Brain (2000), 123, 484498

Atypical and typical presentations of Alzheimers

disease: a clinical, neuropsychological,
neuroimaging and pathological study of 13 cases
Clare J. Galton,1 Karalyn Patterson,3 John H. Xuereb2,4 and John R. Hodges1,3
1University

Neurology Unit, 2The Cambridge Brain Bank

Laboratory, Department of Histopathology, Addenbrookes
Hospital, 3MRC Cognition and Brain Sciences Unit and
4University Department of Pathology, Cambridge, UK

Correspondence to: John R. Hodges, MRC Cognition and

Brain Sciences Unit, 15 Chaucer Road, Cambridge
CB2 2EF, UK
E-mail: John.hodges@mrc-cbu.ac.uk

Summary
There has been increasing awareness that some slowly
progressive focal cortical syndromes can be the presenting
features of Alzheimers disease, but pathological evidence
has been sparse. This clinico-pathological series presents
our experience with pathologically proven atypical as well
as typical Alzheimers disease presentations. We report
and compare four patterns of presentation: a typical
pattern with initial amnesic syndrome (n 4 cases),
progressive visual dysfunction (n 1), progressive
biparietal syndrome (n 2) and progressive aphasia
(n 6). The aphasic presentations include both fluent and
non-fluent aphasic syndromes. The neuropsychological

profiles and neuroimaging clearly reflect the presenting

clinical features, and show a close relationship to the
distribution of pathology in these cases. Of note was the
sparing of medial temporal structures (hippocampus
and/or entorhinal cortex) in several aphasic cases and
the severe occipito-parietal involvement in those with
prominent visuospatial disorders at presentation. Our
data demonstrate the wide spectrum of Alzheimers
disease presentations. The recognition of atypical
presentations of Alzheimers disease is important when
attempting to make an early accurate pre-morbid
diagnosis of neurodegenerative disease.

Keywords: Alzheimers disease; atypical presentations of Alzheimers disease; progressive aphasia; posterior cortical
atrophy
Abbreviations: BA Brodmann area

Introduction
Alzheimers disease is widely considered to be clinically
homogeneous with a characteristic profile of neuropsychological deficits (McKhann et al., 1984; Morris et al.,
1989; Locascio et al., 1995). It is true that, using histological
diagnosis as the gold standard, current research criteria
(McKhann et al., 1984) are accurate in up to 90% of cases.
Such criteria, however, are heavily weighted towards memory
impairment as the central deficit and may, therefore, exclude
atypical cases. A means for early accurate diagnosis is the
aim of much research, as treatment interventions would be
most likely to benefit patients in the earliest disease stages
(Hodges, 1998). It is important, therefore, to identify the
complete spectrum of clinical presentations of histologically
proven Alzheimers disease.
In group studies of patients with Alzheimers disease, the
most prominent and earliest neuropsychological impairment
is of anterograde episodic memory (Grady et al., 1988; Welsh
Oxford University Press 2000

et al., 1991; Greene et al., 1996b). After the prodromal phase

of amnesic problems, which may last a number of years
(Linn et al., 1995), inevitable progression of the disease
leads to involvement of attentional and executive processes,
semantic memory, praxis and visuoperceptual abilities (Grady
et al., 1988; Mendez et al., 1990; Greene et al., 1995; Hodges
and Patterson, 1995; Locascio et al., 1995; Binetti et al., 1998;
Perry and Hodges, 1999). This pattern of neuropsychological
changes reflects the current view regarding the progression
of pathology which is thought to involve initially the
transentorhinal (or perirhinal) region before spreading into
the hippocampal complex proper in the medial temporal
lobe structures and thereafter the temporal lobes and basal
forebrain (Hyman et al., 1986, 1990; Braak and Braak, 1991;
Van Hoesen et al., 1991; Van Hoesen, 1997). It is clear from
neuropathological studies that while this classic staging may
fit the majority of cases, a significant proportion do not

Atypical Alzheimers disease

adhere to this orderly pattern (Gertz et al., 1998). This
conclusion raises the further question of just how commonly
patients with Alzheimers disease might have atypical
presentations with prominent early deficits other than
episodic memory.
Over the past 15 years, there has been increasing awareness
of slowly progressive focal cortical syndromes in which
memory impairment is not a prominent feature and other
symptoms predominate. These include progressive aphasia
(Chawluk et al., 1986; Snowden et al., 1989; Hodges et al.,
1992) and visuoperceptual or spatial syndromes (Cogan,
1985; De Renzi, 1986; Benson et al., 1988; Freedman et al.,
1991; Ross et al., 1996). Whether these cases are due to
Alzheimers disease pathology or to other, non-Alzheimer
pathology such as spongiform change with or without Pick
bodies, is often unconfirmed and therefore controversial.
Benson and colleagues, for example, suggested that in their
five cases, of what was named posterior cortical atrophy, the
long progressive decline and relative preservation of memory
argued against Alzheimers disease; but lacking pathological
evidence, this view remains speculative (Benson et al., 1988).
Similarly, Chawluk and colleagues hypothesized that it was
highly unlikely that Alzheimers disease was the underlying
cause of progressive aphasia in their patients, on the basis
of the long course of the disease and sparing of memory,
plus evidence from a biopsy of one of their original six cases
(Chawluk et al., 1986). Since Chawluk and colleagues report
in 1986, it has become clear that although the language
syndrome in progressive aphasia is heterogeneous, two main
patterns can be identified: progressive non-fluent aphasia
and progressive fluent aphasia. In the latter syndrome, the
linguistic deficit reflects a breakdown in the conceptual
knowledge base for language comprehension and production
as well as other cognitive capacities requiring semantic
memory. This has led to adoption of the term semantic
dementia to describe this syndrome (Snowden et al., 1989;
Hodges et al., 1992; Hodges and Patterson, 1996).
Despite definitive documentation of non-Alzheimers
disease pathology in some cases within this spectrum of
disorders, it is also now clear that pathologically proven
Alzheimers disease can present with a focal cortical
syndrome. Cases with progressive occipitoparietal atrophy,
causing either visual agnosia and alexia, a biparietal syndrome
with symptoms of Balints syndrome (Kobayashi et al., 1987;
Hof et al., 1989, 1990; Berthier et al., 1991; Levine et al.,
1993; Victoroff et al., 1994; Ross et al., 1996) or a right
parietal syndrome (Crystal et al., 1982; Ball et al., 1993),
have revealed clear Alzheimers disease pathology at postmortem. Review of the literature concerning the pathological
basis of progressive aphasia also indicates that, while the
majority of cases have had non-Alzheimers disease
pathology, there are at least four well documented cases
of progressive aphasia with Alzheimers disease pathology
(Pogacar and Williams, 1984; Green et al., 1990; Benson
and Zaias, 1991; Greene et al., 1996a); these included both
fluent and non-fluent aphasic syndromes.

