in the older adult population are provided.
... This included an assessment of multiple geriatric domains, including cognition, physical function, nutrition, revision of medication in use and detailed medical history. Cognitive diagnosis -such as dementia (McKhann et al., 1984;Román et al., 1993;Neary et al., 1998;McKeith et al., 2005;Dubois et al., 2007;Rascovsky et al., 2011), mild cognitive impairment (MCI) (Albert et al., 2013), or subjective cognitive decline (SCD) (Studart and Nitrini, 2016) -were evaluated in a multidisciplinary consensus meeting. Our analysis included only patients who underwent brain Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) as part of the diagnostic work-up. ...
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IntroductionGlobally, women with dementia have a higher disease burden than men with dementia. In addition, women with diabetes especially are at higher risk for cognitive impairment and dementia compared to men with diabetes. Differences in the influence of diabetes on the cerebral vasculature and brain structure may contribute to these sex-specific differences. We examined sex-specific patterns in the relationship between diabetes and brain structure, as well as diabetes and cognitive function.Methods In total, 893 patients [age 79 ± 6.6 years, 446 (50%) women] from the Amsterdam Ageing Cohort with available data on brain structures (assessed by an MRI or CT scan) and cognitive function were included. All patients underwent a thorough standardized clinical and neuropsychological assessment (including tests on memory, executive functioning, processing speed, language). Brain structure abnormalities were quantified using visual scales.ResultsCross-sectional multivariable regression analyses showed that diabetes was associated with increased incidence of cerebral lacunes and brain atrophy in women (OR 2.18 (1.00–4.72) but not in men. Furthermore, diabetes was associated with decreased executive function, processing speed and language in women [B −0.07 (0.00–0.13), −0.06 (0.02–0.10) and −0.07 (0.01–0.12) resp.] but not in men.Conclusions Diabetes is related to increased risk of having lacunes, brain atrophy and impaired cognitive function in women but not in men. Further research is required to understand the time trajectory leading up to these changes and to understand the mechanisms behind them in order to improve preventive health care for both sexes.
... Subjective cognitive complaints are correlated with dementia pathology, and predicts cognitive decline measured by objective cognitive tests. 3,4 Subjective motoric complaints (SMC) were reported to capture the earliest stages of disability, before developing objective or clinical signs of slowing of gait, and predicted disability. 5 We developed a subjective definition of MCR (MCR-S) defined using only cognitive and motoric complaints in a prospective cohort of community-dwelling and non-demented older adults. ...
Background: Motoric Cognitive Risk syndrome (MCR) is a gait-based pre-dementia syndrome associated with risk of dementia. Ascertaining subjective cognitive and motoric complaints may facilitate early and remote identification of individuals with MCR as they are reported to precede and predict objective cognitive and motoric impairments in aging. Methods: We examined the validity of five subjective motoric complaint (SMC) and 10 subjective cognitive complaint (SCC) questions for discriminating MCR in 538 non-demented community-dwelling adults. Backward logistic regression was used to identify questions to develop a weighted score to define subjective MCR (MCR-S). Receiver operating characteristic (ROC) analysis was applied to determine the discriminative ability of MCR-S for the objective MCR (MCR-O) definition based on SCC and objectively measured gait. Cox proportional hazard models adjusted for potential confounders were used to examine the predictive validity of MCR-S for incident dementia. Results: Five subjective complaints questions (3 SCC and 2 SMC) were associated with MCR-O. They were combined to define a MCR-S score (range 0 to 7), which yielded AUC of 0.89 for discriminating MCR-O from ROC analysis. An optimal cut-score of 2 on the MCR-S score was determined to have good sensitivity (84%) and specificity (82%) for MCR-O. Over a median follow-up of 2.5 years, 29 participants developed dementia. Both MCR-S (adjusted hazard ratio: 2.39) and MCR-O at baseline (adjusted hazard ratio: 3.16) predicted risk of incident dementia. Conclusions: MCR-S had high concordance with MCR-O, and can provide a remote screening assessment for MCR-O, which can identify those at high-risk for dementia.
