The new conceptualization

of Alzheimers Disease
Dr. Jos L Molinuevo
Alzheimers disease and other cognitive disorders unit
ICN, Hospital Clinic I Universitari, Barcelona
BarcelonaBeta Brain Research Centre
Fundaci Pasqual Maragall

Where are we know?

Clinic pathological dual diagnosis:1
Definitive AD diagnosis:
Dementia + pathological lesions on
postmortem exam

Probable AD diagnosis
Possible AD diagnosis
original publication
Current clinical AD diagnostic methods Dr Alzheimers
(Bielchowsky's technique)
shows much variability among studies
General impression that clinical diagnosis is
accurate

NINCDS-ADRDA CRITERIA are considered the Gold Standard2

AD, Alzheimers disease, NINCDS-ADRDA, Mational Institute of Neurological and Communicative Disorders and Stroke-Alzheimers Disease and Related Disorders Association; 1.
McKhann G, et al. Neurology 1984;34:93944; 2. Beach TG, et al. J Neuropathol Exp Neurol 2012;71(4):266 73.

xx

Assessing the accuracy

of the clinical diagnosis
Study performed on US-NACC data 2005
2010:
- N = 919 demented with neuropathological
diagnosis
- Mean age: 79
- Gender: 368 women, 551 male
- Clinical diagnoses prob/poss AD: 70.5%
- Pathological diagnoses: AD in 67.2%
Non AD pathological diagnosis (clinical
diagnosis AD): tauopathies (15), other FTLD
(16), CVD (11), LBD (9), hippocampal sclerosis
(9) Hallervorden-Spatz (2), amyloid angiopathy
(2), limbic encephalities, no pathology

No AD
pathology

Yes AD
pathology

No probable
AD (clinical)

213

180

NPV=54
%

Probable AD
(clinical)

88

438

PPV=83
%

Specificity
=
70.8%

Sensitivity
=
70.9%

Pathological diagnosis:
moderate or frequent plaques AND Braak* IVVI

*Braak IV-VI it is the needed pathological threshold to make the pathological diagnosis of AD
AD, Alzheimers disease, NINCDS-ADRDA, Mational Institute of Neurological and Communicative Disorders and Stroke-Alzheimers Disease and Related Disorders Association;
1. Beach TG, et al. J Neuropathol Exp Neurol 2012;71(4):26673; Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and
Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging 1997;18:S1S2

The new AD conceptualization

Clinical Research

Normal

AD Preclinical Stage

Normal
pathology
No symptoms

Incipient AD
pathology
No symptoms

Medical attention
Differential diagnosis

Mild Cognitive
Impairment due to AD
Moderate pathology

Dementia due to AD
Intense
pathology

Memory disorders

Pathological continuum

Dementia

AD is a clinical-biological entity with a clinical

phenotype ranging from normal cognition to severe

Preclinical AD
The preclinical stage has been postulated to be a
long asymptomatic period during which the
pathophysiological process is progressing.
Preclinical AD subjects have been defined as
individuals who have evidence of early AD
pathological changes but do not meet clinical
criteria for MCI or dementia (Sperling et al., 2011).
Presymptomatic subjects: this state applies to
individuals who will develop AD (monogenic AD)
Asymptomatic at risk state for AD: this state can
be identified in vivo by evidence of amyloidosis of
the brain (PET or CSF).

Alzheimer Biomarker Pathochronology in

Autosomal Dominant AD

Morris et al., Clin Invest 2012

Presymptomatic subjects
41 participants (May 2014):
11 symptomatic mutations carriers (SMC)
16 asymptomatic mutation carriers (AMC)
(mean age -16y Estimated age of onset)
14 asymptomatic non-carriers (NC)
Clinical and cognitive evaluations
Blood and CSF biomarkers
Structural and functional MRI
Amyloid-PET
FDG-PET

Presymptomatic subjects
AMC
A42 or A42/ptau vs EAO
Spearman rho 0,771
p= 0,036

Symptomatic mutation carriers

Asymptomatic mutation carriers

N=6

Interpretation: At early preclinical stages, CTh in PPC and posterior association areas and
caudate volume increase in PSEN1 MC and decrease thereafter with disease progression.
These findings are concurrent with reduced MD suggesting underlying microstructural
changes in the GM.
Reactive neuronal hypertrophy or/and inflammation may account for these features in AMC.

13 AMC vs 14 NC
AMC: mean age -16,6y EAO

Longitudinal study
Cross-sectional study

Statistical maps of the clusters with significant differences

(corrected p<0.05) between AMC and NC

Results of the longitudinal analysis comparing CTR

with AMC. (A) Statistical maps of the clusters with
significant differences in spc between AMC and CTR
(corrected p<0.05).

The analysis of restingstate fMRI data revealed

alterations in the default
mode network in PSEN1
mutation carriers, with
increased frontal
connectivity and reduced
posterior connectivity in
AMC and decreased
frontal and increased
posterior connectivity in
SMC

Preclinical AD: asymptomatic at risk

When does cognitive dysfunction

start?