485

To our knowledge, there have only been three longitudinal

clinico-pathological series examining the neuropsychological
patterns in Alzheimers disease. Neary and colleagues
prospectively studied 24 patients with presenile dementia
who had a temporal or frontal cerebral biopsy, which revealed
Alzheimers disease pathology in 75% of the cases (Neary
et al., 1986). Neuropsychologically, the Alzheimers disease
patients presented with selective amnesia in two cases,
amnesia, anomia and visuoperceptual impairment in 11
patients, amnesia and severe visuoperceptual impairment in
three patients, and amnesia, dyspraxia and executive
difficulties in two patients. These findings clearly demonstrate
heterogeneous patterns of cognitive decline in Alzheimers
disease. In a retrospective study, Price and colleagues
documented the neuropsychological profiles of 20 patients
with autopsy-proven Alzheimers disease (Price et al., 1993).
Again there was heterogeneity within the group regarding
the presenting cognitive syndrome. Although episodic
memory was affected in all patients, the memory disorder
was mild by comparison with language disorders in two
patients and with visuospatial problems in two further cases.
Interestingly, in the majority of cases, the aphasia was anomic,
with late effects on language comprehension. Non-fluent
aphasia was not observed, even in the last stages of the disease.
In the most recent study, Kanne and colleagues investigated
the relationship between initial presentation and pathology
in 41 patients (Kanne et al., 1998). Having established
three principal cognitive factors corresponding to executive,
memory and visuospatial functions, in a larger clinical cohort
they then documented a significant correlation between these
factors and the relative burden of pathology in frontal,
temporal and parietal regions, respectively. This indicates
that, as one would predict, the heterogeneity in earliest
clinical presentation relates to the underlying distribution of
Alzheimers disease pathology. It should be noted that the
patients studied by Kanne et al. died on average 5 years after
their last cognitive assessment, and that their neuropyschological evaluation was limited and did not, for
example, include a comprehensive language assessment.
Despite the accruing evidence of atypical presentations of
Alzheimers disease, a number of issues remain unresolved.
For instance, why do some areas not usually affected early
in the disease become affected preferentially in specific
patients? What is the range of atypical presentations
particularly with respect to the profile of aphasic and visual
symptoms? How precise is the correspondence between
clinical phenotype, neuroradiological findings and distribution
of pathological changes? Are atypical cases under-diagnosed,
or diagnosed later than typical presentations? Some authors
have argued that patients with progressive focal atypical
cortical syndromes due to Alzheimers disease are impaired
additionally in episodic memory and general intellectual
function at the time of initial diagnosis, and that the
differentiation between Alzheimers disease and other
progressive focal cortical syndromes is not a clinical dilemma
(De Renzi, 1986).

486

C. J. Galton et al.

In this study, we attempt to address some of these questions.

We present the neuropsychological profiles, neuroimaging
and neuropathological data of a group of nine patients with
pathologically proven Alzheimers disease who presented
with atypical patterns of deficit. We contrast them with
four pathologically proven Alzheimers disease patients with
classical initial memory dysfunction. To our knowledge,
this is the first pathologically proven cohort of atypical
Alzheimers disease patients investigated with both a
comprehensive battery of neuropsychological tests and
parallel neuroimaging.

Patients and methods

Patients
The 13 patients, who all presented to the Memory Clinic at
Addenbrookes Hospital, Cambridge, between 1990 and 1995,
were all fully investigated with a standard neurological
examination and blood investigations. They underwent, as
far as possible, extensive neuropsychological examination,
with longitudinal follow-up in many cases, and neuroimaging.
All had post-mortem examinations performed by the same
neuropathologist (J.H.X.). Table 1 provides demographic
details. The four patients with typical Alzheimers disease
represent the first four cases who have come to autopsy of
the cohort of 52 cases followed longitudinally by our group
(Hodges and Patterson, 1995). The nine atypical cases all
came to autopsy over the period 19941997 and represent
50% of cases seen in Cambridge with a focal dementia
syndrome who have had autopsies (the remainder had nonAlzheimer forms of dementia).

Neuropsychological tests
The neuropsychological tests detailed below were
administered to all of the patients where possible. Table 2
displays the results of neuropsychological assessment for all
patients except C.M.
The Mini Mental State Examination (Folstein et al., 1975)
was used as a general measurement. Memory tests included:
(i) digit span; (ii) logical memory [immediate and delayed
story recall from the Wechsler Memory ScaleRevised
(Wechsler, 1987)]; (iii) recognition memory test for words
and faces, 50 item versions (Warrington, 1984); and (iv)
recall of the Rey Complex Figure.
Perceptual tests included: (i) fragmented letters, dot
counting and cube analysis subtests from the Visual Object
and Space Perceptual Battery (Warrington and James, 1991);
(ii) object matching (unusual views test) (Humphreys and
Riddoch, 1984); and (iii) Bentons Judgement of Line
Orientation Test (Benton et al., 1983). Language tests
included: (i) letter fluency for words beginning with F, A
and S; (ii) reading of 126 pairs of regular and exception
words varying in frequency (Patterson and Hodges, 1992);
(iii) writing or oral spelling of 36 words (Patterson and

Hodges, 1992); and (iv) Test for the Reception of Grammar

(Bishop, 1989). The semantic tests included: (i) category
fluency for three categories each of living and man made
items; (ii) picture naming and wordpicture comprehension
tests (n 48 for each) from the semantic battery of
Hodges and Patterson (Hodges and Patterson, 1995); and
(iii) pyramids and palm trees test [three picture version
(Howard and Patterson, 1992)].

Neuroimaging
Imaging for all patients was carried out in the Department
of Radiology, Addenbrookes Hospital, Cambridge. CT and
MRI scans were reported by senior neuroradiologists and
SPECT (single photon emission computed tomography) scans
by a nuclear medicine consultant. Eleven patients had a CT
scan of the brain, six had MRI of the brain, with 3D set
acquisition in the coronal plane using an SPGR (spin gradient
echo) T1-weighted sequence, and a T2-weighted axial
sequence, and 12 (i.e. all except one case) had a 99mTcHMPAO SPECT scan.

Neuropathology
All 13 cases were examined neuropathologically after death
in the Pathology Department, University of Cambridge by a
senior neuropathologist (J.H.X.). J.H.X. was blinded to the
clinical diagnosis, although he was aware that the cases were
those of possible Alzheimers disease patients. At the time
of autopsy, the brain was weighed, and the brainstem and
attached cerebellum were separated from the cerebral
hemispheres by a horizontal incision at the diencephalomesencephalic junction. The cerebral hemispheres were
separated by an incision through the length of the corpus
callosum. The left cerebral hemisphere and the attached half
of the midbrain were immersed in formol saline. The left
half of the brainstem and the right cerebellar hemisphere
were fixed in formalin with the left cerebral hemisphere. The
right cerebral hemisphere, right hemi-brainstem and left
cerebellar hemisphere were then prepared for rapid freezing,
but only after sampling of the right cerebral cortex. Small
blocks of fresh tissue from the cortex of the right cerebral
hemisphere were removed from Brodmann areas (BAs) 8,
24, 44, 45, 47, 20, 21, 22, 41, 42, 37 and 40; these were put
into cassettes and fixed in formol saline. They were used to
provide neuroanatomical data for the non-dominant
hemisphere to complement the morphometric studies on the
left hemisphere (see below). Horizontal slices through the
left half of the brainstem and a vertical slice through the
right cerebellar hemisphere were also frozen rapidly. These
frozen slices of brain were stored at 70C.
After fixation, the left cerebral hemisphere, left hemibrainstem and the right cerebellar hemisphere were
photographed and subsequently cut into slices 0.5 cm
(cerebrum) and 0.3 cm (brainstem and cerebellum) thick.
The slices were photographed.

6
7
14
4

5
3

CT/M/79
CM/M/76

Poor episodic memory

Poor episodic memory

FR/M/84
AB/M/68

0
0

0
0

NT

Visuospatial

Language

NT

Semantic Episodic
memory

Initial neuropsychological presentation

Mild
Mild

Normal
Normal

N/A
N/A

N/A
N/A

L hemi cerebral
L perisylvian
N/A
L temporal

N/A

L temporoparietal

N/A

MRI
atrophy

Biparietal

Biparietal

Bi-occipital

SPECT
hypoperfusion

Medial temporal
Biparietal and L
temporal
N/A
Normal

Normal
Normal
L parieto-temporal
Bilat
frontotemporal
LR temporal L temporal
Bitemporal
N/A
LR esp temporal L parieto-occipital
bitemporal

N/A
N/A
Normal
N/A

N/A

N/A

Occipital

CT
atrophy

Neuroimaging

0 no abnormality; mild abnormality; moderate abnormality; severe abnormality; NT not tested; L left; R right; N/A not available. * Age at
presentation. Length of illness (in years) was estimated from the reported initial symptoms to death. Episodic memory as judged by performance on non-verbal memory tests.