Early detection of cognitive impairment is of paramount importance in clinical settings, with several brief screening tools having been developed for that purpose. The present study sought to evaluate the clinical utility of the Saint Louis University Mental Status examination (SLUMS) at identifying examinees with normal cognition, mild cognitive impairment, or dementia syndrome using the criterion of a comprehensive neuropsychological assessment. Two hundred sixty-three examinees (M age = 67.84 ± 12.72; 59.3% female; 81.4% white) were referred for comprehensive neuropsychological evaluation at a private, Mid-Atlantic medical center. Using original cutoff scores, the SLUMS correctly classified just over half (55.1%) of examinees. Classification statistics suggested modified cutoff scores for mild cognitive impairment (≤24) and dementia (≤17) with strong discriminability between cognitive status groups (AUCs ranged from .834 to .986). These proposed revised cutoff scores improved overall concordance between SLUMS and diagnostic conclusions from comprehensive clinical neuropsychological testing, correctly classifying nearly two-thirds of examinees (65.4%). The SLUMS and its revised cutoff scores appear to have clinical utility for cognitive screening in primary care and neurological settings to inform treatment plans and appropriate referrals for comprehensive neuropsychological assessment.
Mild cognitive impairment (MCI) is a prevalent and complex condition among older adults that often progresses into Alzheimer’s disease (AD). Although MCI affects individuals differently, there are specific indicators of risk commonly associated with the development of MCI. The present study explored the prevalence of seven established MCI risk categories within a large sample of older adults with and without MCI. We explored trends across the different diagnostic groups and extracted the most salient risk factors related to MCI using partial least squares. Neuropsychological risk categories showed the largest differences across groups, with the cognitively unimpaired groups outperforming the MCI groups on all measures. Apolipoprotein E4 (ApoE4) carriers were significantly more common among the more severe MCI group, while ApoE4 non‐carriers were more common in the healthy controls. Participants with subjective and objective cognitive impairment were trending towards AD‐like cerebral spinal fluid (CSF) biomarker levels. Increased age, being male, and having fewer years of education were identified as important risk factors of MCI. Higher CSF tau levels were correlated with ApoE4 carrier status, age, and a decrease in the ability to carry out daily activities across all diagnostic groups. Amyloid beta1‐42 CSF concentration was positively correlated with cognitive and memory performance and non‐ApoE4 carrier status regardless of diagnostic status. Unlike previous research, poor cardiovascular health or being female had no relation to MCI. Altogether, the results highlighted risk factors that were specific to persons with MCI, findings that will inform future research in healthy aging, MCI, and AD.
This study examined preliminary evidence of construct validity in a stand-alone memory concerns scale constructed from the Patient-Reported Outcomes Measurement Information System (PROMIS®) Cognitive Function item bank. A sample of 396 individuals, ages 18-75 (M = 33.7, SD = 12.7), from Spain and Latin America completed an online survey regarding lifetime exposure to factors associated with neurological compromise. The sample was 69.4% female. Respondents completed 8 items from the PROMIS® Cognitive Function item bank v1.0 dealing with memory concerns (MCS-8) along with the PROMIS® 8-item short form reflecting general cognitive concerns (CCS-8). The MCS-8 had high internal consistency reliability (Cronbach's alpha = 0.90), and represented a factor distinct from general cognitive concerns items on the CCS-8 in confirmatory factor analysis. Analysis of covariance controlling for sex, age, and education, showed that individuals endorsing history of exposure to sources of neurological compromise scored significantly lower T-scores on the MCS-8 than those who did not report any such history, F(1,390) = 6.4, p = 0.012. Older age was significantly associated with greater memory concerns, a relationship with age not observed with the CCS-8. As a stand-alone self-report measure, the MCS-8 appears to measure a construct distinct from general cognitive concerns that may be of interest for further research in clinical populations.