~12/13 years

Presymptomatic AD

Asymptomatic at risk

Study of florbetapir (18F AV-45)

in normal elderly subjects
WMS immediate

Digit-symbol substitution

WMS delayed

16
14

Recall score

12

10
8
6
4
2
0

Digit-symbol substitution score

60
50
40
30
20
10
0

A-

A+

WMS=Wechsler Memory Scale

A-

A+

A-

A+

Sperling et al. Neurol Aging 2012

Neuropsychological differences between SMD

patients with positive and negative A1-42
Subjective memory complaint (SMC)
A 1-42
(>495 pg/ml)

A 1-42
(<495 pg/ml)

11

66.0 (6.4)

73.6 (6.3)

A 1-42

680.2 (139.6)

315.8 (81.3)**

t-tau

401.1 (294.3)

585.3 (750.1)

p-tau

67.3 (40.2)

82.7 (74.2)

Mini Mental State

Examination

28.2 (1.3)

26.5 (1.8)

Boston naming test

51.3 (4.6)

50.0 (2.8)

FCSRT-total recall

14.4 (1.3)

10.8 (1.6)**

n
Age (years)

**p<0.005
FCSRI=Free and Cued Selective Reminding Test

In subjective memory complaint patients, A1-42 levels

positively correlated with the total recall score of the Free and
Cued Selective Reminding Test (FCRST)
Scatter plot showing CSF A1-42 levels and total recall from the
FCSRT in subjective memory complaint subjects

(r=0.666; p<0.005)

Rami et al. J Alzheimers Dis 2011; 23 (2): 319326

In subjective memory complaint patients, A1-42 levels

positively correlated with the CERAD word list
learning
Scatter plot showing CSF A1-42 levels and learning from the
CERAD in subjective memory complaint subjects

(r=0.697; p<0.005)

CERAD=Consortium to Establish a Registry for AD

Rami et al. J Alzheimers Dis 2011; 23 (2): 319326

Cortical thickness and VBM in preclinical AD

The relationship between A and Cortical

thickness in different automatically extracted
ROIs.
A and B show two AD related areas;
C and D show two unrelated or control areas.

CTh

CTh

CTh

CTh

CTh

We decided to analyzed tha samples divide in tertiles

Cortical thickness in early preclinical AD

Increased cortical thickness in AD areas in subjects with -amyloid

levels in the middle tertiles (transitional levels) respect those
with normal levels

GRAY MATTER THICKNESS AS A FUNCTION OF PATHOLOGICAL LOAD

Preclinical AD exhibit increased activation of precuneus

Preclinical AD with high CR exhibit more gray matter

loss
E.M. Arenaza-Urquijo et al. / CR and A42 -Related Structural Changes

Fig. 2. Scatter plots showing interactions between cognitive reserve proxies and A -related areas of cortical thinning or atrophy in elderly with
normal versus abnormal A 42 CSF levels. In red, statistically signicant correlation coefcients (see Results for statistical details). Cth, cortical
thickness, CR, cognitive reserve.

Tracts showing increased AxD in Pre-AD

subjects compared with controls (blue)

Relationship between the areas showing increased AxD and the level of
A42 on CSF (r=-0.52, p<0.0001) and cognitive reserve (Pre-AD group
r=0.57, p<0.012).

YKL40: GLIAL
INFLAMMATORY RESPONSE

YKL40: GLIAL
INFLAMMATORY RESPONSE

Correlations between CSF YKL-40 levels with A42), t-tau and p-tau,
performed by partial correlation models with age as co-variate. (A) all
sample excluding iRBD group, (B) Preclinical AD (Pre-AD) subjects.
Statistical significance was observed for tau biomarkers in both

Preclinical AD
CSF and imaging biomarkers present interactive
dynamics along the AD continuum
The preclinical stage is biologically active, showing
AD signature areas an initial increase in cortical
thickness and posterior decrease before the clinical
appearance of cognitive impairment
Preclinical AD present distinct functional activity in
key encoding regions
This stage may last around 15-20 years

The new AD conceptualization

Clinical Research

Normal

AD Preclinical Stage

Normal
pathology
No symptoms

Incipient AD
pathology
No symptoms

Medical attention
Differential diagnosis

Mild Cognitive
Impairment due to AD
Moderate pathology

Dementia due to AD
Intense
pathology

Memory disorders

Pathological continuum

Dementia

Prodromal AD can be defined through the presence

of a specific symptom plus biomarker

IWG diagnostic criteria

Probable AD: A plus one or more supportive features B, C, D, or E
Core diagnostics criteria
Presence of an early and significant episodic memory impairment that includes the
following features:
Gradual and progressive change in memory function over more than 6 months
Objective evidence of significantly impaired episodic memory consists of recall
deficit that does not improve signficantly with cueing or recognition testing and
after effective encoding of information
The episodic memory impairment can be isolated or associated with other
cognitive changes at the onset of AD or as AD advances to dementia
Supportive features
Presence of medial temporal lobe atrophy
Volume loss of hippocampi, entorhinal cortex, amygdala evidenced on MRI
Abnormal cerebrospinal fluid biomarker
Low amyloid 1-42 concentrations, increased total tau or p-tau concentrations
Other well validated markers to be discovered in the future
Specific pattern on functional neuroimaging with PET
Reduced glucose metabolism in bilateral temporal-parietal regions
Other well validated ligands, including amyloid imaging
Proven AD autosomal dominant mutation