9
5

Poor episodic memory

Poor episodic memory

Group 4 Memory
GW/M/69
6
GT/M/60
8

Anomia and comprehension problems

Anomia

Loss of speech fluency

Loss of speech fluency
Anomia and comprehension problems
Anomia and comprehension problems

Visual difficulties

NK/F/58
Group 3
Language
PG/F/74
AS/M/66
PB/M/65
OM/F/67

10

Presentation

Dyspraxia/dysgraphia/visual
disorientation
Dyspraxia/dysgraphia/simultanagnosia

Group 1 Visual
AP/F/69
Group 2
Biparietal
JM/M/68

Length of
illness

Patient/sex/age* Clinical features

Table 1 Summary of demographic and presenting features and neuroimaging

Atypical Alzheimers disease

487

488

C. J. Galton et al.

Table 2 Summary of neuropsychological profiles at presentation

Tests

MMSE (30)

Visual

Bi-parietal

A.P.

J.M.

15

Memory
Digit span F/B
3/2
Logical memory immed 0
Logical memory delay
0
RMT faces (50)
RMT words (50)
Rey copy (36)
Rey recall (36)
Visuospatial
Fragmented letters (20)
Dot counting (10)
Cube analysis (10)
Rey copy (36)
Object matching (40)
Line orientation (30)
Language
Letter fluency (FAS)
19
Reading regular (126)
Reading irregular (126)
Writing (36)
TROG (80)
Semantic
Category fluency
11
Naming (48)
Wordpic matching (48)
PPT (52)

3/2
4.5
3.5
23
38
0
0

Aphasia presentations
N.K.

P.G.

A.S.

P.B.

14

28

27

3/2
3
1
34
33
1
0

4/4
6.5
7.25
36
46
29
13

3/
6
3

20
0
27
0

18
16
45
38

O.M.
6

C.T.

G.W.

17

26

8/7
8
5
40
44
34
2

42

3/2
0
0
30

33
17

17
0

29

34
38
27

19
10

4/3
0.25
0
29
3

G.T.

F.R.

A.B.

22

22

19

6/5
5
0
39
29

5/3
3
0
24
27
18
0

5/3
3
0
28
24
13.5
0

14
6
5

17
10

10
29
37
29

7
30
17

33
39
23

9
10
17
26
19

11
126
122
35
60

0
109
79
1
60

0
64
61
10
56

16
123
117
24
60

42
124
119
36
80

23

111
78
22
62

16
122
122
34
75

12
121
114
30
62

12
39
48
50

18
18
47
42

4
11
36
38

0
2
35
30

10
23

48
46
48
52

28
44
48
52

18
34
43
40

25
41
46
48

1
23
0

2
13
110
124
94
120
1 (oral sp) 27(oral sp)
44
45

26
7
7.5

3/

Amnesic presentations

42
28
40
36

35

18
36
21

13.5
37
23

MMSE Mini Mental State Examination; RMT recognition memory test; TROG Test for the Reception of Grammar; PPT
Pyramids and Palm trees test.

After neuropathological examination, blocks of fixed tissue

were sampled according to the CERAD (Consortium to
Establish a Registry of Alzheimers Disease) protocol
(Mirra et al., 1991). Additional blocks were taken from
the BAs noted above, from lateral and medial occipital
cortex to allow application of Braak and Braaks staging
for Alzheimer-type pathology (Braak and Braak, 1991) and
from the basal ganglia at the level of the subthalamic
nucleus, including putamen, globus pallidus, dorsal
thalamus, subthalamic nucleus and insular cortex. Apart
from routine haematoxylin and eosin staining on all
blocks, immunohistochemical techniques were used for the
assessment of neurodegenerative changes. The immunohistochemical panel of antibodies included those against
abnormal tau, A4 -peptide and ubiquitin, which were
used to assess the presence and extent of neurofibrillary
inclusions, neuropil threads, Pick bodies, cortical Lewy
bodies, total (pre-amyloid and amyloid) plaque load,
neuritic plaques and cerebral amyloid angiopathy. Nerve
cell loss, spongiosis and gliosis were assessed on the
haematoxylin and eosin and GFAP (glial fibrillary acidic
protein) preparations. All these parameters were assessed
semi-quantitatively according to CERAD criteria.

Illustrative cases
Progressive visual dysfunction
A.P.
This 69-year-old retired medical secretary presented with a
4 year history of poor vision. She was referred initially to
an ophthalmologist who found no retinal or ocular problems
to account for her extreme difficulty in reading. At this stage,
A.P. was living alone without evidence of memory or other
cognitive deficits. One year before assessment by our clinic,
memory problems developed although perceptual problems
still predominated. She was unable to read or watch television.
She had to dress herself by feel and had difficulty using a
knife and fork. She continued to enjoy listening to the radio
although other pastimes were no longer possible. She had
suffered one episode of formed visual hallucinations when
she saw swarms of insects inside her house. Her mobility
was affected by her visual problems and she had sustained
a fractured neck of femur after a fall 3 years before.
On examination, her visual fields were severely restricted
and visual acuity was 6/18 bilaterally. Fundoscopy revealed
normal discs, lenses and maculae. She had normal pupillary
reflexes and her eye movements appeared full. She was

Atypical Alzheimers disease

partially orientated. Her severe visual disorientation and
perceptual deficits meant that only verbal formal
neuropsychological tests were administered. On general
intellectual tasks, A.P. achieved high average scores on
comprehension and vocabulary. She obtained low average
scores on information and digit span, and mental arithmetic
was very poor. Free recall of a prose passage was severely
impaired, as was verbal paired associate learning, and she
had a very reduced verbal fluency score. She was not willing
to undergo more extensive neuropsychological assessment,
but the results obtained demonstrate impairments of attention
and memory in addition to her visual deficit. A SPECT scan
demonstrated marked bilateral reduction in occipital lobe
perfusion, and a CT scan showed an enlarged calcarine fissure
with posterior brain atrophy. Continued deterioration meant
that A.P. was soon unable to live independently and moved
into a nursing home; she died 2 years after presentation
to our clinic. Neuropathological examination after death
demonstrated established Alzheimers disease (CERAD
definite, Braak stage VI) with particularly severe involvement
of the occipital visual cortex.
In summary, this patient presented with primary visual
malfunction followed by memory impairment and more
global cognitive decline. The pathological diagnosis was of
visual variant Alzheimers disease.

Progressive biparietal syndrome

J.M.
A 63-year-old right-handed ex-lecturer (first reported as case
3 in Ross et al., 1996) complained in 1987 of problems in
performing manual tasks and an inability to write. He
had particular difficulties tying his shoelaces, dressing and
performing bimanual tasks such as washing up, peeling
vegetables or gardening. He was only able to sign his name
and was otherwise unable to write. At this stage, his memory
was reported as normal by relatives and there was no
personality change. Over the next 5 years, J.M. progressed
from the initial biparietal syndrome to a more global dementia.
By 1992, when he first underwent neuropsychological
assessment, he had evidence of generalized intellectual
impairment. He was extremely impaired on all visuospatial
tasks and grossly apraxic. Language assessment demonstrated
impairment of syntactic comprehension as well as semantic
knowledge. Oral spelling was also severely impaired (only
1/36 items correct) which, together with the almost total
inability to write, indicated both a central and a peripheral
agraphia. He also performed poorly on tests of phonological
competence including a rhyme production task and phoneme
blending. SPECT scanning revealed biparietal reduction in
perfusion, and MRI showed gross posterior cortical atrophy
especially of the left parietal and temporal lobes (Fig. 1) (see
Ross et al., 1996). J.M. continued to deteriorate in language
and reading tasks and died aged 73. Neuropathological
examination confirmed the pre-morbid diagnosis of

489

Alzheimers disease (CERAD definite, Braak stage VI) with

a single small incidental microscopic infarct in the
hippocampus. There was moderate cortical atrophy with
discernible emphasis on the superior parietal lobules.
Microscopically, neuronal loss was most severe in BA 7.
In summary, this case presented atypically with severe
difficulties in writing, poor hand coordination and impaired
visuospatial skills. There was biparietal hypoperfusion on
SPECT, and MRI revealed left parietal and temporal atrophy.
Neuropathologically, the parietal lobes, particularly
superiorly, were most affected.

