Abstract Amyotrophic lateral sclerosis (ALS) is charac- terized by degeneration of upper and lower motor neu- rons. In some ALS patients, dementia or aphasia may be present (ALS-D). The dementia is most commonly a fron- totemporal dementia (FTD), and many of these cases have ubiquitin-positive, tau-negative inclusions in neurons of the dentate gyrus and superficial layers of the frontal and temporal lobes. Identical inclusions have been found in cases presenting with FTD and have been designated mo- tor neuron disease (MND)-inclusions. Cases of ALS-D without MND-inclusions have been reported to show neo- cortical gliosis, neuronal loss, and superficial spongiosis, but there have also been scattered case reports of ALS with Alzheimer’s disease (AD). To determine whether AD pathology may play a role in the dementia or aphasia syn- dromes in ALS, we reviewed 30 cases of sporadic ALS diagnosed at the University of Pittsburgh Medical Center. A clinical history of ALS-D was found in 24.1% of the cases, of which 57% had MND-inclusions. Although the ALS-D cases with MND-inclusions typically had amy- loid-beta (Aβ) plaques, there were no neuritic plaques. Three cases of ALS-D had no MND-inclusions, and two of these fulfilled pathological criteria for AD. One ALS-D case showed severe amyloid angiopathy but no neuritic plaques or MND-inclusions. MND-inclusions were not found in any ALS case without dementia; however, four patients without dementia or aphasia showed moderate or frequent numbers of neuritic plaques. In conclusion, we found that approximately 30% of ALS cases with demen- tia have AD and that some ALS cases without frank de- mentia have significant AD pathology. Keywords Alzheimer’s disease · Amyotrophic lateral sclerosis · Aphasia · Dementia · Motor neuron disease inclusions Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenera- tive disease of motor neurons located in the spinal cord, brainstem, and motor cortex [1]. The clinical hallmarks of the disease are progressive muscle weakness, atrophy, and spasticity [2,3]. Approximately 10% of ALS cases are fa- milial (FALS), with mutations in the SOD1 gene repre- senting about 15% of FALS [4,5]. The neuropathological findings in sporadic and familial forms of ALS are identi- cal, consisting of severe loss of lower motor neurons and variable loss of upper motor neurons. Lower motor neu- rons often contain cytoplasmic inclusions, including hyaline inclusions, small eosinophilic inclusions known as Bunina bodies, and ubiquitin-positive filamentous inclusions (skeins) [1, 6,7]. These inclusions are not typically found in upper motor neurons. In the motor cortex, neuronal loss and gliosis are most commonly encountered. The ALS/ Parkinsonism-dementia complex of Guam (ALS-PDC) is distinct from sporadic and familial ALS because it is as- sociated with the presence of numerous widespread tau- positive neurofibrillary tangles [8,9]. It has become apparent that cognitive difficulties (de- mentia or aphasia) may accompany, or even precede, the motor symptoms in ALS [10, 11, 12, 13, 14, 15, 16, 17, 18]. Over 100 cases of ALS with dementia have been re- ported in Japan since 1964 [15]. The dementia is clini- cally of the frontal-lobe type [9, 13,19], and functional imaging studies have supported the frontotemporal distri- bution of the defects [20, 21,22]. Subtle cognitive abnor- malities have also been noted in ALS cases without frank dementia [19, 23,24]. Dementia and aphasia in both sporadic and familial ALS have been associated with ubiquitin-positive, tau-negative cytoplasmic inclusions in neurons of the fascia dentata, entorhinal cortex, and substantia nigra, and in the superfi- Ronald L. Hamilton · Robert Bowser Alzheimer disease pathology in amyotrophic lateral sclerosis Acta Neuropathol (2004) 107 : 515–522 DOI 10.1007/s00401-004-0843-1 Received: 19 August 2003 / Revised: 2 February 2004 / Accepted: 5 February 2004 / Published online: 16 March 2004 REGULAR PAPER R. L. Hamilton (✉) A-506, Presbyterian University Hospital, 200 Lothrop Street, Pittsburgh, PA 15213, USA Tel.: +1-412-6476615, Fax: +1-412-6475602, e-mail: hamilton@np.awing.upmc.edu R. L. Hamilton · R. Bowser Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA © Springer-Verlag 2004