Objectives This study identified different multimorbidity patterns among adults with subjective cognitive decline (SCD) and examined their association with SCD-related functional difficulties. Methods Data were obtained from the 2019 Behavioral Risk Factor Surveillance System. Latent class analysis was applied to identify different patterns of chronic conditions. Logistic regression was implemented to examine relationships between multimorbidity patterns and risk of SCD-related functional difficulties. Results Five multimorbidity patterns were identified: severely impaired (14.6%), respiratory/depression (18.2%), obesity/diabetes (18.6%), age-associated (22.3%), and minimal chronic conditions group (26.3%). Compared with minimal chronic conditions group, severely impaired group was most likely to report SCD-related functional difficulties, followed by respiratory/depression and obesity/diabetes group. Discussions Individuals in the three multimorbidity groups had elevated risk of SCD-related functional difficulties compared with minimal chronic conditions group. Characteristics of the high-risk groups identified in this study may help in development and implementation of interventions to prevent serious consequences of having multiple chronic conditions.
Background Subjective cognitive complaints (SCC) are associated with higher risk of mild cognitive impairment (MCI) and dementia. Cardiovascular risk factors (CVRF) have been also associated with cognitive decline, MCI, and dementia. Few studies have examined the associated of CVRF and SCC. Methods Participants were cognitively normal Mexican Americans from the HABLE study. Participants were categorized as with and without SCC, and SCC was also measured as a continuous variable. CVRF diagnosis were ascertained during consensus review. Cognitive measures used were MMSE, Trails B, SEVLT, and digit span. Logistic regression and linear regression were used to asses the association of SCC with CVRF and cognitive scores. Results A total of 673 participants [mean age 63.3 (SD=7.71), 69.2% female] were included. SCC was present in 323 participants (47.99%). Dyslipidemia and depression were associated with SCC. Individuals with dyslipidemia had 1.72 times the odds (95% CI = 1.20 to 2.47) of SCC, and those with depression had 3.15 times the odds (95% CI = 2.16 to 4.59) of self-reporting SCC. Higher SCC scores, were significantly associated with MMSE (B = 0.07; SE = 0.03; p = 0.02), and SEVLT immediate and delayed (B= -0.03; SE = 0.00; p = 0.000 and B = -0.03; SE = 0.00; p = 0.000, respectively). Conclusions In a cognitively normal Mexican Americans sample of older adults, depression and dyslipidemia were correlated with self-reported SCC. A greater self-perception of cognitive decline correlated with lower scores on the MMSE and SEVLT.
Introduction: Timely detection of cognitive impairment among older adults has shown to lead to better health and financial outcomes but is hampered by psychological, financial, and physical barriers to participation in cognitive assessment. Home-based cognitive assessment (HBCA) could help overcome some of these barriers. This study aimed to examine older adults' likelihood of participation in HBCA and identify factors predicting this likelihood. Materials and methods: A cross-sectional online survey distributed through Amazon Mechanical Turk, was used to collect data from adults aged 50 years or older residing in the USA The survey was designed to gauge attitudes toward technology and cognitive assessment and to measure psychological variables including subjective cognitive decline (SCD), depression, and anxiety. Information on income and geographic location (rural vs. suburban and urban) was also collected. Univariate and hierarchical regression analyses were conducted to examine the contributions of these variables to a composite measure of likelihood of participation in HBCA. Results: Complete data were obtained on n = 483 (age 50-79). Approximately, two-thirds of respondents described themselves as likely or very likely to participate in HBCA. In univariate analyses, younger age, higher income, higher technology assessment acceptance scores, and higher SCD burden were associated with higher likelihood of participation. Hierarchical regression revealed significant stepwise increments in explained variance: demographic variables 4.1%, technology acceptance 25.2%, assessment acceptance 15.4%, and SCD burden 1.6%. The contribution of SCD was moderated by sex and found for women but not for men. Discussion/conclusion: A large proportion of adults aged 50 and above described themselves likely to participate in HBCA. Middle-aged, technology-savvy, higher income adults expressed the most positive attitudes toward this type of service. Of interest is that HBCA may be particularly acceptable among older women with SCD, a group known to be at risk of cognitive decline. Our findings support the expansion of cognitive assessment services to the home setting.