Progressive aphasia syndromes

Non-fluent aphasia: P.G.
This 74-year-old right-handed ex-secretary (reported as case
1 in Hodges and Patterson, 1996; also Croot et al., 1998)
presented in 1991 with a 2 year history of progressive loss
of speech fluency. She complained of an inability to converse
due to hesitancy, word finding difficulties and speech
distortion. Her reading, writing and memory were unaffected
and she was living independently and able to drive.
Spontaneous speech was poorly articulated, with abnormal
prosody and frequent phonemic errors, mild word finding
difficulty and abnormally short phrase length. Comprehension
of single words was normal, but she had difficulty
understanding syntactically complex sentences. Repetition
of short words was good, but the requirement to repeat
multisyllabic words and phrases produced frank phonological
errors. Visuospatial abilities were very well preserved.
Neuroimaging revealed minimal left cerebral atrophy with
widening of the sylvian fissure on MRI and a normal SPECT
image. Over the subsequent 3 years, P.G.s language abilities
continued to decline dramatically, in stark contrast to no
deterioration in general cognitive abilities or in her ability to
live independently. By this time, she had almost no
spontaneous speech; although she was sometimes able to
give appropriate 12 word answers to direct questioning,
many of her utterances were incomprehensible. It is notable
that at this stage her visuospatial abilities and non-verbal
memory remained normal. Comprehension also became
severely impaired and she had difficulty understanding even
single words. A repeat MRI scan of her brain revealed a
more obvious degree of generalized atrophy involving both
frontal lobes with more marked widening of the left sylvian
fissure (Fig. 2) (see Hodges and Patterson, 1996).
The clinical diagnosis was progressive non-fluent aphasia.
We confidently predicted that this syndrome was unlikely to
be due to Alzheimers disease (Hodges and Patterson, 1996;
Croot et al., 1998) as P.G.s language deficit was the only
impairment for 3 years, with little change in her general
cognitive abilities or activities of daily living over this time.
She died aged 78, four years after initial presentation.
Neuropathological examination, contrary to pre-morbid
expectations, demonstrated features of Alzheimers disease

490

C. J. Galton et al.

Fig. 1 (A) Coronal T1 and (B) axial T2 MRI of a progressive biparietal syndrome patient with biparetal
atrophy.

(Braak stage IV, CERAD probable Alzheimers disease), but

with unusual features: the entorhinal cortex was relatively
spared, with only a few tangles in the entorhinal cortex
proper; there were, however, moderate numbers of tangles
in CA1 and the transentorhinal cortex. Well defined plaques
were not a feature of this case.
In summary, this case presented with a non-fluent aphasic
pattern, including difficulties in communicating due to
hesitant, distorted speech with syntactic abnormalities and
some word finding difficulties. MRI demonstrated some mild

left cerebral atrophy around the perisylvian region without

obvious hippocampal atrophy. Pathologically, there was
relative sparing of the medial temporal lobe structures and
severe involvement of superiolateral temporal lobe areas.

Mixed aphasia: P.B.

This 65-year-old right-handed man first sought medical advice
in 1984 because of speech difficulties that had progressed
slowly since his retirement from being a senior business

Atypical Alzheimers disease

491

was marked cell loss in the temporal cortex and no evidence

of Picks pathology. The lesions were typical of Alzheimers
disease but the distribution was very atypical. There were a
few isolated Lewy bodies in the cortex with insignificant
brainstem involvement. The pathological diagnosis was
Alzheimers disease (Braak Stage V, CERAD definite) with
incidental Lewy body disease.
This case illustrates a mixed aphasic presentation with
initial problems in both semantic aspects of language (naming
and word comprehension) and syntactic features (impairments
both in expressive and receptive grammar), plus some phonological errors in spontaneous speech. Neuropathologically,
there was a highly atypical distribution of Alzheimers
disease-type pathology, principally involving the temporal
poles.

Fluent aphasia: O.M.

Fig. 2 Coronal T1 MRI of a progressive aphasia case.

manager in 1981. He complained of difficulty in finding the

right words, in putting words in the correct order and in
following conversations and books. His non-verbal memory
and practical skills were very well preserved, and he continued
to enjoy driving, cycling, fishing and golf. When he was first
assessed by us in 1990, P.B. had a severe impairment in
naming and comprehension, and disruption to semantic
memory. He also made some phonological errors and stuttered
in spontaneous speech. His oral reading of single words
showed a striking pattern of surface alexia, which has
been reported in two publications (reading performance at
presentation, Patterson and Hodges, 1992; longitudinal
decline in reading, Patterson et al., 1996); his writing also
showed clear surface dysgraphia. He had no visuospatial
deficits and, although his non-verbal reasoning was outside
the normal range, it was relatively well preserved 6 years after
initial presentation. The clinical diagnosis was of progressive
aphasia (mixed type). He had a family history of dementia
in that his mother had been demented in her late life. CT
scans performed in 1984 and 1988 were normal, but a
SPECT scan in 1991 revealed some left temporoparietal
hypoperfusion.
For some time, P.B. maintained an impressive ability to
find his own way around by either bicycle or car; but from
1991 his other abilities (as well as his willingness to be
tested) gradually deteriorated. Language impairment was,
however, always the prominent feature. By 1994, he had
become virtually mute and required institutionalized care.
He died in 1995.
Pathological examination revealed severe atrophy of the
left temporal lobe and mild generalized cerebral atrophy (Fig.
3). Microscopically, there was extensive Alzheimer-type
pathology throughout the cerebral cortex, particularly in the
temporal association cortex and perisylvian cortex. There

This 67-year-old lady presented with a 23 year history of

insidious decline in language abilities affecting both
production and comprehension. She more recently had
developed difficulties using objects and preparing meals. At
presentation, her day-to-day memory was poor. On
neuropsychological assessment, her language skills were
globally disrupted, with impairments in receptive as well as
expressive vocabulary. She had difficulties understanding all
but the most common words and made numerous errors on
a sentence comprehension task. Her speech was fluent but
with a very limited vocabulary, and she was unable to perform
on a test of word definitions, or to name pictures of common
objects. She made some errors in repetition, but this simple
aspect of language was relatively well preserved. Although
in the context of such profound language impairments it
was difficult to assess other cognitive functions, there was
evidence of some impairment in non-verbal skills. For
instance, on Ravens Coloured Matrices, a relatively easy test
of non-verbal reasoning, she performed in the low average
range. She also scored outside normal limits on a short, easy
test of recognition memory for faces (17/25). Although her
dot counting and cube analysis scores were normal, she did
show some impairment of perceptual analysis of incomplete
drawings and fragmented letters. Thus the patient had a
severe progressive fluent aphasia and semantic impairment
with evidence of a more general deterioration of memory
and visuoperceptual skills. In view of these non-semantic
deficits, we had not characterized her as a case of semantic
dementia, but instead favoured a diagnosis of probable
Alzheimers disease with profound aphasia.
MRI showed very striking left temporal atrophy. A SPECT
scan demonstrated bilateral reduction of uptake in the
frontotemporal regions, which were more marked on the left.
The pathological diagnosis was of CERAD definite, Braak
stage V Alzheimers disease. There was moderate cerebral
gyral atrophy with emphasis on the frontal lobe (pole and
superomedial portions), temporal pole and medial temporal
lobes. Microscopically, there was no asymmetry in the

492

C. J. Galton et al.

Fig. 3 Macroscopic pathological appearance of case 6 (P.B.) showing the severe left temporal atrophy.

cerebral cortical Alzheimer-type pathology between the right

and left hemispheres, and in the left hemisphere there was
no apparent difference in the severity of Alzheimer-type
change between primary language areas and association
cortex. There was some evidence of incidental meningeal
cerebral amyloid angiopathy.
In summary, this case presented with fluent progressive
aphasia, characterized by severe anomia and word
comprehension problems. There was involvement of other
cognitive domains at presentation, especially non-verbal
memory, and these showed a fairly rapid deterioration.
Structural imaging demonstrated left temporal atrophy in this
and the two other fluent cases, and functional imaging showed
bitemporal hypoperfusion in all cases, with more extensive
cortical involvement in two patients. Pathologically, the
temporal lobes were severely affected.