Prodromal DA diagnosis: MRI and neuropsychology

Brain regions representing increased GM volume in

controls compared to:
A) PrdAD patients
B) mild AD patients
(corrected at FDR p<0.05)
Rami et al. Int J Geriatr Psychiatry 2012; 27 (2): 127134

New research criteria

Presence of an objective episodic memory loss,
defined through the Free and Cued Selective Recall
Reminding Test (Grober & Buschke, 1987)
CDR of 0.5 with memory box of 0.5 or 1
Essentially preserved activities of daily living
Absence of dementia
AD CSF profile (low beta-amyloid <495 pg/mL,
and high t-tau >356 or p-tau181 >75 pg/mL)

Association between cognition and CSF

in the prodromal AD subjects
Higher total tau levels associated to poorer memory:
CERAD list (r = -0.487; p<0.005)
FCSRT (free recall) (r = -0.420; p <0.005)

Higher p-tau levels associated to poorer memory:

M@T (r = -0.521; p<0.001)
CERAD retention list (r = -0.527; p<0.001)
Total Learning (Buschske) (r = 0.518; p<0.005)

A1-42 associated to poorer semantic fluency

(r=0.54; p<0.005)
FCSRT=Free and Cued Selective
Recall Reminding Test

Control versus prodromal AD

FEW correction:
parahippocampal
gyrus,
uncus, precuneus
and
medial frontal
gyrus (left)

Correlation of FCSRT with neuroimaging

Clinical evolution
All patients followed over 2 years converted to AD according
to NINCDS-ADRDA criteria (2 or more cognitive areas
affected plus significant daily living activities impairment
according to FAQ).
All patients followed one year had lower cognition (3 of them
with 2 or more cognitive areas affected) and one with lower
functionality (only memory affected)
Patients followed less than one year no significantly
cognitive (number of cognitive areas affected) or functional
changes.

Prodromal or predementia AD
Alzheimers disease may be diagnosed
through a clinic-biological approach
The prodromal, predementia or MCI stage
represents the earliest phase to establish a
clinical diagnosis
Biologic: biomarkers correlate with pathology
Clinic: episodic memory is a specific symptom

There are active trials with disease

modifying drugs in this population

41

IWG diagnostic criteria

A. SPECIFIC CLINICAL PHENOTYPE
Presence of an early and significant episodic memory impairment (isolated
or associated with other cognitive changes suggestive of a mild cognitive
impairment or of a dementia syndrome) which includes the following
features:
i) Gradual and progressive change in memory function reported by patient
or informant over more than 6 months
ii) Objective evidence of an amnestic syndrome of the hippocampal type
(*), based on a defective performance on an episodic memory test with
established specificity for AD, which is high in case of cued recall paradigm
with control of encoding.
B. IN VIVO EVIDENCE OF AD PATHOLOGY (one of the following)
- Decreased A1-42 together with increased T-tau or P-tau in CSF
- Increased tracer retention on amyloid PET
- AD related autosomal dominant mutation (in PSEN1, PSEN2, or APP)

MCI Clinical diagnostic Criteria

Alzheimers disease diagnostic

biomarkers
Amyloid Markers
Imaging: PET with amyloid tracer
Biochemical: low A42 CSF levels

Injury markers
Imaging:
FDG PET
SPECT
MRI: hippocampal volume or atrophy rate

Biochemical: high Ptau or Ttau CSF levels

COMBINING BOTH GREATER DIAGNOSTIC

CERTAINTY

Biomarker probability of AD

Amyloid Markers

Injury markers

aetiology

Uninformative

Intermediate
Highest

Untested, conflicting,
indeterminant or non
informative results

Untested, conflicting,
indeterminant or non
informative results

Positive
Unavailable

Unavailable
Positive

Positive

Positive

Negative

Negative

Lowest: Unlikely due to

AD

TAKE HOME MESSAGE

The preclinical stage is biologically active, showing
AD signature areas an initial increase in cortical
thickness followed by a decrease cognitive impairment
Different brain areas evolve with distinct patterns
An earlier and more specific diagnosis is feasible
through biomarkers
Therefore, new diagnostic approaches include
Clinical information
Biomarker results

Thank You