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Objective: To determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high β-amyloid burden (CN Aβ+). Methods: Fifty-eight CN Aβ+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed. Results: In CN Aβ+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4-20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume. Discussion: High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic implications for CN Aβ+, more sensitive measures may be required to detect early subtle cognitive change.
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Objective: To propose a Memory Complaints Scale (MCS) as an instrument for actively searching for memory complaints and to investigate its utility for discriminating demented from cognitively normal elderly. Methods: A total of 161 patients from a teaching behavioral neurology outpatient unit of a tertiary hospital were studied. The MCS was used in two ways, by direct application to the patient and by application to the patient's companion. Cognitive tests assessing depression and daily living activities were also applied. Results: High Cronbach's alpha coefficients were found for the two application methods. Correlations between the two versions and the other instruments administered for patients grouped by type and severity of dementia were also found. Conclusion: The MCS is a useful scale for identifying memory complaints and discriminating demented from cognitively normal elderly. Further studies confirming these findings are warranted.
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Background: Determination of Alzheimer's disease (AD) by cerebrospinal fluid (CSF) biomarkers - 42-amino-acid amyloid-β (Aβ42), total tau and phosphorylated tau (p-tau) - has demonstrated high validity for detecting AD neuropathological changes. However, their prognostic utility to predict the onset of dementia in predementia subjects is still questioned. We aimed to study the prospective clinical evolution of a group of subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) and to determine the prognostic capacity of AD CSF biomarkers. Methods: 149 subjects with MCI or SCD, not meeting dementia criteria, underwent a prospective clinical, neuropsychological and CSF biomarker study. Patients were initially classified as SCD or MCI following internationally accepted criteria. CSF sampling was obtained and analysed following consensus protocols. Neuropsychological and clinical evaluations were conducted at the follow-up. Statistical analysis considering the final clinical diagnosis, regression analysis to define risk factors and survival curves for progression were made. Results: 72.4% of subjects (83% MCI and 27% SCD) with a pathological CSF ratio (Aβ42/p-tau) met criteria for dementia during the 5-year follow-up versus 18.7% of subjects from the group with a normal ratio. The pathological CSF ratio was a powerful marker of risk for AD dementia (OR 27.1; 95% CI 10.3-71.2). Kaplan-Meier survival curves showed that only 15% of subjects with a pathological CSF ratio remained free of AD dementia at 5 years of follow-up. All subjects who reverted to normal cognition presented a normal CSF profile at baseline. Conclusion: An abnormal AD CSF biomarker profile in predementia subjects is a powerful predictor of cognitive and/or functional decline in the medium term.
Background: Cognitive complaints occur frequently in elderly people and may be a risk factor for dementia and cognitive decline. Results from studies on subjective cognitive decline are difficult to compare due to variability in assessment methods, and little is known about how different methods influence reports of cognitive decline. Methods: The Subjective Memory Complaints Scale (SMC) and The Memory Complaint Questionnaire (MAC-Q) were applied in 121 mixed memory clinic patients with mild cognitive symptoms (mean MMSE = 26.8, SD 2.7). The scales were applied independently and raters were blinded to results from the other scale. Scales were not used for diagnostic classification. Cognitive performances and depressive symptoms were also rated. We studied the association between the two measures and investigated the scales' relation to depressive symptoms, age, and cognitive status. Results: SMC and MAC-Q were significantly associated (r = 0.44, N = 121, p = 0.015) and both scales had a wide range of scores. In this mixed cohort of patients, younger age was associated with higher SMC scores. There were no significant correlations between cognitive test performances and scales measuring subjective decline. Depression scores were significantly correlated to both scales measuring subjective decline. Linear regression models showed that age did not have a significant contribution to the variance in subjective memory beyond that of depressive symptoms. Conclusions: Measures for subjective cognitive decline are not interchangeable when used in memory clinics and the application of different scales in previous studies is an important factor as to why studies show variability in the association between subjective cognitive decline and background data and/or clinical results. Careful consideration should be taken as to which questions are relevant and have validity when operationalizing subjective cognitive decline.