Illustrative typical presentation of Alzheimers

disease
G.W.
This 69-year-old man, a retired antiques dealer, was referred
to the Memory Clinic in July 1992 with a 12 month history
of episodic memory problems. Both the patient and his wife
described his difficulty in remembering recent events such
as conversations, television programmes and family news.
He had become repetitive but was able to continue to enjoy
his hobbies (writing poetry and articles), collecting antiques
and followed current events. Language and spatial abilities
were intact. He had a medical history of ischaemic heart
disease. A SPECT scan was unremarkable. On initial
presentation, his neuropsychological profile demonstrated

only a mild amnesic syndrome which was particularly marked

for non-verbal material as evidenced by his poor performance
on recall of the Rey figure (Table 3). Over the next 2 years,
his amnesia worsened as measured by logical memory
delayed recall, but his semantic memory, language, attention,
visuospatial and perceptual abilities all remained intact (Table
3). He died of acute cardiac failure in 1996. The pathological
picture was one of relatively early Alzheimers disease (Braak
stage IV). The hippocampus and parahippocampal gyrus
showed numerous neurofibrillary tangles in neurons from the
CA1 pyramidal cell layer, and there were numerous tangles
in the entorhinal cortical neurons. There was also some
involvement of BA 38 (the temporal pole).

Discussion
It is clear from this study that pathologically proven
Alzheimers disease can present with a range of cognitive
symptoms. Although there may be more, we have identified
three main patterns: posterior cortical atrophy with either
major visual deficits or a predominantly biparietal syndrome;
progressive aphasia which may be fluent, non-fluent or mixed;
and the typical amnesic prodrome. All of these are followed by
global impairment. We will now discuss each of these patterns.

Typical cases
The clinical presentation of our four typical patients supports
the current view of both the standard initial neuropsychological profile and the nature of its progression.
Episodic memory complaints were the primary feature, with
subsequent involvement of attentional, language, semantic

Atypical Alzheimers disease

Table 3 Longitudinal neuropsychological data from
amnestic patient G.W.
G.W.
Tests

Jul-92
MMSE (30)
26
DRS (144)
137
Memory
Digit span F/B
8/7
Logical memory
8
immediate
Logical memory
5
delay
RMT faces (50) 40
RMT words (50) 44
Rey copy
34
Rey recall
2
Visuospatial Object matching 38
(40)
Line orientation 27
(30)
Language Letter fluency
42
(FAS)
Reading regular 124
(126)
Reading irregular 119
(126)
Writing (36)
36
TROG (80)
80
Semantic
Category fluency 48
Naming (48)
46
Wordpic
48
matching (48)
PPT (52)
52

Feb-93 Aug-93 Aug-94

28
30
28
140
137
122
8/5
8/5
8/5
9.5
11
6
4

4.75

36
39
35
5
40

44
40
35
3.5
40

29

30

41

57

2.5
39
41
33
4.5
NT
29
50

126

126

NT

126

126

NT

36
80
45
44
48

36
80
46
45
48

35
80
43
48
48

52

52

52

DRS dementia rating scale; NT not tested.

and visuospatial abilities in most cases. Biparietal

hypoperfusion on SPECT scanning was seen in some, but
not all, of the typical cases, as is well described in the
literature (Testa et al., 1988; Holman et al., 1992; Greene
et al., 1996c). Brain CT scans (without temporal orientated
alignment) were normal or demonstrated mild generalized
atrophy (Table 1).
Our pathological data documenting the distribution of
disease in the typical cases are concordant with descriptions
of Alzheimers disease pathology throughout the literature,
namely the early and severe involvement of the
transentorhinal region, the hippocampal complex spreading
to the temporal neocortex, and association neocortex affecting
particularly the frontal and parietal association areas (Table
4) (Hyman et al., 1990; Braak and Braak, 1991; Van Hoesen
et al., 1991; Van Hoesen, 1997).
Of particular interest is the patient (G.W.) who died at an
early stage of the disease. This patients only significant
abnormality at presentation was amnesia. Longitudinal
neuropyschological data showed a hint of decline in category
fluency but an impressively stable performance (and
sometimes even improvement, perhaps attributable to
familiarity with the tests) across other cognitive domains
(Table 3). Of note was his poor non-verbal and verbal recall,

493

as measured by reproduction of the Complex Rey Figure

after a delay and by logical memory. He exhibited a relatively
better performance on the recognition memory test for faces
and words (Table 3). Pathologically, disease was limited to
the temporal lobe with severe involvement of the entorhinal
cortical neurons and hippocampus, which would explain the
neuropsychological profile of poor recall (Aggleton and
Shaw, 1996). Preservation of recognition memory would not
be predicted with the marked involvement of the perirhinal
cortex (Suzuki, 1996); but G.W.s recognition memory
performance was only relatively preserved, not flawless and
we suggest that his relatively good scores may be due in part
to insensitivity of the tests.

Progressive aphasic cases

Mesulam argued that primary progressive aphasia represents
a distinct syndrome which can be distinguished from the
aphasic presentation of Alzheimers disease by the clinical
profile, and suggested that this syndrome had a high likelihood
of being associated with a non-Alzheimers disease
degenerative process (Mesulam, 1987). In differentiating the
two syndromes, he offered preserved insight, social skills
and episodic memory as features of primary progressive
aphasia, in contrast to the aphasia secondary to Alzheimers
disease, which was associated with early loss of insight and
rapid deterioration in memory and other cognitive functions.
Several of our patients also had a long history of aphasia
prior to general cognitive decline. One patient, P.G., had
a non-fluent progressive aphasia without other cognitive
difficulties which persisted for 5 years. Another, P.B., with
a more mixed aphasic syndrome, also had normal episodic
memory for at least 6 years as judged by performance on
non-verbal tasks, thus fulfilling even very strict criteria for
a diagnosis of primary progressive aphasia (Chawluk et al.,
1986). All other aphasic cases had a definite informantconfirmed history of a selective aphasic syndrome as the
original symptom, followed by a phase of more rapid
progression with severe memory and visuospatial problems.
In these cases, a diagnosis of Alzheimers disease was
suspected at presentation despite the prominent aphasic
component.
The range of language disorders in our cases is worthy of
comment. Two patients presented with non-fluent,
agrammatic aphasia with relative preservation of single-word
comprehension. Only three previous cases of non-fluent
aphasia in Alzheimers disease have been reported in the
literature (Pogacar and Williams, 1984; Green et al., 1990;
Benson and Zaias, 1991). Three of our cases presented with
fluent aphasia with semantic impairments leading to anomia
and impaired comprehension. O.M. had severe involvement
of semantic memory (Table 2), while C.T. and C.M. had a
more anomic presentation. The pattern of language
impairments in these patients is similar to the pattern seen
later in the clinical course in typical Alzheimers disease
(Price et al., 1993) with severe anomia and comprehension

494

C. J. Galton et al.
Table 4A Summary of medial temporal lobe pathological data
Patient

Clinical
syndrome

Medial temporal lobe

Hippocampus CA1 pyramidal layer

Entorhinal cortex

Neuronal loss

Tangles

Plaques

Neuronal loss

Tangles

Plaques

A.P.*
J.M.
N.K.
P.G.
A.S.

Visual variant
Biparietal
Biparietal
Aphasia
Aphasia

/0
/0

NA

NA

NA
()

NA
0

P.B.
O.M.*
C.T.
C.M.*
G.W.
G.T.
F.R.
A.B.*

Aphasia
Aphasia
Aphasia
Aphasia
Typical AD
Typical AD
Typical AD
Typical AD

NA

NA

NA
NA

NA

()
0

NA
0

Mildly affected; moderately affected; severely affected; NA not available.

Incidental pathology: * cerebral amybid angiopathy; Lewy bodies present.

becoming progressively impaired. It is interesting to note,

however, that although these patients had impairments in
semantic memory, they also had evidence of impairments in
episodic and working memory, and deficits in visuospatial
function, such that none met criteria for semantic dementia
(Hodges et al., 1992). Moreover, a meta-analysis of 13 cases
of semantic dementia with post-mortem pathology revealed
non-Alzheimers disease pathology in all cases (Hodges et al.,
1998). It seems, therefore, that although both fluent and nonfluent aphasia can be the initial presentation of Alzheimers
disease, cases rarely, if ever, have the characteristics of
semantic dementia. One patient, P.B., had a more mixed
presentation, with marked semantic anomia and a deficit in
single word comprehension, as well as phonological errors
and grammatical problems.
On structural imaging, five of the six progressive aphasia
cases demonstrated striking left temporal or more general
asymmetrical left hemispheric atrophy, while on functional
imaging, temporal hypoperfusion (with more extensive
cortical hypoperfusion) was seen in four cases.
Pathologically, there was widespread involvement of the
temporal lobe (Table 4A and B), with all patients having
severe involvement of the temporal neocortex. Interestingly,
in the two non-fluent aphasia cases (P.G. and A.S.), there
was relative sparing of the hippocampus and entorhinal cortex
with regard to neuronal loss and plaque formation. These
areas, as mentioned above, are usually affected early and
severely in the disease. P.B. also had a highly atypical
distribution of pathology with severe anterior temporal
atrophy. The fluent cases (O.M., C.T. and C.M.) had severe
involvement of the medial temporal lobe and temporal
neocortex. Thus the spectrum of language impairments of
these atypical Alzheimers disease patients is wide and

suggests that both non-fluent and fluent aphasic presentations

are more common than previously recognized as initial
features of Alzheimers disease. Occasionally, the patients
who fulfil stringent criteria for primary progressive aphasia
and language impairment may remain isolated for many years.

Posterior cortical cases

The posterior cortical cases in the literature with progressive
occipitoparietal atrophy have presented with either visual
agnosias (alexia, achromatopsia and aperceptual object
agnosia), features of Balints syndrome (optic ataxia, visual
disorientation and simultanagnosia) or apraxic disorders
(Cogan, 1985; De Renzi, 1986; Benson et al., 1988; Berthier
et al., 1991; Freedman et al., 1991; Victoroff et al., 1994;
Ross et al., 1996). Although these patients have been grouped
together throughout the literature under the name posterior
cortical atrophy (as termed by Benson et al., 1988), a
more differentiated classification was suggested by Ross and
colleagues (Ross et al., 1996). They noted that there were
two broad groups of presentations reflecting the predominant
site of pathology, namely either occipitotemporal or biparietal.
Those with predominant occipitotemporal pathology
[disrupting the ventral (what) visual processing stream that
is important for object, face and written word recognition
(Ungerleider and Mishkin, 1982)] suffer from visual
distortion, apperceptive object agnosia, topographical agnosia
and alexia. The biparietal patients have predominant
pathology in the region of the dorsal or where stream
(which is important for object location, visually guided motor
movements and motor planning) and suffer initial visuospatial
problems, agraphia and dyspraxia, which may progress to
Balints syndrome, but with preserved visual fields, basic

Atypical Alzheimers disease

495

Table 4B Summary of neocortical pathological data

Patient

A.P.
J.M.
N.K.
P.G.
A.S.
P.B.
O.M.
C.T.
C.M.
G.W.
G.T.
F.R.
A.B.

Clinical
syndrome

Visual variant
Biparietal
Biparietal
Aphasia
Aphasia
Aphasia
Aphasia
Aphasia
Aphasia
Typical AD
Typical AD
Typical AD
Typical AD

Neocortex
Temporal cortex

Parietal cortex

Frontal cortex

Visual cortex

Primary M/S cortex

Tangles Plaques

Tangles Plaques

Tangles Plaques

Tangles Plaques

Tangles

Plaques

()

/0
()

NA
0

0
/0
NA
/0
0
0
0
0

NA
0

/0
0

/0
0

NA

NA
0

/0
0

/0
0

NA

NA

NA

/0

NA

NA
0

0
/0
NA
/0
0
0
0
0

* Severe neuronal loss in BA 38. BA 38 (temporal pole) most severely affected. AD Alzheimers disease; NA not available.
mildly affected; moderately affected; severely affected.

perceptual abilities, object recognition and reading. The

initially sharp distinctions between these two presentations
undoubtedly become less clear as the pathological process
advances. The clinical presentations of our two progressive
biparietal cases (J.M. and N.K.) were in keeping with the
biparietal variant in this classification, with initial dyspraxic
difficulties, poor visuospatial abilities and difficulty writing,
progressing in the case of N.K. to simultanagnosia, but with
preserved basic visual abilities. Although there was evidence
of other cognitive impairments at the time of the first
neuropsychological assessment, both J.M. and N.K. had a
definite history of a selective biparietal syndrome at
presentation. The finding of biparieto-occipital hypoperfusion
on SPECT imaging in these patients also concurs with
previous findings (Freedman et al., 1991; Pietrini et al., 1996)
although these studies used [18F]fluorodeoxyglucose PET.
Primary visual failure appears to be even rarer than
occipitotemporal or biparietal syndromes as a presenting
feature of Alzheimers disease, with only one previous
pathologically proven case in the literature (Levine et al.,
1993). This patient with the so-called visual variant of
Alzheimers disease was a 59-year-old man with initial
problems in reading, identifying objects by sight and locating
objects. Although visual acuity was normal and colour
identification preserved, peripheral fields were constricted,
contrast sensitivity was severely impaired and flicker fusion
frequencies were depressed peripherally. He also developed
widespread visuospatial abnormalities. Over a 12 year followup, his visual symptoms progressively worsened, and his
memory and language abilities, which were mildly impaired
at presentation, also deteriorated. Autopsy examination
demonstrated marked atrophy of the parieto-occipital region
and mild atrophy of the hippocampus. Microscopically, gliosis
was more prominent posteriorly and neurofibrillary tangle

density was greatest in the posterior cingulate cortex (area

23), the visual cortex (area 17) and association cortex (areas
18 and 20) compared with the frontal lobes. The percentage
of plaques (with amyloid cores and neuritic change) was
very high in the primary and association visual cortex, and
very low in the frontal cortex (Levine et al., 1993). Our case,
A.P., had a similar unusual presentation with impairment of
basic perceptual abilities which was reflected by both her
neuroimaging (a SPECT scan demonstrated bioccipital
hypoperfusion, and a CT scan showed posterior cortical
atrophy), and the distribution of pathology, where there was
particularly severe involvement of the primary visual cortex
(Table 4B).
With regard to the dichotomy in posterior cortical cases
suggested by Ross et al. (Ross et al., 1996), the case of
Levine et al. was assigned to the occipitotemporal subgroup.
With the additional and congruent evidence from our case
A.P., we now suggest that there are three broad groups of
posterior cortical presentations reflecting the cortical areas
of most severe pathological involvement: occipitotemporal,
biparietal and primary visual. The occipitotemporal and
biparietal presentations may be more common than the
primary visual variant, as these former syndromes would
suggest early involvement of association cortex which is
generally more susceptible to Alzheimers disease pathology
(Pearson et al., 1985). Primary visual cortex, if affected, is
usually involved late in the disease process (Braak and Braak,
1991). The distribution of pathology in our cases supports
this description, with severe parietal involvement in the
biparietal cases and severe involvement of the primary visual
cortex in the visual variant case (Table 4) (see also Hof et al.,
1989, 1990, 1997; Hof and Bouras, 1991).
A recent review of the literature indicated that the vast
majority of patients with this presentation who have been

496

C. J. Galton et al.

examined pathologically have histological features of

Alzheimers disease (Pantel and Schroder, 1996), suggesting
that posterior cortical atrophy is primarily an atypical pattern
of Alzheimers disease presentation. These cases are different
from typical Alzheimers disease cases in both the time
course and relative severity of perceptual and visuospatial
impairments