View largeDownload slide See Sarazin et al . (doi: 10.1093/brain/aww041 ) for a scientific commentary on this article. The PET tracer [ ¹⁸ F]-AV-1451 allows visualization of tau pathology in living subjects. Ossenkoppele et al. employ the tracer in patients with distinct Alzheimer's disease variants to investigate correlates of tau deposition. Pathological aggregation of tau, but not amyloid-β, is linked to patterns of neurodegeneration and clinical manifestations of Alzheimer’s disease. View largeDownload slide See Sarazin et al . (doi: 10.1093/brain/aww041 ) for a scientific commentary on this article. The PET tracer [ ¹⁸ F]-AV-1451 allows visualization of tau pathology in living subjects. Ossenkoppele et al. employ the tracer in patients with distinct Alzheimer's disease variants to investigate correlates of tau deposition. Pathological aggregation of tau, but not amyloid-β, is linked to patterns of neurodegeneration and clinical manifestations of Alzheimer’s disease.
Background: Evidence suggests a link between the presence of subjective memory complaints (SMC) and lower volume of the hippocampus, one of the first regions to show neuropathological lesions in Alzheimer's disease. However, it remains unknown whether this pattern of hippocampal atrophy is regionally specific and whether SMC are also paralleled by changes in peripheral levels of amyloid-beta (Aβ). Methods: The volume of hippocampal subregions and plasma Aβ levels were cross-sectionally compared between elderly individuals with (SMC(+); N = 47) and without SMC (SMC(-); N = 48). Significant volume differences in hippocampal subregions were further correlated with plasma Aβ levels and with objective memory performance. Results: Individuals with SMC exhibited significantly higher Aβ1-42 concentrations and lower volumes of CA1, CA4, dentate gyrus, and molecular layer compared with SMC(-) participants. Regression analyses further showed significant associations between lower volume of the dentate gyrus and both poorer memory performance and higher plasma Aβ1-42 levels in SMC(+) participants. Conclusions: The presence of SMC, lower volumes of specific hippocampal regions, and higher plasma Aβ1-42 levels could be conditions associated with aging vulnerability. If such associations are confirmed in longitudinal studies, the combination may be markers recommending clinical follow-up in nondemented older adults.
Objectives: To investigate the association between subjective memory complaints (SMCs) and long-term risk of cognitive impairment in aging because most previous studies have followed individuals for only a few years. Methods: Participants were 1,107 cognitively normal, community-dwelling older women (aged 65 years and older at baseline) in a prospective study of aging. SMCs were assessed shortly after baseline and repeatedly over time with the yes/no question, "Do you feel you have more problems with memory than most?" Cognitive status 18 years later (normal or impaired with mild cognitive impairment or dementia) was determined by an expert panel. Using logistic regression, we investigated the association between SMCs over time and risk of cognitive impairment, adjusting for demographics, baseline cognition, and characteristics that differed between those with and without SMCs. Results: At baseline, 8.0% of participants (n = 89) endorsed SMCs. Baseline SMCs were associated with increased risk of cognitive impairment 18 years later (adjusted odds ratio [OR] = 1.7, 95% confidence interval 1.1-2.8). Results were unchanged after excluding participants with depression. The association between SMCs and cognitive impairment was greatest at the last SMC assessment time point (18 years before diagnosis: adjusted OR = 1.7 [1.1-2.9]; 14 years before diagnosis: adjusted OR = 1.6 [0.9-2.7]; 10 years before diagnosis: adjusted OR = 1.9 [1.1-3.1]; 4 years before diagnosis: adjusted OR = 3.0 [1.8-5.0]). Conclusions: SMCs are associated with cognitive impairment nearly 2 decades later among older women. SMCs may be a very early symptom of an insidious neurodegenerative disease process, such as Alzheimer disease.