General comments
This series of patients and the detailed neuropyschology,
neuroimaging and neuropathology enable us to comment on
the range of Alzheimers disease presentations. All our
patients presented with slowly progressive insidious initial
symptoms. There were no differences between the typical
and atypical presentations with respect to age at presentation
(age range 5884 years), length of illness (310 years) or in
the length of time that the symptoms were reported before
presentation at the memory clinic (15 years). By the time
of neuropsychological assessment, most but not all of our
patients, in both the atypical and typical groups, had evidence
of a more global cognitive impairment (Table 2). Although
the majority of patients had deficits in episodic memory, this
was not a universal feature. Thus, the contention of both De
Renzi and Mesulam that focal cortical syndromes without
episodic memory impairment are not likely to be due to
Alzheimers disease (De Renzi, 1986; Mesulam, 1987) is
largely substantiated; but our series draws attention to the
fact that there are exceptions to this rule, and that occasional
patients such as P.G. and P.B. do present without episodic
memory impairment and go on to have pathologically proven
Alzheimers disease.
The absolute and relative frequencies of these different
presentations of Alzheimers disease are not known, and the
specialist clinic-based nature of our sample makes it difficult
to draw firm conclusions. We estimate that 180 patients with
probable Alzheimers disease were seen in our memory clinic
from 1990 to 1995 and that 26 had atypical presentations
(six visuospatial and perceptual and 20 aphasic), although
only nine of these have come to post-mortem. An approximate
estimate of atypical presentations is therefore 14%. In a
previous clinico-pathological study, prominent aphasic and
visuoperceptual presentations occurred in a fifth of the series
of 20 consecutive post-mortem Alzheimers disease cases
(Price et al., 1993). Obviously selection bias may affect these
results, but atypical presentations may be more common than
previously described. The neuropsychological profiles and
neuroimaging clearly reflect the clinical syndrome, and have
a close relationship with the distribution of the pathology.
The pathology of the typical and atypical cases was otherwise
indistinguishable. Our series demonstrates that the underlying
pathological process is difficult to predict pre-mortem:
Alzheimers disease should be clinically considered in a wide
spectrum of focal cortical syndromes. Advances in the
understanding of the molecular pathology in Alzheimers
disease and of specific neuronal sensitivities to the

pathological process may, in the future, be able to explain

this heterogeneity.
A point worthy of comment is the number of our atypical
cases that had additional incidental pathology. Three atypical
cases had incidental cerebral amyloid angiopathy ranging in
severity from mild to moderate. Two cases had cortical Lewy
bodies present. This raises the question of whether a functional
or structural interaction between different disease processes
may alter the involvement of different cortical areas. The
proportion of cases with secondary pathology was similar to
that found in other series (Mirra et al., 1991).
Our data clearly demonstrate the heterogeneity of
Alzheimers disease presentations. An obvious point, but one
that is frequently overlooked, is that it is the distribution of
pathology rather than the nature of the disease that is reflected
in the clinical syndrome. The profiles of both atypical and
typical presentations can appear focal in nature for many
years before inevitable deterioration. Although certain
distributions of pathology are typical in Alzheimers disease,
further characterization of the range and frequency of atypical
presentations is important in order to improve the diagnosis
of cortical dementia syndromes.

Acknowledgements
We thank Naida Graham, Elaine Giles, Lindsay Stuart-Green,
John Greene, Karen Croot and Sarah Ross for help with data
collection. C.J.G. is supported by an MRC-link project grant
to J.R.H. and Barbara Sahakian, and this research has been
supported by MRC research project grants to J.R.H. and the
Cambridge Brain Bank.

References
Aggleton JP, Shaw C. Amnesia and recognition memory: a reanalysis of psychometric data. Neuropsychologia 1996; 34: 5162.
Ball JA, Lantos PL, Jackson M, Marsden CD, Scadding JW, Rossor
MN. Alien hand sign in association with Alzheimers histopathology.
J Neurol Neurosurg Psychiatry 1993; 56: 10203.
Benson DF, Zaias BW. Progressive aphasia: a case with postmortem
correlation. Neuropsychiatry Neuropsychol Behav Neurol 1991; 4:
21523.
Benson DF, Davis RJ, Snyder BD. Posterior cortical atrophy. Arch
Neurol 1988; 45: 78993.
Benton AL, Hamsher KD, Varney NR, Spreen O. Judgement of
line orientation. New York: Oxford University Press; 1983.
Berthier ML, Leiguarda R, Starkstein SE, Sevlever G, Taratuto A.
Alzheimers disease in a patient with posterior cortical atrophy. J
Neurol Neurosurg Psychiatry 1991; 54: 11101.
Binetti G, Cappa SF, Magni E, Padovani A, Bianchetti A,
Trabucchi M. Visual and spatial perception in the early phase of
Alzheimers disease. Neuropsychology 1998; 12: 2933.
Bishop DV. Test of the reception of grammar. London: Medical
Research Council; 1989.

Atypical Alzheimers disease

Braak H, Braak E. Neuropathological stageing of Alzheimer-related
changes. [Review]. Acta Neuropathol (Berl) 1991; 82: 23959.

dementia: a comparative neuropsychological

Neuropsychol Soc 1996; 2: 51124.

Chawluk JB, Mesulam MM, Hurtig H, Kushner M, Weintraub S,

Saykin A, et al. Slowly progressive aphasia without generalized
dementia: studies with positron emission tomography. Ann Neurol
1986; 19: 6874.

Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia.

Brain 1992; 115: 1783806.

Cogan DG. Visual disturbances with focal progressive dementing

disease. Am J Ophthalmol 1985; 100: 6872.

study.

497
J

Int

Hodges JR, Garrard P, Patterson K. Semantic dementia. In: Kertesz

A, Munoz DG, editors. Picks disease and Pick complex. New York:
Wiley-Liss; 1998. p. 83104.

Croot K, Patterson K, Hodges JR. Single word production in

nonfluent progressive aphasia. Brain Lang 1998; 61: 22673.

Hof PR, Bouras C. Object recognition deficit in Alzheimers disease:

possible disconnection of the occipito-temporal component of the
visual system. Neurosci Lett 1991; 122: 536.

Crystal HA, Horoupian DS, Katzman R, Jotkowitz S. Biopsy-proved

Alzheimer disease presenting as a right parietal lobe syndrome.
Ann Neurol 1982; 12: 1868.

Hof PR, Bouras C, Constantinidis J, Morrison JH. Balints syndrome

in Alzheimers disease: specific disruption of the occipito-parietal
visual pathway. Brain Res 1989; 493: 36875.

De Renzi E. Slowly progressive visual agnosia or apraxia without

dementia. Cortex 1986; 22: 17180.
Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A
practical method for grading the cognitive state of patients for the
clinician. J Psychiatr Res 1975; 12: 18998.
Freedman L, Selchen DH, Black SE, Kaplan R, Garnett ES,
Nahmias C. Posterior cortical dementia with alexia:
neurobehavioural, MRI, and PET findings. J Neurol Neurosurg
Psychiatry 1991; 54: 4438.
Gertz HJ, Xuereb J, Huppert F, Brayne C, McGee MA, Paykel E,
et al. Examination of the validity of the hierarchical model of
neuropathological staging in normal aging and Alzheimers disease.
Acta Neuropathol (Berl) 1998; 95: 1548.
Grady CL, Haxby JV, Horwitz B, Sundaram M, Berg G, Schapirio M,
et al. Longitudinal study of the early neuropsychological and
cerebral metabolic changes in dementia of the Alzheimers type. J
Clin Exp Neuropsychol 1988; 10: 57696.

Hof PR, Bouras C, Constantinidis J, Morrison JH. Selective

disconnection of specific visual association pathways in cases of
Alzheimers disease presenting with Balints syndrome. J
Neuropathol Exp Neurol 1990; 49: 16884.
Hof PR, Vogt BA, Bouras C, Morrison JH. Atypical form of
Alzheimers disease with prominent posterior cortical atrophy: a
review of lesion distribution and circuit disconnection in cortical
visual pathways. [Review]. Vision Res 1997; 37: 360925.
Holman BL, Johnson KA, Gerada B, Carvalho PA, Satlin A. The
scintigraphic appearance of Alzheimers disease: a prospective study
using technetium-99m-HMPAO SPECT. J Nucl Med 1992; 33:
1815.
Howard D, Patterson K. Pyramids and palm trees: a test of semantic
access from pictures and words. Bury St. Edmunds (UK): Thames
Valley Test Company; 1992.
Humphreys GW, Riddoch MT. Routes to object constancy:
implications for neurological impairment of object constancy. Q J
Exp Pyschol 1984; 36A: 384415.

Green J, Morris JC, Sandson J, McKeel DW Jr, Miller JW.

Progressive aphasia: a precursor of global dementia? Neurology
1990; 40: 4239.

Hyman BT, Van Hoesen GW, Kromer LJ, Damasio AR. Perforant
pathway changes and the memory impairment of Alzheimers
disease. Ann Neurol 1986; 20: 47281.

Greene JD, Hodges JR, Baddeley AD. Autobiographical memory

and executive function in early dementia of Alzheimer type.
Neuropsychologia 1995; 33: 164770.

Hyman BT, Van Hoesen GW, Damasio AR. Memory-related neural

systems in Alzheimers disease: an anatomic study. Neurology 1990;
40: 172130.

Greene JD, Patterson K, Xuereb J, Hodges JR. Alzheimer disease

and nonfluent progressive aphasia. [Review]. Arch Neurol 1996a;
53: 10728.

Kanne SM, Balota DA, Storandt M, McKeel DW Jr, Morris JC.

Relating anatomy to function in Alzheimers disease:
neuropsychological profiles predicit neuropathology 5 years later.
Neurology 1998; 50: 97985.

Greene JD, Baddeley AD, Hodges JR. Analysis of the episodic

memory deficit in early Alzheimers disease: evidence from the
doors and people test. Neuropsychologia 1996b; 34: 53751.
Greene JD, Miles K, Hodges JR. Neuropsychology of memory and
SPECT in the diagnosis and staging of dementia of Alzheimer type.
J Neurol 1996c; 243: 17590.
Hodges J. The amnestic prodrome of Alzheimers disease [editorial].
Brain 1998; 121: 16012.
Hodges JR, Patterson K. Is semantic memory consistently impaired
early in the course of Alzheimers disease? Neuroanatomical and
diagnostic implications. Neuropsychologia 1995; 33: 44159.
Hodges JR, Patterson K. Nonfluent progressive aphasia and semantic

Kobayashi S, Hirota N, Saito K, Utsuyama M. Aluminum

accumulation in tangle-bearing neurons of Alzheimers disease
with Balints syndrome in a long-term aluminum refiner. Acta
Neuropathol (Berl) 1987; 74: 4752.
Levine DN, Lee JM, Fisher CM. The visual variant of Alzheimers
disease. Neurology 1993; 43: 30513.
Linn RT, Wolf PA, Bachman DL, Knoefel JE, Cobb JL, Belanger
AJ, et al. The preclinical phase of probable Alzheimers disease.
Arch Neurol 1995; 52: 48590.
Locascio JJ, Growdon JH, Corkin J. Cognitive test performance in
detecting, staging and tracking Alzheimers disease. Arch Neurol
1995; 52: 108799.

498

C. J. Galton et al.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan

EM. Clinical diagnosis of Alzheimers disease: report of the
NINCDS-ADRDA Work Group under the auspices of the
Department of Health and Human Services Task Force on
Alzheimers Disease. Neurology 1984; 34: 93944.
Mendez MF, Mendez MA, Martin R, Smyth KA, Whitehouse PJ.
Complex visual disturbances in Alzheimers disease. Neurology
1990; 40: 43943.
Mesulam MM. Primary progressive aphasiadifferentiation from
Alzheimers disease [editorial]. [Review]. Ann Neurol 1987; 22:
5334.
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee
LM, et al. The Consortium to Establish a Registry for Alzheimers
Disease (CERAD). Part II. Standardization of the neuropathologic
assessement of Alzheimers disease. Neurology 1991: 41: 47986.
Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G,
Fillenbaum G, et al. The Consortium to Establish a Registry for
Alzheimers Disease (CERAD). Part I. Clinical and
neuropsychological assessment of Alzheimers disease. Neurology
1989; 39: 115965.
Neary D, Snowden JS, Bowen DM, Sims NR, Mann DM, Benton
JS, et al. Neuropsychological syndromes in presenile dementia due
to cerebral atrophy. J Neurol Neurosurg Psychiatry 1986; 49: 16374.
Pantel J, Schroder J. Posterior cortical atrophya new dementia
syndrome or a form of Alzheimers disease? [Review]. [German].
Fortschr Neurol Psychiatr 1996; 64: 492508.
Patterson K, Plant DC, Seidenberg MS, McClelland JH, Behrmann
M, Hodges JR. Connections and disconnections: A connectionist
account of surface dyslexia. In: Reggia J, Ruppin E, Berndt
RS, editors. Neural modelling of cognitive and brain disorders.
Singapore: World Scientific; 1996. p. 17789.

Pogacar S, Williams RS. Alzheimers disease presenting as slowly

progressive aphasia. R I Med J 1984; 67: 1815.
Price BH, Gurvit H, Weintraub S, Geula C, Leimkuhler E, Mesulam
M. Neuropsychological patterns and language deficits in 20
consecutive cases of autopsy-confirmed Alzheimers disease. Arch
Neurol 1993; 50: 9317.
Ross S, Graham N, Stuart-Green L, Prins M, Xuereb J, Patterson K,
et al. Progressive biparietal atrophy: an atypical presentation of
Alzheimers disease. J Neurol Neurosurg Psychiatry 1996; 61:
38895.
Snowden JS, Goulding PJ, Neary D. Semantic dementia: a form of
circumscribed cerebral atrophy. Behav Neurol 1989; 2: 16782.
Suzuki WA. The anatomy, physiology and functions of the perirhinal
cortex. Curr Opin Neurobiol 1996; 6: 17986.
Testa HJ, Snowden JS, Neary D, Shields RA, Burjan AW, Prescott
MC, et al. The use of (99mTc)-HM-PAO in the diagnosis of primary
degenerative dementia. J Cereb Blood Flow Metab 1988; 8: S1236.
Ungerleider LG, Mishkin M. Two cortical visual systems. In:
Ingle DJ, Goodale MA, Mansfield RJ, editors. Analysis of visual
behaviour. Cambridge (MA): MIT Press; 1982. p. 54986.
Van Hoesen GW. Ventromedial temporal lobe anatomy, with
comments on Alzheimers disease and temporal injury. J
Neuropsychiatry Clin Neurosci 1997; 9: 33141.
Van Hoesen GW, Hyman BT, Damasio AR. Entorhinal cortex
pathology in Alzheimers disease. [Review]. Hippocampus 1991;
1: 18.
Victoroff J, Ross GW, Benson DF, Verity MA, Vinters HV. Posterior
cortical atrophy. Arch Neurol 1994; 51: 26974.
Warrington EK. Recognition memory test. Windsor (UK): NFERNelson; 1984.

Patterson K, Hodges JR. Deterioration of word meaning:

implications for reading. Neuropsychologia 1992; 30: 102540.

Warrington E, James M. The visual object and space perception

battery. Bury St. Edmunds (UK): Thames Valley Test Company;
1991.

Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP.
Anatomical correlates of the distribution of the pathological changes
in the neocortex in Alzheimers disease. Proc Natl Acad Sci USA
1985; 82: 45314.

Wechsler DA. Wechsler Memory ScaleRevised. San Antonio

(TX): Psychological Corporation; 1987.

Perry RJ, Hodges JR. Attention and executive deficits in Alzheimers

disease: a critical review. [Review]. Brain 1999; 122: 383404.
Pietrini P, Furey ML, Graff-Radford N, Freo U, Alexander GE,
Grady CL, et al. Preferential metabolic involvement of visual cortical
areas in a subtype of Alzheimers disease: clinical implications. Am
J Psychiatry 1996; 153: 12618.

Welsh K, Butters N, Hughes J, Mohs R, Heyman A. Detection of

abnormal memory decline in mild cases of Alzheimers disease
using CERAD neuropsychological measures. Arch Neurol 1991;
48: 27881.

Received May 12, 1999. Revised September 6, 1999.

Accepted September 9, 1999